tbuckley/cabot-search huggingface dataset:
Abstract 1549: ACLX-001, a novel BCMA-targeted CAR-T cell therapy that can be activated, silenced, and reprogrammed <i>in vivo</i> with soluble protein adapters in a dose dependent manner
Authors: Justin P. Edwards, Janine Buonato, David LaFleur, Jeffrey Swers, Jenny Mu, Liubov Zaritskaya, Sinnie Ng, Ankit Gupta, Hui Wang, Samantha McCullough, David Hilbert, David Tice
Journal: Cancer Research (2021)

Abstract Genetically engineered T cells have demonstrated great promise in the treatment of hematologic malignancies including Acute Lymphocytic Leukemia, Non-Hodgkin's lymphoma, and Multiple Myeloma. However, those achievements are often associated with uncontrolled toxicities, compromised T cell persistence, and frequent tumor relapse. Herein, we report a novel T cell therapy comprising a soluble tumor targeting protein (SPRX001) that specifically binds BCMA-expressing multiple myeloma cells and “TAGS” those cells for destruction by TAG-specific, ex vivo transduced T cells known as Antigen Receptor Complex (ARC) T cells. Functional in vitro studies of ARC-T cells produced from healthy subjects in combination with SPRX001 after co-culture with multiple BCMA-expressing cancer cell lines demonstrated dose-dependent cytokine production, T cell proliferation, degranulation and cytotoxic activity. The cytolytic machinery of the ARC-T cells is only activated when the tri-complex of the ARC-T cell, SPRX001, and BCMA-expressing cell is fully formed. In the absence of any one component, ARC-T cells are not activated thereby preventing kill of the intended target cells. ACLX-001 demonstrated dose- and schedule-dependent in vivo efficacy in disseminated BCMA-expressing tumor models in NSG immunocompromised mice. SPRX001 doses of 0.3 mg/kg daily or 3 mg/kg twice a week were able to eliminate measurable tumor burden as early as 7 days post dosing that lasted for the duration of the study. ARC-T cell expansion and contraction tracked tumor burden in vivo and displayed a diverse memory phenotype. The data support the paradigm that ARC-T cells can be activated and silenced by controlling the dose and schedule of administered SPRX001, which may improve the safety and effectiveness of T cell therapy. Citation Format: Justin P. Edwards, Janine Buonato, David LaFleur, Jeffrey Swers, Jenny Mu, Liubov Zaritskaya, Sinnie Ng, Ankit Gupta, Hui Wang, Samantha McCullough, David Hilbert, David Tice. ACLX-001, a novel BCMA-targeted CAR-T cell therapy that can be activated, silenced, and reprogrammed in vivo with soluble protein adapters in a dose dependent manner [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 1549.
Functional outcomes rather than complications affect quality of life at 6 months after robot-assisted radical prostatectomy
Authors: M.J. Hagens, H. Veerman, C.N. Tillier, K. De Ligt, L. Van De Poll-Franse, P.J. Van Leeuwen, R.J.A. Van Moorselaar, H.G. Van Der Poel
Journal: European Urology (2021)
Abstract 382: Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort
Authors: Jian-Guo Zhou, Hu Ma, Udo Gaipl, Benjamin Frey, Markus Hecht, Rainer Fietkau
Journal: Cancer Research (2021)

Abstract Background: Numerus studies already proved C-reactive protein (CRP) in pre-treat is a predictive biomarkers to for cancer patients treated with anti-PD(L)-1 antibodies. However, there aren't any study has evaluated CRP levels longitudinally in patients with immune checkpoint inhibitors (ICIs). This study provides a comprehensive investigation of CRP levels as well as its longitudinal trajectories as a dynamic predictor of treatment response and survival outcome in metastatic cancer patients undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: A total number of 104 patients were prospectively enrolled. First, multivariate survival analysis for clinical factors, which including cancer types, line of treatment, PD-L1 expression, brain metastases (BM), etc. Then, used multivariate joint modelling of longitudinal and time to event data to establish the relationship between longitudinal CRP and the overall survival (OS). Results: 92/102 patients with more than 2 times CRP results in all of treatment timepoints. Longitudinal CRP levels combine with clinical factors emerged as independent predictors of worse OS (HR of jointed model= 1.82, 95% CI: 1.45-2.32, p &amp;lt; 0.001), and this dynamic biomarker achieved a high accuracy (C-index 0.81) for predicting OS. However, those clinical factors didn't impact the dynamic CRP in this jointed model (HR of PD-L1= 1.68(0.79-3.65), HR of BM= 0.82(0.42-1.64), HR of PD-L1: BM=0.76(0.30-1.89)). Conclusion: Our study highlights longitudinal CRP serves as potential personalized dynamic predictions for immunotherapeutic benefit of metastatic cancer patients. Keywords: metastatic cancers, immune checkpoint inhibitors, C-reactive protein, dynamic predictor Trial registration: Prospectively registered in ClinicalTrials.gov (NCT03453892) on January 24, 2018. Citation Format: Jian-Guo Zhou, Hu Ma, Udo Gaipl, Benjamin Frey, Markus Hecht, Rainer Fietkau. Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort [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 382.
Alcohol as friend or foe in autoimmune diseases: a role for gut microbiome?
Authors: Blaine Caslin, Kailey Mohler, Shreya Thiagarajan, Esther Melamed
Journal: Gut Microbes (2021)

Alcohol is well known for promoting systemic inflammation and aggravating multiple chronic health conditions. Thus, alcohol may also be expected to serve as a risk factor in autoimmune diseases. However, emerging data from human and animal studies suggest that alcohol may in fact be protective in autoimmune diseases. These studies point toward alcohol's complex dose-dependent relationship in autoimmune diseases as well as potential modulation by duration and type of alcohol consumption, cultural background and sex. In this review, we will explore alcohol's pro- and anti-inflammatory properties in human and animal autoimmune diseases, including autoimmune diabetes, thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis and multiple sclerosis. We will also discuss potential mechanisms of alcohol's anti-inflammatory effects mediated by the gut microbiome.
Abstract 1718: Tumor eradicated by an effective <i>in situ</i> vaccine based on a TLR agonist and an agonistic anti-OX40 antibody
Authors: Yanhong Chu, Qin Liu, Baorui Liu
Journal: Cancer Research (2021)

Abstract As cancers are antigenic, numerous efforts have been devoted to harnessing the exquisite specificity of the immune system to destruct tumors over the past two decades. In this study, we have employed a practical approach called in situ vaccination without the need to previously identify and isolate antigen targets. Intratumoral injection of a TLR7 ligand R837 and an agonistic anti-OX40 antibody showed impressive synergistic anti-tumor effects. R837 upregulated the expression of OX40 on CD4+ T cells in the treated tumor. Then, anti-OX40 antibody triggered systemic tumor-specific T cell responses, with one-fold increase of effector memory T cells properties and stronger toxicity of lymphocytes in spleen. Remarkably, both the injected tumor and the noninjected tumor in the distant lesion of the mice were eliminated after vaccination. IL-1α is a pro-inflammatory cytokine, however IL-10 is an important anti-inflammatory cytokine that plays a central role as a negative immune regulator. In the tumor microenvironment, we found that the level of IL-1α increased and IL-10 decreased after vaccination. From RNA-seq analysis, many immune-related pathways in the tumor microenvironment were activated after vaccination, such as TNF signaling pathway, NOD-like receptor signaling pathway, C-type lectin receptor signaling pathway, Toll-like receptor signaling pathway and so on. This in situ vaccine based on two low doses of immunoomdulators caused little harm to normal organs and provided long-term protection against the same syngeneic tumor rechallenge. It could be applied to various types of late stage solid tumors and worthy of further clinical research. Citation Format: Yanhong Chu, Qin Liu, Baorui Liu. Tumor eradicated by an effective in situ vaccine based on a TLR agonist and an agonistic anti-OX40 antibody [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 1718.
Abstract 2671: SMAD4 as a potential gatekeeper for genomic instability and mTOR-mediated tumorigenesis in esophageal adenocarcinoma
Authors: Julia V. Milne, Jovana R. Gotovac, Kenji M. Fujihara, Cuong P. Duong, Wayne A. Phillips, Nicholas J. Clemons
Journal: Cancer Research (2021)

Abstract Esophageal cancer is the 8th most common cancer worldwide and has the 6th highest mortality rate of all cancers. The 5-year survival rate following esophageal adenocarcinoma (EAC) diagnosis is dismal at less than 15 percent, indicating a dire need for improved therapeutic strategies and early detection. EAC develops stepwise following exposure to chronic gastric reflux: From pre-malignant Barrett's metaplasia, through stages of low- and high-grade dysplasia until developing into invasive cancer. Mutation or loss of common tumor suppressor genes TP53 and SMAD4 act as markers for cancer progression, occurring in high-grade dysplastic tissue and invasive EAC, respectively. Our novel in vivo tumorigenesis model demonstrates progression of Barrett's metaplasia to EAC, in which SMAD4-deficient Barrett's metaplasia cells form tumors in immunodeficient mice after a period of latency and in a dose-dependent manner. This delayed tumor growth onset suggests further drivers are required for oncogenesis, and these SMAD4-deficient cells and tumors display a greater degree of genomic instability than wildtype-SMAD4 controls. A genome-wide CRISPR-Cas9 knockout screen unveiled a synthetic lethal relationship between SMAD4-deficiency and cell cycle checkpoint inhibition, suggesting a role for SMAD4 in maintaining genomic stability and a potential novel therapeutic avenue for SMAD4-deficient EAC. Additionally, a concurrent in vivo CRISPR-Cas9 tumorigenesis screen produced tumors 4-fold faster than the previous model and identified regulators of mTOR signaling as co-operative drivers of tumorigenesis in EAC. Wildtype-SMAD4 cells failed to generate tumors despite undergoing the same genetic perturbations, indicating a potential gatekeeping effect of SMAD4 in mTOR-mediated EAC tumorigenesis. In sum, loss of SMAD4 acts as a double-edged sword, increasing genomic instability and thereby rendering EAC cells sensitive to cell cycle checkpoint inhibition, whilst simultaneously co-operating with modulated mTOR signaling to promote tumorigenesis in EAC xenograft models. Citation Format: Julia V. Milne, Jovana R. Gotovac, Kenji M. Fujihara, Cuong P. Duong, Wayne A. Phillips, Nicholas J. Clemons. SMAD4 as a potential gatekeeper for genomic instability and mTOR-mediated tumorigenesis in esophageal adenocarcinoma [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 2671.
Abstract 2418: PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression
Authors: Karina Miller, Seamus Degan, Yanqing Wang, Sheng-Yu Ku, David W. Goodrich, Irwin H. Gelman
Journal: Cancer Research (2021)

Abstract Background: The loss of PTEN function, one of the most frequent mutations in prostate cancer (CaP), is presumed to drive disease progression through AKT activation. However, two transgenic mouse CaP models, Pten/RbPE:-/- and Akap12-/-;RbPE:-/-, exhibited different CaP and metastasis development even though both shared Rb loss plus Akt activation, based on increased relative AKTpoS473 levels. Experimental Procedures: We analyzed whether PI3K-p110 and/or AKT isoform reliance, using isoform-specific RNAi or small molecule inhibitors, played a role in the different CaP outcomes. Findings: In comparison to Akap12/Rb-null high-grade prostatic intraepithelial neoplasias, Pten/Rb-null adenocarcinomas had increased protein and activation levels of AKT2 and decreased relative levels of Smad4, a known CaP metastasis suppressor. Comparison of isogenic PTEN +/- pairs of human or mouse CaP cell lines indicated that PTEN-deficiency correlated with dependence on both p110β and AKT2 for survival or oncogenic growth/invasiveness, whereas PTEN expression correlated with greater dependence on AKT1 plus p110α. Inhibition of AKT2 in PTEN-null CaP cells induced higher SMAD4 levels and decreased chemotaxis and Matrigel invasiveness. Given that PTEN likely regulates non-redundant roles of the AKT isoforms during CaP progression, we sought to characterize AKT isoform substrates by phosphoproteomics analysis. Specifically, after endogenous kinases were inactivated in mouse Pten/Rb-null adenocarcinoma cell lysates using 5'-fluorosulfonylbenzoyl-5'-adenosine (FSBA), dialyzed samples were subjected to in vitro kinase reactions using enzymatically-active, full-length baculovirus-expressed AKT1, AKT2 or AKT3, or as a negative control, a heat-inactivated mixture of all three isoforms. Tryptic peptides isolated on TiO2 beads were subjected to LC-MS/MS. Data will be shown on the role of AKT isoform-shared vs. -preferred substrates in specific parameters of CaP progression controlled by PTEN. Conclusion: Our data suggest that in the context of RB1 loss, PTEN controls a signaling plasticity and drug sensitivity through specific pairings of PI3K-p110 and AKT isoforms. Citation Format: Karina Miller, Seamus Degan, Yanqing Wang, Sheng-Yu Ku, David W. Goodrich, Irwin H. Gelman. PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer 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 2418.
Standardisation of allergen products: 4. Validation of a candidate European Pharmacopoeia standard method for quantification of major grass pollen allergen Phl p 5
Authors: Julia Zimmer, Sandra Schmidt, Susanne Kaul, Angèle Costanzo, Karl‐Heinz Buchheit, Shannon Brown, Jerónimo Carnés, Martin Chapman, Aaron Chen, Michalade De Neergaard, Sascha Döring, James Phillip Hindley, Thomas Holzhauser, Sylvie Jorajuria, David Le Tallec, Manuel Lombardero, Patrizia Iacovacci, Gerald Reese, Ingrid Sander, Bryan Smith, Daniel Strecker, Ronald van Ree, Myriam Zebina, Stefan Vieths
Journal: Allergy (2021)

The aim of the BSP090 project is the establishment of European Pharmacopoeia Chemical Reference Substances (CRSs) in combination with corresponding standard ELISA methods for quantification of major allergens in allergen products. Here, we present data of a Phl p 5-specific sandwich ELISA that proved suitable for the quantification of Phl p 5, one of the major Timothy grass (Phleum pratense) pollen allergens.A Phl p 5-specific ELISA system was assessed with respect to accuracy, precision, inter-assay (within laboratory) and inter-laboratory variations, in a ring trial including 14 laboratories in Europe and the USA. Model samples containing recombinant Phl p 5a CRS as well as native grass pollen extracts were analysed. Each participant was instructed to perform at least one preliminary assay to familiarise with the protocol, followed by three independent assays.The candidate standard ELISA proved suitable to quantify recombinant and native Phl p 5 with satisfactory precision (93% of results within ±30% acceptance range). Inter-assay variation (max. GCV 24%) and especially inter-laboratory variation (max. GCV 13%) showed conclusive results. When assessing accuracy by means of recovery of recombinant spikes from a grass pollen extract matrix, similarly satisfactory spike recovery results were observed for the two spikes with higher concentrations (all within ±30% acceptance range), whereas recovery of the lowest concentration spike was slightly poorer with mean results of six laboratories exceeding acceptance range.Based on the collaborative study results, the assessed Phl p 5-specific immunoassay is appropriate to be proposed as European Pharmacopoeia standard method.
Abstract 635: Response to novel imipridone combination therapies targeting H3K27M mutant diffuse midline glioma (DMG)
Authors: Robyn Borsuk, Lanlan Zhou, Yiqun Zhang, Varun V. Prabhu, Joshua E. Allen, Nikos Tapinos, Rishi Lulla, Wafik S. El-Deiry
Journal: Cancer Research (2021)

Abstract ONC201, a first-in-class, small molecule, imipridone therapy, is known to induce apoptosis via upregulation of TNF-related apoptosis inducing ligand (TRAIL) and its proapoptotic death receptor (DR5), independent of p53. Current trials have been exploring ONC201 as a monotherapy or in conjunction with radiotherapy, in treatment of patients with newly diagnosed and refractory diffuse intrinsic pontine gliomas (DIPG), a disease which remains incurable at present. We sought to identify synergy between ONC201 or second generation impridones (ONC206 and ONC212), and other chemotherapeutics with known promising pre-clinical activity against DMGs. Seven patient derived H3K27M mutant DIPG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SUDIPG-27, SU-DIPG-29, SU-DIPG-36, SF8628) were grown in culture and exposed to ONC201, ONC206, or ONC212 either as monotherapy or in combination with other FDA approved chemotherapeutics (histone de-acetylase inhibitors [HDACi], marizomib, etoposide, and temozolomide). Dose dependent response to imipridone therapy was noted in all cell lines, with mean half maximal inhibitory concentration (IC50) of 1.46 µM in ONC201, 0.11 µM in ONC206, and 0.03 µM in ONC212. Synergy was identified via combination studies, with combination indices of &amp;lt;1 indicating some degree of synergy, and &amp;lt;0.5 indicating very strong synergy. We identified strong synergy between ONC201 and HDAC inhibitors: Panobinostat (CI 0.01) and Romidepsin (CI 0.08), with lesser synergy detected with Entinostat (CI 0.59). Romidepsin similarly showed robust synergy with ONC206 (CI 0.1), as did proteasome inhibitor Marizomib (CI 0.1). Combination of ONC212 and Panobinostat demonstrated induction of apoptosis as measured by the induction of poly (ADP-ribose) polymerase (PARP) cleavage. Our results suggest an increased sensitivity of H3K27M DIPG cell lines to second generation imipridones as compared to ONC201. Additionally, we have shown promising synergism between imipridones with Panobinostat or Romidepsin, which should be considered for clinical translation. Citation Format: Robyn Borsuk, Lanlan Zhou, Yiqun Zhang, Varun V. Prabhu, Joshua E. Allen, Nikos Tapinos, Rishi Lulla, Wafik S. El-Deiry. Response to novel imipridone combination therapies targeting H3K27M mutant diffuse midline glioma (DMG) [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 635.
Immune Phenotype and Response to Neoadjuvant Therapy in Triple-Negative Breast Cancer
Authors: Clinton Yam, Er-Yen Yen, Jeffrey T. Chang, Roland L. Bassett, Gheath Alatrash, Haven Garber, Lei Huo, Fei Yang, Anne V. Philips, Qing-Qing Ding, Bora Lim, Naoto T. Ueno, Kasthuri Kannan, Xiangjie Sun, Baohua Sun, Edwin Roger Parra Cuentas, William Fraser Symmans, Jason B. White, Elizabeth Ravenberg, Sahil Seth, Jennifer L. Guerriero, Gaiane M. Rauch, Senthil Damodaran, Jennifer K. Litton, Jennifer A. Wargo, Gabriel N. Hortobagyi, Andrew Futreal, Ignacio I. Wistuba, Ryan Sun, Stacy L. Moulder, Elizabeth A. Mittendorf
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Experimental Design: We obtained pretreatment core-needle biopsies from 105 patients with stage I–III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. Results: The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. Conclusions: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
Physiology and Pathophysiology of Mechanically Activated PIEZO Channels
Authors: Ruhma Syeda
Journal: Annual Review of Neuroscience (2021)

Nearly all structures in our body experience mechanical forces. At a molecular scale, these forces are detected by ion channels that function as mechanotransducers converting physical forces into electrochemical responses. Here we focus on PIEZOs, a family of mechanically activated ion channels comprising PIEZO1 and PIEZO2. The significance of these channels is highlighted by their roles in touch and pain sensation as well as in cardiovascular and respiratory physiology, among others. Moreover, mutations in PIEZOs cause somatosensory, proprioceptive, and blood disorders. The goal here is to present the diverse physiology and pathophysiology of these unique channels, discuss ongoing research and critical gaps in the field, and explore the pharmaceutical interest in targeting PIEZOs for therapeutic development.
Clinical outcomes for surgical straightening procedures for persistence of penile curvature after a modified CCH treatment protocol: A multicenter experience
Authors: A. Cocci, D. Ralph, R. Djinovic, G. Hatzichristodoulou, G. Morelli, A. Salonia, P. Capogrosso, A. Romano, G. Cito, F. Di Maida, E. Fernández-Pascual, J. Romero-Otero, P. Egydio, M. Falcone, J. Beck, M. Albersen, S. Minhas, G. Cacciamani, J.I. Martinez-Salamanca, N. Mondaini, G.I. Russo
Journal: European Urology (2021)
Near-Infrared Fluorescence In-Vivo Imaging of Non-Hodgkin Lymphoma Using Cy7-Bevacizumab
Authors: Ximena Camacho, Carolina Perroni, Mara de Souza Junqueira, Marcelo Fernandez, Silvina Bustos, Carlos Buchpiguel, Roger Chammas, Juan Pablo Gambini, Pablo Cabral, Eloisa Riva
Journal: Blood (2017)
Radical nephrectomy and caval thrombectomy with heart beating technique for renal cell cancer with tumor thrombus extension into inferior vena cava and right atrium: A less invasive multidisciplinary approach
Authors: S. Guzzo, S. Nazzani, C. Vaccaro, R. Di Benedetto, C. Signorini, D. Vizziello, A. Conti, E. Finkelberg, G. Bortolussi, P. Acquati, C. De Vincetiis, L. Carmignani
Journal: European Urology (2021)