tbuckley/cabot-search huggingface dataset:
Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming
Authors: Mautin Hundeyin, Emma Kurz, Ankita Mishra, Juan Andres Kochen Rossi, Shannon M. Liudahl, Kenna R. Leis, Harshita Mehrotra, Mirhee Kim, Luisana E. Torres, Adesola Ogunsakin, Jason Link, Rosalie C. Sears, Shamilene Sivagnanam, Jeremy Goecks, K.M. Sadeq Islam, Igor Dolgalev, Shivraj Savadkar, Wei Wang, Berk Aykut, Joshua Leinwand, Brian Diskin, Salma Adam, Muhammad Israr, Maeliss Gelas, Justin Lish, Kathryn Chin, Mohammad Saad Farooq, Benjamin Wadowski, Jingjing Wu, Suhagi Shah, Dennis O. Adeegbe, Smruti Pushalkar, Varshini Vasudevaraja, Deepak Saxena, Kwok-Kin Wong, Lisa M. Coussens, George Miller
Journal: Cancer Discovery (2019)

Abstract Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4−CD8−NK1.1− innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. Significance: We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy. See related commentary by Banerjee et al., p. 1164. This article is highlighted in the In This Issue feature, p. 1143
Abstract 19096: Cytochrome P450 Single-Nucleotide Polymorphisms and Cardiovascular Events in Patients Treated With Drug-Eluting Stent
Authors: Il-Young Oh, Jin-Joo Park, Kyung-Woo Park, Hyun-Jai Cho, Sang-Hoon Na, Hae-Young Lee, Hyun-Jae Kang, Bon-Kwon Koo, Hyo-Soo Kim
Journal: Circulation (2010)

Background: Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. Several studies have demonstrated th...
Abstract 23: Small molecule targeting of gankyrin reduces cell migration and proliferation in certain cancers
Authors: Pamela Farrales, Aaron Muth
Journal: Cancer Research (2019)

Abstract Introduction: Gankyrin is an oncoprotein involved in regulating numerous pathways important to cell growth, signaling, proliferation and death. The overexpression of gankyrin and subsequent increased protein-protein interactions have been identified as key to increased proliferation in a variety of cancers. Consequently, small molecules that bind to and disrupt these protein-protein interactions are promising therapeutic strategies for the treatment of certain cancers. The first small molecule binder of gankyrin, cjoc42, was recently developed and exhibited efficacy in inhibiting the gankyrin-26S proteasome interaction. The aim of this work is to determine the effects of cjoc42 and its derivatives on cell migration and proliferation in gankyrin-overexpressing cancers. Methods: Wound healing and CyQuant proliferation assays were used to determine the ability of cjoc42 to inhibit migration and proliferation in the gankyrin-overexpressing cell lines A549, MDA-MB231 and Huh6 cells. A protein thermal shift assay was used to screen new cjoc42 derivatives for their ability to bind gankyrin. Western blot experiments will determine if binding of cjoc42 and its derivatives to gankyrin is the mechanism of action in cells. Results: Cjoc42 demonstrated an ability to inhibit the migratory and proliferative activity of A549 and MDA-MB231 cells. While only a modest inhibition of migration was observed, cjoc42 exhibited a significant antiproliferative effect against these cell lines. Utilization of a protein thermal shift assay yielded cjoc42 derivatives with more potent gankyrin-binding ability. These compounds will be evaluated in-cellulo for their ability to inhibit cell migration and proliferation. Western blot experiments will confirm that gankyrin-binding of cjoc42 attributes to the anti-migration and anti-proliferative effects observed. Conclusions: These studies show that cjoc42 directly inhibits cell migration and proliferation by inhibiting the interaction between gankyrin and the 26S proteasome. Consequently, this work provides background for the development of small molecule inhibitors as a gankyrin-mediated therapy for the treatment of lung, breast and liver cancers. Citation Format: Pamela Farrales, Aaron Muth. Small molecule targeting of gankyrin reduces cell migration and proliferation in certain cancers [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 23.
Abstract 2002: Computational drug repositioning identifies bortezomib as a novel metastatic inhibitor of lung cancer
Authors: Ok-Seon Kwon, Haeseung Lee, Wankyu Kim, Hyuk-Jin Cha
Journal: Cancer Research (2019)

Abstract Although many molecular targets for cancer therapy have been discovered, they often show poor druggability, which is a major obstacle to develop targeted drugs. As an alternative route to drug discovery, we adopted an in silicodrug repositioning (in silicoDR) approach based on large-scale gene expression signatures, with the goal of identifying inhibitors of lung cancer metastasis. Our analysis of clinicogenomic data identified GALNT14, an enzyme involved in O-linked N-acetyl galactosamine glycosylation, as a putative driver of lung cancer metastasis leading to poor survival. To overcome the poor druggability of GALNT14, we leveraged Connectivity Map approach, an in silicoscreening for drugs that are likely to revert the metastatic expression patterns. It leads to identification of bortezomib (BTZ) as a potent metastatic inhibitor, bypassing direct inhibition of poorly druggable target, GALNT14. The anti-metastatic effect of BTZ was verified in vitroand in vivo. Notably, both BTZ treatment and GALNT14knockdown attenuated TGFβ-mediated gene expression and suppressed TGFβ-dependent metastatic genes, suggesting that BTZ acts by modulating TGFβsignaling. Taken together, these results demonstrate that our in silicoDR approach is a viable strategy to identify a candidate drug for undruggable targets, and to uncover its underlying mechanisms. Citation Format: Ok-Seon Kwon, Haeseung Lee, Wankyu Kim, Hyuk-Jin Cha. Computational drug repositioning identifies bortezomib as a novel metastatic inhibitor of lung 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 2002.
Development of a Prognostic Model That Predicts 3- and 5-Year Overall Survival in Multiple Myeloma Using the Connect® MM Patient Registry
Authors: Howard R. Terebelo, Rafat Abonour, Cristina J. Gasparetto, Kathleen Toomey, Brian G. M. Durie, James W. Hardin, Sundar Jagannath, Lynne Wagner, Mohit Narang, Shankar Srinivasan, Lihua Yue, Faiza Zafar, Amani Kitali, Amit Agarwal, Robert M Rifkin
Journal: Blood (2017)
Abstract 1325: Prevalence of Electrocardiographic Abnormalities in a Middle-Aged, Biracial Population: Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Joseph A Walsh, Ronald Prineas, Martha Daviglus, Hongyan Ning, Kiang Liu, Cora E Lewis, Steven Sidney, Carlos Iribarren, Pamela J Schreiner, Donald M Lloyd-Jones
Journal: Circulation (2009)
Abstract 602: Biological monitoring to clarify potential causes of colorectal cancer in Korean diet
Authors: Mihi Yang, Myungah Lee, Jeongseon Kim Kim, Jong Park, Aeson Om, Jennifer Damonte
Journal: Cancer Research (2019)

Abstract We performed a pilot study (N=30) to look for the Korean specific risk factors, which can explain an increased incidence rate of colorectal cancer (CRC) among Korean population. Based on the promising data from the pilot study, we performed a case-control study (N=218, age: 64.4 ±13.4 years; N of men=116, 53.2%) with biological monitoring to analyze various biomarkers including clinical/hematological indices, oxidative or inflammatory biomarkers, e.g., c-reactive protein (CRP), malondialdehyde (MDA) or homocysteine, the metabolites of polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs), e.g., urinary 1-OHP, MeIQx and PhIP, and their DNA adducts, e.g., dG-C8-MeIQx and -PhIP, with UPLC/MS/MS. We also obtained participants’ epidemiological, clinical, and behavioral information and developed food frequency questionnaires (FFQ) to collect their food information for one year before cancer diagnoses. Total subjects consumed 53.4±74.0g/day of red meat, and 1.1±3.7g/day of processed meat. After adjustment for sex and age, there were no associations between CRC risk and red or processed meat intake, or urinary MeIQx or PhIP levels. However, there were inverse associations between CRC and milk or calcium intake (ps&amp;lt;0.05). In addition, urinary MeIQx levels were positively associated with intake of lipid or coffee (p=0.06, p&amp;lt;0.01, respectively). LDL-C and CRP levels in the cases were higher than ones from controls (ps&amp;lt;0.05). Among biomarkers, MDA levels were positively correlated to urinary levels of 1-OHP, PhIP and MeIQx (ps&amp;lt;0.05). These relations support the fact that PAHs or HCAs indirectly induce oxidative stress. Finally, fruits and milk intake showed protective effects, however, gender (man), CRP, and lipid intake were risk factors to CRC, based on multivariable regression analyses. Therefore, total lipid intake, oxidative stress, or inflammation may increase risks of CRC in Korean population rather than red or processed meat intake. Citation Format: Mihi Yang, Myungah Lee, Jeongseon Kim Kim, Jong Park, Aeson Om, Jennifer Damonte. Biological monitoring to clarify potential causes of colorectal cancer in Korean diet [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 602.
Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
Authors: Jason D. Roberts, Nathaniel P. Murphy, Robert M. Hamilton, Ellen R. Lubbers, Cynthia A. James, Crystal F. Kline, Michael H. Gollob, Andrew D. Krahn, Amy C. Sturm, Hassan Musa, Mona El-Refaey, Sara Koenig, Meriam Åström Aneq, Edgar T. Hoorntje, Sharon L. Graw, Robert W. Davies, Muhammad Arshad Rafiq, Tamara T. Koopmann, Shabana Aafaqi, Meena Fatah, David A. Chiasson, Matthew R.G. Taylor, Samantha L. Simmons, Mei Han, Chantal J.M. van Opbergen, Loren E. Wold, Gianfranco Sinagra, Kirti Mittal, Crystal Tichnell, Brittney Murray, Alberto Codima, Babak Nazer, Duy T. Nguyen, Frank I. Marcus, Nara Sobriera, Elisabeth M. Lodder, Maarten P. van den Berg, Danna A. Spears, John F. Robinson, Philip C. Ursell, Anna K. Green, Allan C. Skanes, Anthony S. Tang, Martin J. Gardner, Robert A. Hegele, Toon A.B. van Veen, Arthur A.M. Wilde, Jeff S. Healey, Paul M.L. Janssen, Luisa Mestroni, J. Peter van Tintelen, Hugh Calkins, Daniel P. Judge, Thomas J. Hund, Melvin M. Scheinman, Peter J. Mohler
Journal: Journal of Clinical Investigation (2019)

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.
Abstract 398: Overriding drug resistance in Philadelphia chromosome-positive acute B lymphoblastic leukemia by targeting both BCR-ABL and MAP4K signaling pathways
Authors: Ruibao Ren, Xinhua Xiao, Jianming Zhang, Bo Jiao
Journal: Cancer Research (2019)

Abstract The Philadelphia chromosome (Ph) translocation, which leads to creation of a fusion gene product BCR-ABL, is found in chronic myelogenous leukemia (CML) and 20% of adult and 2-5% pediatric acute B-lymphoblastic leukemia (B-ALL). The selective ABL tyrosine kinase inhibitor (TKI) has been shown a remarkable clinical activity in patients with CML. The ABL TKI has also improved the clinical outcome of Ph+ B-ALL dramatically in combination with standard chemotherapy, but the morbidity and mortality of this disease remain high. The existence of ABL inhibitor-resistant leukemia cells in these patients indicates the presence of additional oncogenic pathways in Ph+ B-ALL. Discovery of a new therapeutic strategy to eradicate Ph+ B-ALL cells is, therefore, urgently needed. By using a chemical genetics approach, we identified a novel small molecule, AR4-13, which shows robust ABL kinase inhibition and potent pharmaceutical efficacy in Ph+ leukemias among 1094 cell lines from the Cancer Cell Line Encyclopedia (CCLE) project. Interestingly, AR4-13 possesses preferable potency than Dasatinib, a potent dual SRC/ABL TKI approved to treat CML and Ph+ B-ALL, to kill Ph+ B-ALL cells, but not do so in CML cells, both in vitro and in vivo. In particular, AR4-13 inhibits S6 and p38 phosphorylation much more potently than that of Dasatinib. Furthermore, kinome profiling data indicate that AR4-13 also inhibits Mitogen-activated protein kinase (MAPK) kinase kinase kinases (MAP4Ks), which belong to a kinase family that controls the MAPK signaling in lymphoid cells. Consistently, RNAi-based synthetic lethal screen with TKIs show that suppression of MAP4Ks could significantly enhance the sensitivity to ABL TKIs in Ph+ B-ALL cells, implying that MAP4K family kinases function as a parallel pathway to BCR-ABL signaling and confer ABL TKI resistance in Ph+ B-ALL. Our findings indicate that simultaneous targeting both the ABL and MAP4K signaling pathways might serve as a promising TKI therapeutic strategy for Ph+ B-ALL. Citation Format: Ruibao Ren, Xinhua Xiao, Jianming Zhang, Bo Jiao. Overriding drug resistance in Philadelphia chromosome-positive acute B lymphoblastic leukemia by targeting both BCR-ABL and MAP4K signaling pathways [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 398.
Time to first treatment is an independent prognostic factor for multiple myeloma (MM).
Authors: Gaurav Goyal, Sri Harsha Tella, Anuhya Kommalapati, Urshila Durani, Jonas Paludo, Ronald S. Go
Journal: Journal of Clinical Oncology (2019)

e19523 Background: Previous studies have shown a disparity in outcomes of MM between clinical trials and real-world practice. This could be partly due to clinical trial exclusion of patients who need urgent treatment due to high burden of disease or significant illness. In this study, we aim to analyze the impact of time to initiation of systemic therapy for MM on overall survival (OS). Methods: We included MM patients reported to National Cancer Data Base (2004-2014). We excluded 2,860 patients with suspected smoldering MM due to initial treatment beyond 120 days. Relative risk of delayed time to systemic therapy was assessed by logistic regression model. Kaplan-Meier method and Cox multivariate analysis were used to evaluate the association between time to therapy and OS. Results: A total of 53, 519 MM patients were included. Median time to systemic therapy in our cohort was 18 days (range 0-120). Of the entire cohort, 24% patients received systemic therapy for MM &lt; 7 days from diagnosis, and 32% received it after 30 days. Factors associated with time to systemic therapy &gt; 30 days were Black race (OR 1.12, CI 1.07-1.16), female sex (OR 1.10, CI 1.06-1.14), lower Charlson comorbidity score (OR 1.36, CI 1.28-1.45), and academic facility (OR 1.18, CI 1.13-1.24). The median OS for patients who initiated therapy &gt; 30 days after diagnosis was longer than those who received it within 7 days (37 vs. 29 month, p &lt; 0.001). Similarly, on multivariate analysis, patients who received treatment &gt; 30 days after diagnosis were found to have a lower mortality as compared to those who initiated treatment &lt; 7 days (HR 0.81, CI 0.79-0.83; Table). Conclusions: In our study, time to initiation of systemic therapy was an independent prognostic factor in MM. This could be related to the high-risk nature of disease of patients treated within a short duration of diagnosis. These findings have implications for future clinical trial design, which should allow for a pragmatic approach toward enrollment of these high-risk patients to improve external validity. [Table: see text]
Abstract 2388: In vitro assessment of tumor associated I.O. markers in cancer cell lines following Vicinium treatment
Authors: Shilpa Chooniedass, Rachelle L. Dillon, Arjune Premsukh, Glen C. MacDonald, Jeannick Cizeau, Gregory P. Adams
Journal: Cancer Research (2019)

Abstract Vicinium is a fusion protein that comprises a scFv fragment specific for the Epithelial Cell Adhesion Molecule (EpCAM) genetically fused to a truncated form of Pseudomonas exotoxin A, ETA, via a flexible linker. Vicinium is used for the treatment of loco-regionally accessible tumors and is currently in a phase III clinical trial (VISTA) for the treatment of high-grade non-muscle invasive bladder cancer and a phase I study in combination with durvalumab for the same indication. In a different phase I study in late stage squamous cell carcinoma of the head and neck, direct injection of Vicinium led to shrinkage of the principal injected tumor as well as non-targeted tumors in some patients suggesting the activation of a T cell-mediated anti-tumor response through cross-priming. Supporting this hypothesis, in vitro studies have demonstrated that Vicinium mediated tumor cell killing elicits biological features of an immunogenic cell death (ICD). Tumor cells’ ability to evade the innate and adaptive immune response plays a major role in cancer development and progression. Altered expression of immune modulators is a key mechanism responsible for tumor escape. Recent studies have shown that exposure to chemotherapeutic drugs results in the selection of tumor cells expressing immunosuppressive markers such as PD-L1, CD47 and CD39. Following in vitro treatment with Vicinium, the enrichment of tumor cell population expressing I.O. markers was examined and compared to chemotherapeutic agents. Unlike small molecule chemotherapies, Vicinium treatment did not lead to an enrichment of CD47 or CD39 positive tumor cell populations. Taken together, the data suggests that Vicinium does not induce an immunosuppressive environment. Citation Format: Shilpa Chooniedass, Rachelle L. Dillon, Arjune Premsukh, Glen C. MacDonald, Jeannick Cizeau, Gregory P. Adams. In vitro assessment of tumor associated I.O. markers in cancer cell lines following Vicinium treatment [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 2388.
Neurovascular Coupling in the Dentate Gyrus Regulates Adult Hippocampal Neurogenesis
Authors: Jia Shen, Depeng Wang, Xinxing Wang, Shashank Gupta, Bhargav Ayloo, Song Wu, Paras Prasad, Qiaojie Xiong, Jun Xia, Shaoyu Ge
Journal: Neuron (2019)
Abstract 2842: Vesal Yaghoobi
Authors: Vesal Yaghoobi, Vasiliki Pelekanou, Tess O'Meara, Andrea Silber, Lajos Pusztai, David Rimm
Journal: Cancer Research (2019)

Abstract Background: It has been shown that even after adjusting for clinical stage at presentation and socio-economic variables, Triple Negative Breast Cancer (TNBC) still has a worse overall outcome in African American (AA) compared to Non-African American (NAA) patients. The abundance and composition of immune cells in the tumor microenvironment is a powerful prognostic factor in TNBC. Our goal was to assess if differences exist in CD8, CD68 and PD-L1 protein expression between AA and NAA TNBC. We hypothesize that the microenvironment of African AA TNBC patients may be different than that of NAAs. Method: We selected N=43 AA and N=43 NAA TNBC samples from the Yale Pathology archives that were matched by diagnosis date. We measured CD8, CD68 and PD-L1 protein expression in both the tumor and stromal compartments in whole slides from formalin fixed paraffin embedded (FFPE) tissues using multiplexed quantitative immunofluorescence (QIF). The average of each marker expression was calculated in all Fields of View (FOV), and the top 10% brightest FOV of each slide (i.e. hotspot). Results: The frequency of macrophages, as assessed by the expression of CD68 was significantly higher in AA compared to NAA. This was seen by overall assessment for all FOV (mean NAA=2273au versus mean AA=3627au; p = 0.0052), and in hotspot FOVs (mean NAA=4858au versus mean AA=6371au; p = 0.0411), and also for assessments in tumor and stromal subcompartments. Expression of CD8 positive cytotoxic T cells was significantly lower in AA compared to NAA, but only when measuring hotspots in the tumor compartment (p=0.017). Conclusion: The significantly higher CD68 and lower CD8 expression in AA compared to NAA TNBC might contribute to a more immune attenuated microenvironment. We are currently further characterizing the macrophage polarity and the cytokine milieu of these samples. Citation Format: Vesal Yaghoobi, Vasiliki Pelekanou, Tess O'Meara, Andrea Silber, Lajos Pusztai, David Rimm. Vesal Yaghoobi [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 2842.
NHS to change GP registration rules in response to growth of digital providers
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Digital first GP providers such as Babylon’s GP at Hand should have to establish a physical location and to contract in all areas where they serve large numbers of patients, to protect efforts to integrate local services, NHS England has proposed.

A consultation it launched on 27 June sets out plans to amend current GP registration rules so that where a practice exceeds a threshold number of registered patients who live in a different clinical commissioning group area, that practice must hold a separate contract in that CCG area, have physical premises, and join a …