tbuckley/cabot-search huggingface dataset:
Monocyte and macrophage subpopulations in epithelial ovarian cancer
Authors: Ilyssa A. Okrent, Ralph S. Freedman
Journal: Cancer Research (2004)

1259  Monocytes and macrophages (MO/MA) are a heterogeneous population of cells along a differentiation continuum. Functions of certain MO/MA, such as antibody-dependent cell mediated cytotoxicity (ADCC) and phagocytosis, may depend on phenotypic expression of certain cell surface antigens. MO/MA subpopulations may shift toward more differentiated phenotypes in certain cancers and may be important contributors to the immunopathobiology of epithelial ovarian cancer (EOC). Therefore, characterization of the immunophenotype and function of MO/MA subpopulations will be important in understanding the immunopathobiology of EOC and in developing optimal immunotherapy. We hypothesized that peripheral blood and ascitic MO/MA in EOC patients would show a more differentiated surface phenotype. We therefore compared MO/MA subpopulation proportions in whole peripheral blood of healthy subjects (n=9) and EOC patients (n=7), and in ascites of EOC patients (n=6) by three-color flow cytometry. MO/MA were identified by characteristic size and granularity and by CD14 positivity. Gated MO/MA subpopulations were further identified by intensity of CD14 (lipopolysaccharide receptor) expression, as well as the presence of cell surface antigens CD16 (FcγRIII, involved in ADCC and phagocytosis) and HLA-DR (MHC-II receptor, involved in antigen presentation). Proportions were calculated based on 100% equaling total CD14+ MO/MA (i.e. CD14bright plus CD14dim). Proportions of CD14brightCD16−HLA-DR+ MO/MA in peripheral blood of EOC patients (57%) were less than in healthy subjects (88%; p
Abstract CT212: Expanded phase 1/2a study of PLX8394, a novel next generation BRAF inhibitor in patients with advanced, unresectable solid tumors with alterations in BRAF
Authors: Filip Janku, Eric Sherman, Rona Yaeger, Aparna Parikh, Ryan Sullivan, Lynn Feun, Macarena De La Fuente, Frank Yung-Chin Tsai, Michael Gordon, Carl Allen, Marc S. Rudoltz, Kathe Balinski, Steven Averbuch, Michael Vidne, Gabi Tarcic
Journal: Cancer Research (2021)

Abstract The authors did not submit an updated abstract. The original abstract should be considered final. Citation Format: Filip Janku, Eric Sherman, Rona Yaeger, Aparna Parikh, Ryan Sullivan, Lynn Feun, Macarena De La Fuente, Frank Yung-Chin Tsai, Michael Gordon, Carl Allen, Marc S. Rudoltz, Kathe Balinski, Steven Averbuch, Michael Vidne, Gabi Tarcic. Expanded phase 1/2a study of PLX8394, a novel next generation BRAF inhibitor in patients with advanced, unresectable solid tumors with alterations in BRAF [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 CT212.
Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia
Authors: Diana P. Benitez, Shenyi Jiang, Jack Wood, Rui Wang, Chloe M. Hall, Carlijn Peerboom, Natalie Wong, Katie M. Stringer, Karina S. Vitanova, Victoria C. Smith, Dhaval Joshi, Takashi Saito, Takaomi C. Saido, John Hardy, Jörg Hanrieder, Bart De Strooper, Dervis A. Salih, Takshashila Tripathi, Frances A. Edwards, Damian M. Cummings
Journal: Molecular Neurodegeneration (2021)

Abstract Background Microglia are active modulators of Alzheimer’s disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. Methods App NL-F and App NL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer’s disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. Results Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in App NL-F mice but was not evident in App NL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. Conclusions Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer’s disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2 . Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer’s disease.
Abstract 20: HiBiT tagging system for high throughput chemical screening for chemotherapy
Authors: Yutaro Uchida, Takahide Matsushima, Ryota Kurimoto, Tomoki Chiba, Yuki Inutani, Hiroshi Asahara
Journal: Cancer Research (2021)

Abstract Chemical screening is an essential procedure for finding novel drugs of cancer treatments. Especially, cell-based screenings are mostly used for discovery of novel compounds or drug repositioning of already-used drugs. Cell viability or cell proliferation are usually used for evaluation of effects of candidate novel compounds for cancer treatments. However, high throughput system for rapid evaluation of endogenous target protein expression changes has not been established so far. Therefore, an easy and quick method for detection of endogenous target protein expression changes has been strongly needed for drug discovery. Herein, we established a novel chemical compound screening system using the HiBiT-tagging system for this aim using PD-L1 as an example. HiBiT tag is a small peptide tag composed of only 11 amino acids forming a dimer with LgBiT, and functions as a Nanoluciferase. The shortness of the peptide tag is useful for insertion of tag using genome editing technology. Thereby, we established a rapid chemical screening method using HiBiT-tagged cell lines created by CRISPR-Cas9 system. With this method, we made it possible to detect endogenous target protein expression changes within 10 minutes by just adding lytic buffer and LgBiT. For validation of this method, we performed chemical screening of PD-L1 using a HiBiT-tagged lung adenocarcinoma cell line with 1,280 compounds. As a result, we identified microtubule inhibitors as compounds upregulating PD-L1, and validated its upregulation of PD-L1 with qPCR and western blotting. In conclusion, we succeeded in establishing the method for chemical compounds detecting endogenous target protein expression changes with HiBiT-tagging system. Furthermore, we validated this method by performing chemical screening with PD-L1, and succeeded in identifying microtubules inhibitors as up-regulators of PD-L1. Citation Format: Yutaro Uchida, Takahide Matsushima, Ryota Kurimoto, Tomoki Chiba, Yuki Inutani, Hiroshi Asahara. HiBiT tagging system for high throughput chemical screening for chemotherapy [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 20.
BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in systemic lupus erythematosus
Authors: Quentin Moyon, Delphine Sterlin, Makoto Miyara, François Anna, Alexis Mathian, Raphael Lhote, Pascale Ghillani-Dalbin, Paul Breillat, Sasi Mudumba, Sophia de Alba, Fleur Cohen-aubart, Julien Haroche, Micheline Pha, Thi Huong Du Boutin, Hedi Chaieb, Pedro Macedo Flores, Pierre Charneau, Guy Gorochov, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2021)

Our aim was to evaluate systemic lupus erythematosus (SLE) disease activity and SARS-CoV-2-specific immune responses after BNT162b2 vaccination.In this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine until day 15 after the second dose in 126 patients with SLE. SARS-CoV-2 antibody responses were measured against wild-type spike antigen, while serum-neutralising activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T cell responses were quantified by interferon-γ release assay after the second dose.BNT162b2 was well tolerated and no statistically significant variations of BILAG (British Isles Lupus Assessment Group) and SLEDAI (SLE Disease Activity Index) scores were observed throughout the study in patients with SLE with active and inactive disease at baseline. Mycophenolate mofetil (MMF) and methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody response (β=-78, p=0.007; β=-122, p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total immunoglobulin G serum levels, naïve B cell frequencies (β=2, p=0.018; β=2.5, p=0.003) and SARS-CoV-2-specific T cell response (r=0.462, p=0.003). In responders, serum neutralisation activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients.MMF, MTX and poor baseline humoral immune status, particularly low naïve B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating patients with SLE who might need adapted vaccine regimens and follow-up.
冠動脈疾患患者におけるマイクロRNA-146ファミリーに対するレニン-アンギオテンシン系遮断およびスタチンの効果
Authors: Takahashi Yuji, Satoh Mamoru, Minami Yoshitaka, Tabuchi Tsuyoshi, Itoh Tomonori, Nakamura Motoyuki
Journal: Circulation (2010)
Romidepsin and lenalidomide‐based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase <scp>I</scp> studies with expansion cohorts
Authors: Neha Mehta‐Shah, Matthew A. Lunning, Alison J. Moskowitz, Adam M. Boruchov, Jia Ruan, Peggy Lynch, Paul A. Hamlin, John Leonard, Matthew J. Matasar, Patricia L. Myskowski, Evan Marzouk, Sumithra Nair, Tamir Sholklapper, Veena Minnal, Maria L. Palomba, James Vredenburgh, Anita Kumar, Ariela Noy, David J. Straus, Andrew D. Zelenetz, Heiko Schoder, Jurgen Rademaker, Wendy Schaffer, Natasha Galasso, Nivetha Ganesan, Steven M. Horwitz
Journal: American Journal of Hematology (2021)

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
Abstract 2632: Fostering engagement in biobanking and research through the NCI Cancer Moonshot Biobank patient and provider engagement website
Authors: Esmeralda Casas-Silva, Lokesh Agrawal, Helena J. Ellis, Veena Gopalakrishnan, Ping Guan, Mark Jensen, Natalie Madero, Sean McDermott, Jeffrey McLean, Abhi Rao, James Suh, Jane Wanyiri, Carol J. Weil, Mickey Williams, Helen M. Moore
Journal: Cancer Research (2021)

Abstract The National Cancer Institute's (NCI) Cancer Moonshot Biobank (the Biobank) aims to accelerate cancer research on treatment resistance and sensitivity through collection of longitudinal biospecimens and health data donated by participants diagnosed with late-stage cancer and receiving standard of care therapy at participating NCI Community Oncology Research Program (NCORP) sites. Participant and provider engagement are a central tenet of the Biobank. We therefore created an innovative website to interface directly with participants and providers and to meet our engagement goals of returning value to stakeholders, operating with transparency, maintaining bi-directional communication, and enrolling a diverse population that represents the U.S. including racial/ethnic minorities, rural populations and others that are historically underrepresented in clinical research. The Biobank engagement website has several features designed to provide return of value to stakeholders. This includes clear information about the program, transparency about how biospecimens and data will be used in research, and the ability to access and download documents such as clinical biomarker tests and signed consent forms. The website also includes project updates, participant and provider resources, and educational material. The Cancer Moonshot Biobank Participant and Provider Engagement website serves as an important interface between the Biobank and its stakeholders. Its ultimate aim is to facilitate project engagement and return value to participants and providers. Citation Format: Esmeralda Casas-Silva, Lokesh Agrawal, Helena J. Ellis, Veena Gopalakrishnan, Ping Guan, Mark Jensen, Natalie Madero, Sean McDermott, Jeffrey McLean, Abhi Rao, James Suh, Jane Wanyiri, Carol J. Weil, Mickey Williams, Helen M. Moore. Fostering engagement in biobanking and research through the NCI Cancer Moonshot Biobank patient and provider engagement website [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 2632.
Abstract 1593: Mitazalimab, a potent CD40 agonist with potential for combination with chemotherapy
Authors: Adnan Deronic, Mia Thagesson, Anneli Nilsson, Peter Ellmark, Anette Fält, Charlotte Fält, Karin Enell Smith
Journal: Cancer Research (2021)

Abstract Mitazalimab (ADC-1013, JNJ-64457107) is a human CD40 agonistic antibody developed for immunotherapy of cancer. Activation of CD40, expressed on antigen-presenting cells (APC), leads to improved T cell priming and initiation of T cell-dependent anti-tumor responses. There are several CD40 agonists in clinical development with different characteristics, affecting both efficacy and tolerability. Mitazalimab is an FcγR crosslinking-dependent IgG1 antibody, with potential for high efficacy and safety. Immunologically “cold” tumors, such as pancreatic cancer, are defined by low infiltration of immune cells as well as low expression and release of neoantigens. In pancreatic cancer, infiltration of effector CD8+ T cells is blocked by the desmoplastic tumor stroma, which surrounds the tumor and hosts immune-suppressive macrophages that dampen the immune response in the tumor microenvironment (TME). By activating and re-directing the immunosuppressive M2 macrophages into tumoricidal M1 macrophages in the TME, CD40 agonists such as mitazalimab, have the potential to augment the response to chemotherapy and spark an effective immune reaction by i) priming T cells reactive to the tumor neoantigens released by the chemotherapy, and ii) inducing degradation of the stroma surrounding the tumor enhancing the efficacy of chemotherapy. The ability of mitazalimab to augment the response to chemotherapy was demonstrated in mice, transgenic for human CD40 (hCD40tg), inoculated with the syngeneic tumor cell line MB49. Mitazalimab, administered repeatedly together with FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil and folinic acid), synergized effectively with chemotherapy and induced a long-term survival. Further, it was also demonstrated that mitazalimab induced a concentration-dependent activation of tumor-associated macrophages (TAMs), purified from human tumor samples, into a more tumoricidal M1 like phenotype, by upregulation of cell surface markers such as CD83.In conclusion, mitazalimab re-directs human macrophages into a M1 like tumoricidal, less immunosuppressive phenotype, and synergizes effectively with chemotherapy, leading to induction of a long-term survival in a preclinical tumor mouse model. These preclinical data, together with the clinical data of mitazalimab from the phase 1 study (NCT02829099) where mitazalimab was well tolerated up to 1200 μg/kg with manageable side effects, support further clinical development of mitazalimab in combination with chemotherapy in pancreatic cancer. Citation Format: Adnan Deronic, Mia Thagesson, Anneli Nilsson, Peter Ellmark, Anette Fält, Charlotte Fält, Karin Enell Smith. Mitazalimab, a potent CD40 agonist with potential for combination with chemotherapy [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 1593.
Abstract 862: Transcriptomics analysis reveals unique immunoinflammatory signatures of nigerian prostate cancer
Authors: Solomon Oladapo Rotimi, Abidemi E. Omonisi, Faruk Mohammed, Paul Jibrin, Babatunde Duduyemi, Daniel B. Olusina, Yili Xu, Yuxin Jin, Xiyu Liu, Guang Q. Xiao, Folakemi Odedina, John Carpten, Renee Reams, Zarko Manojlovic
Journal: Cancer Research (2021)

Abstract Background: Prostate cancer (PCa) is the leading cause of cancer death among Nigerian men, with most men presenting late and with high grade disease. Furthermore, improved PCa diagnosis and treatment could rely on genomics-driven precision approaches. Mounting evidence supports potential population enriched molecular features of cancer, however the extent of which is hampered due to a dearth of genomic data in diverse cohorts. This study, therefore, aims at utilizing transcriptomics analysis to deduce transcriptional states in PCa from Nigerian men. Methodology: RNA was extracted from macro-dissected prostate tumor and adjacent normal tissue from 35 archival formalin fixed paraffin-embedded (FFPE) blocks from Gleason 8-9 cancers, of which 25 had cribriform morphologic architecture. High resolution hybrid-capture mRNA-seq libraries were sequenced using Illumina NovaSeq 6000 system and generated an average of 124 million read pairs per sample. Raw reads were processed using a custom pipeline based upon industry standard algorithms along with the deduction of genetic ancestry. Molecular annotation was also performed to investigate tumor and immune cell heterogeneity. Result: The Nigerian data were compared with high grade PCa data of Caucasian obtained from TCGA. The Nigerian PCa tumors where characterized with uniquely enriched immune-inflammatory microenvironment which include crosstalk between dendritic cells and natural killer cells, and natural killer cell signaling. While the Nigerian tumors share more features of distal metastatic tumor, their enrichment in NKT Cells is a unique feature. Conclusion: This represents the first report of RNA-seq analysis of PCa in Sub-Saharan Africa and the unique transcriptomics features of Nigerian PCa presents opportunities for precision intervention in addressing its burden in Nigeria. Citation Format: Solomon Oladapo Rotimi, Abidemi E. Omonisi, Faruk Mohammed, Paul Jibrin, Babatunde Duduyemi, Daniel B. Olusina, Yili Xu, Yuxin Jin, Xiyu Liu, Guang Q. Xiao, Folakemi Odedina, John Carpten, Renee Reams, Zarko Manojlovic. Transcriptomics analysis reveals unique immunoinflammatory signatures of nigerian prostate 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 862.
Retrospective evaluation of Proclarix as a companion to mpMRI for the detection of clinically significant prostate cancer
Authors: J. Morote Robles, M. Campistol Torres, A. Celma, L. Regis, J. Planas, A. Santamaria, E. Trilla, R. Schiess, H. Pye, H.C. Whitaker, T. Steuber, H.U. Ahmed, M. Emberton
Journal: European Urology (2021)
Abstract 1815: Defining cell population diversity and T cell dysfunction in a mouse model of obesity
Authors: Gisele V. Baracho, Stephanie Widmann, Aaron Tyznik
Journal: Cancer Research (2021)

Abstract Obesity creates a chronic inflammatory environment that can lead to an exhausted phenotype among T cells. Since exhausted T cells gradually lose their effector functions, obese patients may be at higher risk of developing different disorders, including infectious diseases and cancer. Using the BD FACSymphonyTM A5 Cell Analyzer, we applied a 21-color high-parameter flow cytometry panel to assess various immune cell types in a mouse model of obesity. Also, a flow-based functional assay provided insights into obesity-associated T cell dysfunction. To address progressive changes that might have been caused by a high-fat diet over time, C57BL/6 mice were fed with a high-fat diet for a period of 4 or 16 weeks. Cell populations were examined in blood, spleen and epididymal fat tissue with the latter being known as a location that harbors local inflammation in obese mice. Computational tools for high-dimensional data analysis allowed a thorough characterization of tissue-specific cell phenotypes and their relationship with obesity. Notably, the frequency of effector/memory CD8 T cells and TCRγδ T cells were increased in the fat of obese mice. However, assessment of T cell effector functions in vitro revealed an impairment in cell proliferation, suggesting that fat CD8 T cells from obese mice may not effectively respond to stimulation. Though further studies are required, these results support previous published evidence that low-grade chronic inflammation associated with obesity may impact T cell responses. The data also represent an efficient stepwise approach for staining of surface and intracellular markers and for evaluation of T cell function in vitro and demonstrates the utility of computational tools available in FlowJo™ v10 Software. For Research Use Only. Not for use in diagnostic or therapeutic procedures. Class 1 Laser Product.BD-23275 (v1.0) 1120BD, the BD Logo, FACSymphony and FlowJo are trademarks of Becton, Dickinson and Company or its affiliates. © 2020 BD. All rights reserved. Citation Format: Gisele V. Baracho, Stephanie Widmann, Aaron Tyznik. Defining cell population diversity and T cell dysfunction in a mouse model of obesity [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 1815.