tbuckley/cabot-search huggingface dataset:
Abstract 1394: Poly ADP-ribose polymerase inhibitor promotes the immunoradiotherapeutical efficacy in small cell lung cancer
Authors: Nannan Zhang, Yanping Gao, Zihang Zeng, Yuan Luo, Xueping Jiang, Jianguo Zhang, Jiali Li, Zhengrong Huang, Yan Gong, Conghua Xie
Journal: Cancer Research (2021)

Abstract This study aimed to investigate the safety and efficacy of radiotherapy combined with poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors in small cell lung cancer (SCLC). Tumor-bearing xenograft mouse model was used to examine the safety and anti-tumor effects of radiotherapy plus niraparib and PD-1 antibodies. SCLC cell lines were used to explore the underlying mechanisms in this combination. PARP inhibitor suppressed SCLC cell proliferation, induced cell apoptosis, and increased cell cycle arrest at G2/M phase. Niraparib treatment augmented radiation-induced double-strand DNA breaks, which subsequently activated the cGAS/STING pathway to increase the expression levels of CXCL10, CCL5 and PD-L1 in SCLC cells. Moreover, the combination of radiation, niraparib and PD-1 antibodies significantly inhibited SCLC tumor growth and prolonged the survival of immunocompetent C57BL/6 mice. The induced CCL5 and CXCL10 activated CD8+ T cells in vivo. Our study indicated that niraparib combined with radiation promoted immune checkpoint inhibitor functions via inducing PD-L1 expression, and activated CD8+ T cells via increasing CXCL10 and CCL5 levels through cGAS/STING pathway. The combination treatment of PARP inhibitors, radiotherapy and immunotherapy were safe in vivo, effectively suppressed SCLC tumor progression, increased survival and decreased the adverse events via lowering the dose of individual treatment. Citation Format: Nannan Zhang, Yanping Gao, Zihang Zeng, Yuan Luo, Xueping Jiang, Jianguo Zhang, Jiali Li, Zhengrong Huang, Yan Gong, Conghua Xie. Poly ADP-ribose polymerase inhibitor promotes the immunoradiotherapeutical efficacy in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1394.
Abstract 114: Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment
Authors: Claire Louise Ihle, Meredith D. Provera, Parvanee A. Karimpour, Desiree M. Straign, Erin Smith, Philip Owens
Journal: Cancer Research (2021)

Abstract The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has complex roles in cancer. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Fibroblasts who are activated in the tumor microenvironment to become cancer associated fibroblasts (CAFs) also carry out diverse functions to support tumor progression, including matrix generation and remodeling as well as angiogenesis and immune cell regulation. We found that conditional deletion of the BMP signaling receptor BMPR1a in mammary fat pad derived fibroblasts (via FSP-Cre) restricts tumor progression in a C57BL/6 syngeneic mammary fat pad MMTV-PyMT breast cancer mouse model. Specific changes in the architecture of collagen were found in the tumors with loss of BMPR1a signaling in CAFs. We analyzed these mammary fat pad tumors using Vectra multiplexed immunohistochemistry (mIHC) to evaluate differential cell phenotypes, spatial distribution, and high-dimensional cell clustering dependent on BMP signaling in CAFs. Vectra mIHC panels were designed to perform tumor and stromal cell classification, immune cell profiling, immune cell function, cell signaling and vascular analysis. Based on Vectra mIHC, changes in myeloid cell populations and immune cell interactions in the tumors were observed with differential BMPR1a expression in CAFs. We profiled the secretome of mammary fat pad fibroblasts and found distinct chemokine and cytokine secretion was altered related on BMPR1a loss. These results indicate a unique necessity for BMP signaling in fibroblasts during tumor progression to influence the stroma, matrix, and immune components of the tumor microenvironment. Citation Format: Claire Louise Ihle, Meredith D. Provera, Parvanee A. Karimpour, Desiree M. Straign, Erin Smith, Philip Owens. Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 114.
Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance
Authors: Tricia Cottrell, Jiajia Zhang, Boyang Zhang, Genevieve J Kaunitz, Poromendro Burman, Hok-Yee Chan, Franco Verde, Jody E Hooper, Hans Hammers, Mohamad E Allaf, Hongkai Ji, Janis Taube, Kellie N Smith
Journal: Journal for ImmunoTherapy of Cancer (2021)

T-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and -uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.
Abstract 12723: Impact of Cardiac Intervention on Long-term Survival and Home Discharge in Trisomy 18 Patients: A Propensity Score-matched Analysis
Authors: Kenichi Okamura, Toshihiko Suzuki, Tao Fujioka, Atsushi Nakao, Keiji Tsuchiya, Jotaro Kobayashi
Journal: Circulation (2019)

Introduction: Trisomy 18 (T18) is a genetic diagnosis that is often associated with cardiac malformations. Limited literature is available on the impact of congenital heart surgery (CHS) on the pro...
Abstract 1695: Activation of B cells by CD73 blocking antibodies
Authors: James Hair, Fabien Garcon, Michelle Hsueh, Laura Dallaway, Elena Bibikova, Maria Letizia Giardino Torchia, Gordon Moody, Alwin Schuller, Simon J. Dovedi, Zachary A. Cooper, Kris Sachsenmeier, Rakesh Kumar, Jim Eyles, Robert W. Wilkinson
Journal: Cancer Research (2021)

Abstract The catabolism of ATP into immunosuppressive adenosine contributes to the dysfunction of tumor infiltrating leukocytes (TIL). CD73 is an ectonucleotidase which catabolizes conversion of AMP to adenosine and is expressed on a range of immune cells including B cells. Oleclumab (MEDI9447) is a monoclonal antibody specific for human CD73 and is currently in clinical development for the treatment of cancer. B cells constitute a significant proportion of human TIL; however, their importance to Immuno-Oncology (IO) treatments remains unclear. Recent publications demonstrate that B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma, their presence within the tumor microenvironment is correlated with improved prognosis in several human tumor types, and CD73 expression has been shown to vary on different human B cell subtypes. Further investigations into the role of CD73 in control of human B cell function are therefore warranted. We show that blockade of CD73 by oleclumab and other monoclonal antibodies on peripheral blood B cells from healthy human donors upregulates expression of CD69, CD83 and CD86, and induces secretion of IL-6, MIP-1α and MIP-1β. Activation is mediated by antibodies that block and internalize CD73 and is reduced by pharmacological inhibition of BTK, thus highlighting involvement of the canonical B-cell receptor signaling pathway. Furthermore, our analyses highlight a differential effect of CD73 blockade on individual B-cell populations, with the most robust increases in activation marker expression being observed on naïve subsets that retain expression of IgD. Our research has identified that oleclumab activates human peripheral blood B cells. Given the renewed interest in B-cell biology in IO, this is an area we believe warrants further clinical investigation. Citation Format: James Hair, Fabien Garcon, Michelle Hsueh, Laura Dallaway, Elena Bibikova, Maria Letizia Giardino Torchia, Gordon Moody, Alwin Schuller, Simon J. Dovedi, Zachary A. Cooper, Kris Sachsenmeier, Rakesh Kumar, Jim Eyles, Robert W. Wilkinson. Activation of B cells by CD73 blocking antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1695.
Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis
Authors: Kristina Elizabeth Neergaard Clark, Corrado Campochiaro, Eszter Csomor, Adam Taylor, Katherine Nevin, Nicholas Galwey, Mary A Morse, Jennifer Singh, Yee Voan Teo, Voon H Ong, Emma Derrett-Smith, Nicolas Wisniacki, Shaun M Flint, Christopher P Denton
Journal: Annals of the Rheumatic Diseases (2021)

Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities.Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis.Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms.
Abstract 2716: P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression
Authors: Eilam Yeini, Paula Ofek, Sabina Pozzi, Nitzan Albeck, Dikla Ben-Shushan, Galia Tiram, Sapir Golan, Ron Kleiner, Ron Sheinin, Shlomit Reich-Zeliger, Rachel Grossman, Zvi Ram, Henry Brem, Thomas Hyde, Prerna Magod, Dinorah Friedmann-Morvinski, Asaf Madi, Ronit Satchi-Fainaro
Journal: Cancer Research (2021)

Abstract Glioblastoma (GB) is an aggressive type of brain cancer with high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells which have been shown to facilitate GB cell invasion and immune suppression. The mechanism by which GB cells alter microglia behavior is yet to be fully understood. One proposed mechanism involves adhesion molecules such as the Selectins family of proteins which are expressed on the surface of endothelial and immune cells and are involved in immune modulation and cancer immunity. We have previously shown that P-Selectin (SELP) is expressed by GB cells. Here, we investigated the factional role of SELP in GB-microglia interactions. First, we found that microglia cells facilitate the expression and secretion of SELP by GB cells, and that GB cells facilitate the expression of P-Selectin ligand by microglia. We then showed that SELP mediates microglia-enhanced GB invasion and proliferation in 2D and 3D in vitro models and has a role in microglia activation state. These findings were validated in vivo, showing that inhibition or downregulation of SELP leads to reduced tumor growth, increased overall survival and improved immune response. Single-Cells RNA-seq analysis of the tumors revealed an increase in pro-inflammatory microglia signature, reduction in cancer cell tumorigenesis potential and improved T cell activation. Our results indicated that SELP has an important role in GB progression and microenvironment activation. This work can improve our understanding of tumor-associated microglia function and the mechanisms by which GB cells suppress the immune system and invade the brain tissue. Citation Format: Eilam Yeini, Paula Ofek, Sabina Pozzi, Nitzan Albeck, Dikla Ben-Shushan, Galia Tiram, Sapir Golan, Ron Kleiner, Ron Sheinin, Shlomit Reich-Zeliger, Rachel Grossman, Zvi Ram, Henry Brem, Thomas Hyde, Prerna Magod, Dinorah Friedmann-Morvinski, Asaf Madi, Ronit Satchi-Fainaro. P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2716.
Mesenchymal stem cells injection attenuates spinal cord injury-induced neurogenic bladder via modulation of myogenesis, angiogenesis, trophic factors and apoptosis in female rats
Authors: H. Salehi-Pourmehr, S. Hajebrahimi, J. Mahmoudi, S. Sadigh-Eteghad, L. Roshangar, R. Rahbarghazi, N. Abolhasanpour, H. Mostafaei
Journal: European Urology (2021)
Preoperative prediction of lymph node invasion in prostate cancer: Ga-68 PSMA PET or nomograms?
Authors: Y. Kordan, E. Köseoğlu, A.F. Sarıkaya, K. Tarım, M. Kılıç, A. Özkan, M.C. Kiremit, A. Musaoğlu, Ö. Acar, A.E. Canda, M.D. Balbay, T. Esen
Journal: European Urology (2021)
Thulium vaporization of the prostate: Postoperative bleeding risk in new vs. old generation anticoagulant therapy
Authors: C. Vaccaro, C. Signorini, S. Guzzo, F. Molinari, A. Conti, A. Batini, E. Finkelberg, P. Acquati, D. Vizziello, L. Carmignani
Journal: European Urology (2021)
Abstract 1067: PDK-1 targeting with SNS-510 in sarcoma
Authors: Elgilda Musi, Pietro Taverna, Gary K. Schwartz
Journal: Cancer Research (2021)

Abstract Soft tissue sarcomas are heterogeneous mesenchymal neoplasms and account for 1% of all cancers in adults. Over 50 sarcomas subtypes have been classified and many have limited treatment options some of which include surgery, chemotherapy and radiation. 3-phosphoinositide dependent protein kinase 1 (PDK1) is overexpressed in many cancers, suggesting a role for PDK1 in cancer progression. In addition, PDK1 has been identified as a key modifier of acquired resistance to CDK4/6 inhibitors. In order to interrogate this in sarcoma, we elected to test SNS-510 a potent, orally bioavailable PDK1 inhibitor against a broad range of sarcoma cell lines (leiomyosarcoma, dedifferentiated liposarcoma, Ewing's sarcoma, osteosarcoma, chondrosarcoma and synovial sarcoma) as well as dedifferentiated liposarcoma cell lines with acquired resistance to ribociclib, which are also cross resistant to palbociclib. All the cell lines expressed PDK1 and, as measured by WST-8 cell proliferation assay, nearly all the cell lines were sensitive to the drug, with IC50s generally between 250 to 500nM. Leiomyosarcoma cell lines (SK-LMS, SK-UT1, SK-UT1b) were seen to be most sensitive to SNS-510 with IC50s determined to be between 50-100nM. In contrast, synovial sarcoma cell lines (SYO-1 and HSSY-II) exhibited relative resistance to SNS-510 with IC50s determined to be &amp;gt; 500nM. As assessed by western blot, SNS-510 exhibited a dose dependent inhibition of the PDK-1/RSK2/AKT pathway with inhibition of p-RSK2(244), p-AKT(308), and pS6(235/236). SNS-510 induced a dose-dependent G1 cell cycle arrest. This was associated with inhibition of p-RB(780) and suppression of cyclin D1 and cyclin E1. The exception to this was the synovial cell lines for which there was no inhibition of p-RB despite inhibition of p-RSK, p-AKT and p-S6. When combined with palbociclib in both the CDK4/6 sensitive (LS141 and DDLS) and CDK4/6 resistant liposarcoma cells (RES.LS141 and RES.DDLS), we observed enhanced inhibition of proliferation with a synergistic effect, as defined by the Chou-Talalay method. These results would suggest a role for PDK-1 targeting with SNS-510 in sarcoma and consideration of combination strategies, especially with CDK4/6 inhibitors in both CDK4/6 sensitive and resistant dedifferentiated liposarcoma. Citation Format: Elgilda Musi, Pietro Taverna, Gary K. Schwartz. PDK-1 targeting with SNS-510 in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1067.
Deutsche Studiengruppe Multiples Myelom (DSMM) Evaluation of the Risk of Relapse and Survival Using a Conditional Survival Approach in 815 MM Patients with Extensive, Complete and Repeated and Long-Term Follow-up
Authors: Maximilian Schinke, Gabriele Ihorst, Inga Promny, Hermann Einsele, Justus Duyster, Ralph Wäsch, Martin Schumacher, Monika Engelhardt
Journal: Blood (2017)
An outbreak caused by the SARS-CoV-2 Delta (B.1.617.2) variant in a care home after partial vaccination with a single dose of the COVID-19 vaccine Vaxzevria, London, England, April 2021
Authors: Sarah V Williams, Amoolya Vusirikala, Shamez N Ladhani, Elena Fernandez Ruiz De Olano, Nalini Iyanger, Felicity Aiano, Kelly Stoker, Guduru Gopal Rao, Laurence John, Bharat Patel, Nick Andrews, Gavin Dabrera, Mary Ramsay, Kevin E Brown, Jamie Lopez Bernal, Vanessa Saliba
Journal: Eurosurveillance (2021)

We investigated a COVID-19 outbreak of the SARS-CoV-2 Delta variant of concern in a London care home, where 8/21 residents and 14/21 staff had received a single dose of Vaxzevria (ChAdOx1-S; AstraZeneca) vaccine. We identified 24 SARS-CoV-2 infections (16 residents, 8 staff) among 40 individuals (19 residents, 21 staff); four (3 residents, 1 staff) were hospitalised, and none died. The attack rate after one vaccine dose was 35.7% (5/14) for staff and 81.3% (13/16) for residents.
Automatic 3D augmented reality RAPN with Indocyanine green guidance: A novel technology for a more precise surgical resection
Authors: F. Porpiglia, D. Amparore, F. Piramide, E. Checcucci, P. Verri, P. Alessio, A. Pecoraro, S. De Cillis, A. Piana, G. Volpi, M. Sica, M. Burgio, A. Bellin, P. Piazzolla, M. Manfredi, E. Vezzetti, C. Fiori
Journal: European Urology (2021)
A NICE combination for predicting hospitalisation at the Emergency Department: a European multicentre observational study of febrile children
Authors: Dorine M. Borensztajn, Nienke N. Hagedoorn, Enitan D. Carrol, Ulrich von Both, Juan Emmanuel Dewez, Marieke Emonts, Michiel van der Flier, Ronald de Groot, Jethro Herberg, Benno Kohlmaier, Emma Lim, Ian K. Maconochie, Federico Martinon-Torres, Daan Nieboer, Ruud G. Nijman, Rianne Oostenbrink, Marko Pokorn, Irene Rivero Calle, Franc Strle, Maria Tsolia, Clementien L. Vermont, Shunmay Yeung, Dace Zavadska, Werner Zenz, Michael Levin, Henriette A. Moll
Journal: The Lancet Regional Health - Europe (2021)

Prolonged Emergency Department (ED) stay causes crowding and negatively impacts quality of care. We developed and validated a prediction model for early identification of febrile children with a high risk of hospitalisation in order to improve ED flow.The MOFICHE study prospectively collected data on febrile children (0-18 years) presenting to 12 European EDs. A prediction models was constructed using multivariable logistic regression and included patient characteristics available at triage. We determined the discriminative values of the model by calculating the area under the receiver operating curve (AUC).Of 38,424 paediatric encounters, 9,735 children were admitted to the ward and 157 to the PICU. The prediction model, combining patient characteristics and NICE alarming, yielded an AUC of 0.84 (95%CI 0.83-0.84).The model performed well for a rule-in threshold of 75% (specificity 99.0% (95%CI 98.9-99.1%, positive likelihood ratio 15.1 (95%CI 13.4-17.1), positive predictive value 0.84 (95%CI 0.82-0.86)) and a rule-out threshold of 7.5% (sensitivity 95.4% (95%CI 95.0-95.8), negative likelihood ratio 0.15 (95%CI 0.14-0.16), negative predictive value 0..95 (95%CI 0.95-9.96)). Validation in a separate dataset showed an excellent AUC of 0.91 (95%CI 0.90- 0.93). The model performed well for identifying children needing PICU admission (AUC 0.95, 95%CI 0.93-0.97). A digital calculator was developed to facilitate clinical use.Patient characteristics and NICE alarming signs available at triage can be used to identify febrile children at high risk for hospitalisation and can be used to improve ED flow.European Union, NIHR, NHS.