tbuckley/cabot-search huggingface dataset:
Abstract 1584: Efficacy and pharmacodynamic effect of anti-CD73/PD-L1 monoclonal antibodies in combination with chemotherapy: Observations from mouse tumor models
Authors: Jim Eyles, Amanda Watkins, Kristina Ilieva, Stef Mullins, Jude Anderton, Elena Galvani, Fabien Garcon, Kelli Ryan, Brajesh P. Kaistha, Andreas Dannhorn, Stephanie Ling, Tim Slidel, Gozde Kar, Alwin Schuller, Zachary A. Cooper, Kris Sachsenmeier, Nadia Luheshi, Rakesh Kumar, Robert W. Wilkinson
Journal: Cancer Research (2021)

Abstract Intratumoral adenosine is a key immunosuppressive factor linked to poor prognosis and reduced efficacy of T cell checkpoint inhibitors. CD73 is an ectoenzyme and key node in the catabolic pathway responsible for sequential hydrolysis of extracellular ATP to adenosine. ATP is released from necrotic and damaged tumor cells; a phenomenon enhanced as consequence of cytotoxic chemotherapy or radiotherapy. A CD73 inhibiting human monoclonal IgG1-TM antibody, Oleclumab, is currently in phase 2 clinical development for treatment of patients with various solid tumors. The combination of CD73 inhibition with chemotherapy and T cell checkpoint inhibition was tested using two murine cancer models, CT26 (colorectal) or MCA205 (fibrosarcoma) implanted subcutaneously in BALB/c mice or C57BL/6 mice, respectively. Tumor bearing mice were treated with combinations of oxaliplatin and 5-fluorouracil and murine surrogate monoclonal antibodies for Oleclumab and Durvalumab (anti-PD-L1). CT26 implanted mice were also treated with the murine surrogate antibodies in the presence and absence of Docetaxel. In an attempt to define contribution of components, comparator groups received monotherapies and other iterations of the combination. Treatment with anti-CD73 and anti-PD-L1 antibodies, concomitantly with chemotherapy, resulted in improved tumor growth inhibition, plus increased proportions of complete tumor regression (P&amp;lt;0.05). FACS analysis of CT26 tumors highlighted elevated frequencies of intratumoral IFN-gamma secreting T and NK cells in the chemotherapy plus double IO combination group (P&amp;lt;0.05). Consistent with this, selective depletion of CD8 T cells significantly diminished tumor control and long term survival (P&amp;lt;0.05). RNAseq and Mass spectrometry based imaging techniques were utilized as tools to explore biomarker changes and mechanism. Citation Format: Jim Eyles, Amanda Watkins, Kristina Ilieva, Stef Mullins, Jude Anderton, Elena Galvani, Fabien Garcon, Kelli Ryan, Brajesh P. Kaistha, Andreas Dannhorn, Stephanie Ling, Tim Slidel, Gozde Kar, Alwin Schuller, Zachary A. Cooper, Kris Sachsenmeier, Nadia Luheshi, Rakesh Kumar, Robert W. Wilkinson. Efficacy and pharmacodynamic effect of anti-CD73/PD-L1 monoclonal antibodies in combination with chemotherapy: Observations from mouse tumor models [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 1584.
Abstract 1567: IL-15 and anti-PD-1 augment the abscopal efficacy of agonistic intratumoral anti-CD40 in the TRAMP-C2 murine tumor model
Authors: Wei Chen
Journal: Cancer Research (2021)

Abstract IL-15 promotes activation and maintenance of natural killer (NK) and CD8+ T-effector memory (TEM) cells making it a potential immunotherapeutic agent for the treatment of cancer. However, high doses of γc cytokines lead to the paralysis/depression of naïve CD4 but not CD8 T-cells that is mediated through transient expression of suppressor of cytokine signaling 3 (SOCS3). Thus, the out-of-normal order addition of γc cytokines is associated with generation of “helpless” tumor antigen nonspecific CD8 T cells. The role of CD4 helper T cells can be alternatively mediated by CD40 signaling through the addition of agonistic anti-CD40 antibodies. However, parenteral administration of an agonistic anti-CD40 antibody is associated with unacceptable toxicity that can be avoided by intratumoral administration. Intratumoral immunotherapy that aims at generating a potent low toxic priming of antitumor immunity uses the tumor as its own vaccine. We investigated the combination of IL-15 with an intratumoral anti-CD40 monoclonal antibody using a dosing schedule based on our previous study in the TRAMP-C2 murine prostate cancer model. Here we demonstrated that given intratumorally anti-CD40 had abscopal efficacy, and that the combination of IL-15 with the intratumoral anti-CD40 showed an augmented immune response with an increase in the number of tumor specific tetramer positive CD8+ T-cells. Furthermore, anti-PD-1 antibody was additive to the anti-CD40 IL-15 combination. These studies support the initiation of a clinical trial in patients with cancer involving IL-15 in association with intratumoral optimized anti-CD40. Citation Format: Wei Chen. IL-15 and anti-PD-1 augment the abscopal efficacy of agonistic intratumoral anti-CD40 in the TRAMP-C2 murine tumor model [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 1567.
Ins and Outs of the TCA Cycle: The Central Role of Anaplerosis
Authors: Melissa Inigo, Stanisław Deja, Shawn C. Burgess
Journal: Annual Review of Nutrition (2021)

The reactions of the tricarboxylic acid (TCA) cycle allow the controlled combustion of fat and carbohydrate. In principle, TCA cycle intermediates are regenerated on every turn and can facilitate the oxidation of an infinite number of nutrient molecules. However, TCA cycle intermediates can be lost to cataplerotic pathways that provide precursors for biosynthesis, and they must be replaced by anaplerotic pathways that regenerate these intermediates. Together, anaplerosis and cataplerosis help regulate rates of biosynthesis by dictating precursor supply, and they play underappreciated roles in catabolism and cellular energy status. They facilitate recycling pathways and nitrogen trafficking necessary for catabolism, and they influence redox state and oxidative capacity by altering TCA cycle intermediate concentrations. These functions vary widely by tissue and play emerging roles in disease. This article reviews the roles of anaplerosis and cataplerosis in various tissues and discusses how they alter carbon transitions, and highlights their contribution to mechanisms of disease.
ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee
Authors: O. Michielin, A. van Akkooi, P. Lorigan, P.A. Ascierto, R. Dummer, C. Robert, A. Arance, C.U. Blank, V. Chiarion Sileni, M. Donia, M.B. Faries, C. Gaudy-Marqueste, H. Gogas, J.J. Grob, M. Guckenberger, J. Haanen, A.J. Hayes, C. Hoeller, C. Lebbé, I. Lugowska, M. Mandalà, I. Márquez-Rodas, P. Nathan, B. Neyns, R. Olofsson Bagge, S. Puig, P. Rutkowski, B. Schilling, V.K. Sondak, H. Tawbi, A. Testori, U. Keilholz
Journal: Annals of Oncology (2020)
Robot-assisted partial nephrectomy with 3D preoperative surgical planning: Video presentation of the florentine experience
Authors: A.A. Grosso, F. Di Maida, R. Tellini, A. Mari, S. Sforza, R. Campi, F. Valastro, L. Lambertini, P. Polverino, P. Verrienti, M. Presutti, L. Masieri, M. Carini, A. Minervini
Journal: European Urology (2021)
Abstract LB228: PD-L1/PD-1 and arsenic lung tumorigenesis
Authors: Wenhua Xu, Gang Chen
Journal: Cancer Research (2021)

Abstract Chronic exposure of environmental arsenic promotes lung cancer. Emerging evidence indicates that compromised host immunity, particularly T cell anti-tumor immunity, may play a critical role in cancer development. However, there is a knowledge gap in terms of the effects of arsenic exposure on T cell anti-tumor immunity and how that may contribute to arsenic lung carcinogenicity. Immunosuppression has been known as a risk factor for many types of cancer, including lung cancer. The development of cancer indicates a success of immunosuppression and escape of cancer cells from host anti-tumor immunity in which T cells are the major component. The anti-tumor immunity is mainly executed by CD8 cytotoxic T cells through their anti-tumor effector function. A/J mice are naturally sensitive to pulmonary carcinogens and prone to develop spontaneous lung tumors later in life and have been frequently used as an animal model for lung tumorigenesis research. Chronic arsenic administration through drinking water has been shown to enhance tumor formation in the lungs of A/J mice. In the current study, using this mouse model we determined that prolonged arsenic exposure up-regulated PD-1/PD-L1, inhibited T cell antitumor function and enhanced lung tumor formation, while inhibition of PD-1/PD-L1 restored T cell anti-tumor effector function and mitigated arsenic-enhanced lung tumorigenesis. In addition, inhibition of PD-1/PD-L1 could be a preventive approach to mitigate tumorigenic action of chronic arsenic exposure. Citation Format: Wenhua Xu, Gang Chen. PD-L1/PD-1 and arsenic lung tumorigenesis [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 LB228.
Abstract 2154: Expression of androgen receptor splice variant, AR-V7, in high grade serous ovarian cancer
Authors: Benjamin Wilson, Joanne Xiu, Michael Ulm, Tiffany Redfern, Ramesh Narayanan, Adam ElNaggar
Journal: Cancer Research (2021)

Abstract Objective: Androgen receptors (AR) are expressed in up to 55% of ERα-negative breast cancers overall and up to 35% of those classified as TNBC. Similarly, AR is expressed in approximately 40% of high grade serous ovarian cancer (HGSOC). The development of AR splice variants (AR-SV), particularly AR-V7, has been shown to be a poor prognostic feature, and mechanism of androgen resistance in breast and prostate cancers. We sought to determine if AR-V7 was present in HGSOC and if there was a correlation with platinum sensitivity and/or treatment outcomes. Methods: Pair-matched chemo-naïve and platinum-treated HGSOC specimens were identified from our tissue repository. Formalin-fixed paraffin-embedded tumor (FFPE) blocks were collected and tested for expression of AR-V7. Gene fusion detection and variant detection were performed on mRNA isolated from a formalin-fixed paraffin-embedded tumor sample using the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA) and Agilent SureSelect Human All Exon V7 bait panel (Agilent Technologies, Santa Clara, CA). FFPE specimens underwent pathology review to diagnose percent tumor content and tumor size; a minimum of 10% of tumor content in the area for microdissection was required. Results: Twelve chemo-naïve specimens collected at time of diagnosis by initial biopsy (n=8) or primary debulking surgery (n=4) were pair-matched with the patients' subsequent platinum-treated specimens from either interval debulking surgery (n=6) or biopsy of recurrence (n=6). Following penultimate platinum, 50% were platinum resistant and 50% were platinum sensitive at time of second pathology. Only 19 of the 24 specimens submitted had sufficient RNA for testing, 8 chemo-naïve and 11 platinum-treated. AR-V7 variant transcript was not detected in any of the specimens submitted. Conclusions: AR-V7 was not expressed in any specimen before or after platinum based chemotherapy suggesting it may not be a useful prognostic marker in the management of HGSOC. Further investigation into gynecologic malignancies with high AR expression and treated with androgen deprivation therapy may elucidate different results. Citation Format: Benjamin Wilson, Joanne Xiu, Michael Ulm, Tiffany Redfern, Ramesh Narayanan, Adam ElNaggar. Expression of androgen receptor splice variant, AR-V7, in high grade serous ovarian 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 2154.
Abstract 288: Revisiting small molecules that influence the nuclear translocation of thioredoxin-1, prohibitin, and galectin-3 for cancer chemotherapy
Authors: Jessica S. Fortin, Thomas E. Wineland, Kelsey E. Duggan, René C.-Gaudreault
Journal: Cancer Research (2021)

Abstract Phenyl-3-(2-chloroethyl)ureas (CEU) are alkylating agents exhibiting potent antiproliferative properties both in vitro and in vivo. CEUs' cytoxicity is not influenced by hypoxia or other clinically relevant mechanisms of chemoresistance, such as alteration of topoisomerase II activity and increased P-glycoprotein over-expression, DNA repair, intracellular gluthatione-S-transferase activity. A first subset of CEU exemplified by the prototypical molecules 4-tert-butyl-CEU (tBCEU) and 4-iodo-CEU (ICEU) have been shown to alkylate the colchicine-binding site on βII-tubulin. In parallel, these molecules disrupted the cytoskeleton and arrested the cell cycle in G2/M leading to anoikis. So far we have conducted several structure-activity relationship and molecular pharmacology studies in an attempt to refine the specificity of CEU for β-tubulin and the colchicine-binding site. Unexpectedly, a prototypical molecule designated as 1-(2-chloroethyl)-3-(4-cyclohexylphenyl)urea (cHCEU) emerged as arresting the cell cycle in G0/G1 phase instead of G2/M. Experiments using [14C-urea]-cHCEU showed its binding to thioredoxin isoform-1 (Trx-1) and prohibitin (PHB), but not β-tubulin. Complementary immunocytofluorometry experiments clearly showed the abrogation of the nuclear translocation of Trx-1 from the cytosol. We report herein that in addition to Trx-1 and PHB, cHCEU also alkylates galectin-1 and -3 isoforms. The cellular localization of thioredoxin-1, prohibitin, and galectin-3 (Gal-3) is changed following cHCEU treatment. In addition, the expression of Trx-1, PHB, and Gal-3 seems unaffected by CEU and its analogues. Interestingly, these proteins are all known to play an important role in the cell cycle regulation through various mechanisms. The mechanism(s) underlying the effect of cHCEU on protein translocation is unknow and might be relevant to design new potent anticancer drugs that will target specific and lethal biological pathways essential to tumor growth. Citation Format: Jessica S. Fortin, Thomas E. Wineland, Kelsey E. Duggan, René C.-Gaudreault. Revisiting small molecules that influence the nuclear translocation of thioredoxin-1, prohibitin, and galectin-3 for cancer 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 288.
Protective Zika vaccines engineered to eliminate enhancement of dengue infection via immunodominance switch
Authors: Lianpan Dai, Kun Xu, Jinhe Li, Qingrui Huang, Jian Song, Yuxuan Han, Tianyi Zheng, Ping Gao, Xuancheng Lu, Huabing Yang, Kefang Liu, Qianfeng Xia, Qihui Wang, Yan Chai, Jianxun Qi, Jinghua Yan, George F. Gao
Journal: Nature Immunology (2021)
The urologist’s learning curve of in-bore magnetic resonance-guided prostate biopsy
Authors: B. Rosenzweig, T.R. Drori, O. Raz, G. Goldinger, G. Shlomai, D.E. Zilberman, M. Shechtman, J. Ramon, O. Portnoy, Z.A. Dotan
Journal: European Urology (2021)
Abstract 3201: Single-cell trajectory analysis reveals a melanoma-driven distinct hematopoietic response in murine spleen
Authors: Nihan Kara, Nikolay Samusik, Xiaoshan Shi, Chip Lomas, Stephanie Widmann, Aaron J. Tyznik
Journal: Cancer Research (2021)

Abstract Growing evidence suggests that tumor progression can interfere with normal hematopoiesis and skew the host system to undergo myeloid biased changes. Hematopoietic stem and progenitor cells (HSPCs) are a rare population of precursor cells giving rise to progeny that replenish blood cells throughout life. HSPCs are mainly localized in the bone marrow niche in healthy adults, however pathophysiological conditions such as cancer can cause extramedullary hematopoiesis in organs like the spleen. In this study, we investigated tumor-driven phenotypic and molecular alterations in the HSPC compartment at a single-cell level during extramedullary hematopoiesis using single-cell multiomics. We used a B16-F10 melanoma mouse model to uncover the tumor-mediated changes. Mice with tumor-burden showed splenomegaly and alterations in the composition of the HSPC compartment in the spleen consistent with extramedullary hematopoiesis. We then isolated four HSPC populations, including Lin- Sca1+ cKit+ (LSK), common myeloid progenitor (CMP), granulocyte-macrophage progenitor (GMP) and megakaryocyte-erythrocyte progenitor (MEP) cells from the spleen and bone marrow of melanoma-burdened mice using the BD FACSMelody™ Cell Sorter. Next, we used an integrated workflow on the BD Rhapsody™ Single-Cell Analysis System for the downstream single-cell multiomics analysis. We utilized oligo-conjugated antibodies for NGS-based sample multiplexing and protein detection (BD® Single-Cell Multiplexing Kit, BD® AbSeq Assay), along with whole transcriptome analysis for a comprehensive analysis of mRNA expression. Data analysis using the X-shift algorithm paired with single-cell force-directed layout visualization enabled delineation of the developmental trajectories of HSPC populations and exploration of phenotypic and transcriptomic changes across different hematopoietic subpopulations and across distinct anatomic sites. The analysis also identified unique hematopoietic cell clusters present during melanoma-driven extramedullary hematopoiesis in the spleen. Overall, our findings highlight melanoma-driven perturbations in hematopoiesis by utilizing advanced single-cell multiomics technology. Disclaimers: For Research Use Only. Not for use in diagnostic or therapeutic procedures. Class 1 Laser Product. BD-23277 (v1.0) 1120 BD, the BD Logo, FACSMelody and Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2020 BD. All rights reserved. Citation Format: Nihan Kara, Nikolay Samusik, Xiaoshan Shi, Chip Lomas, Stephanie Widmann, Aaron J. Tyznik. Single-cell trajectory analysis reveals a melanoma-driven distinct hematopoietic response in murine spleen [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 3201.
Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models
Authors: Deepak Vangala, Swetlana Ladigan, Sven T. Liffers, Soha Noseir, Abdelouahid Maghnouj, Tina-Maria Götze, Berlinda Verdoodt, Susanne Klein-Scory, Laura Godfrey, Martina K. Zowada, Mario Huerta, Daniel L. Edelstein, Jaime Martinez de Villarreal, Miriam Marqués, Jörg Kumbrink, Andreas Jung, Tobias Schiergens, Jens Werner, Volker Heinemann, Sebastian Stintzing, Doris Lindoerfer, Ulrich Mansmann, Michael Pohl, Christian Teschendorf, Christiane Bernhardt, Heiner Wolters, Josef Stern, Selami Usta, Richard Viebahn, Jacob Admard, Nicolas Casadei, Stefan Fröhling, Claudia R. Ball, Jens T. Siveke, Hanno Glimm, Andrea Tannapfel, Wolff Schmiegel, Stephan A. Hahn
Journal: Genome Medicine (2021)

The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.
ARDS subphenotypes: searching for Rorschach among the roentgenograms?
Authors: Andrew Conway Morris, Katharina Kohler, Manu Shankar-Hari
Journal: Thorax (2021)

In 1967, Ashbaugh et al first described acute respiratory distress syndrome (ARDS)—an acute illness, characterised by tachypnoea, hypoxaemia and loss of lung compliance occurring after a variety of pulmonary and non-pulmonary insults (including trauma, acute pancreatitis, viral pneumonitis).1 This concept is retained as the ARDS illness model within the current consensus definitions, with acute defined as within 7 days of insult, and hypoxaemia categorised using partial pressure of oxygen/fraction of inspired oxygen concentration (PaO2/FiO2 ratio) into mild ( 5 cm water.2

Fifty years on, ARDS remains a clinical challenge. Globally, ARDS remains clinically underrecognised, with an acute hospital mortality of 46% in patients with severe ARDS.3 Further, after more than 150 randomised controlled trials (RCTs),4 we do not have a single drug proven to benefit patients with ARDS. Notably, the histopathological hallmark of ARDS, diffuse alveolar damage (DAD),1 is only found in half of the patients, and is difficult to ascertain during acute illness.5 This clinical challenge led to the hypothesis that the heterogeneity of ARDS will manifest as subpopulations with similar clinical, biological, outcome and/or treatment response characteristics. Further, these subpopulations may be unique to ARDS or shared with other critical illness syndromes.

If we could identify ARDS subpopulations based on clinical and/or biological characteristics, this may highlight molecular mechanisms to target in RCTs, subpopulations with a higher risk of adverse outcomes or greater treatment responses.6 Calfee et al have led the field of determining such ARDS subpopulations, primarily with data from patients enrolled into RCTs, using latent class analyses (LCA) of clinical and biomarker data. They consistently report a two class model (two ARDS subpopulations or subphenotypes) as the best fit for the clinical and biomarker data …