tbuckley/cabot-search huggingface dataset:
Abstract 2539: Mutant TP53 action in lung dictated by the cell microenvironment
Authors: Christopher Yin, Li Gao, Miguel A. Villalona-Calero, Wenrui Duan
Journal: Cancer Research (2020)

Abstract TP53 is a well-known tumor suppressor protein involved in many anti-tumor processes such as apoptosis, DNA repair, and cell cycle arrest. Codon 273 is one of the most frequently mutated sites among all p53 mutant types in human lung cancer. Recently, it has been discovered that TP53 and its mutants influence the expression of cancer-relevant microRNAs and vice-versa. Although many experiments have been performed on cell lines, far fewer experiments were geared toward how TP53 mutations affect miRNA expression in complex, in vivo settings. In addition to this, there are competing viewpoints on how TP53-273H could interact with wild type TP53. To investigate the mechanism involved in the oncogenic potential of mutant TP53 protein in vivo, TP53+/+/TG273H transgenic mice were bred into p53 null background. At the age of 5-6 weeks, TP53−/−; TP53−/-/TG273H; TP53+/+; and TP53+/+/TG273H mice were used to evaluate the expression of micro RNAs (miRNAs) as well as TP53 downstream genes. Based on the nanoString miRNA analysis, TP53−/- 273H mice exhibits decreased expression of miR-205, 206, and 1274a when compared against TP53−/− mice. However, TP53+/+ 273H mice resulted in increased expression of these miRNAs when compared against wild-type mice without mutant TP53 (TP53+/+). When comparing p53−/− knockout mice with wild-type mice, miRNAs 205, 206, and 1274a all increased at least 3-fold compared to wild-type. TP53−/− 273H mice exhibited widespread decrease of miRNA expression levels when compared against TP53+/+ 273H mice. The results suggest that the biological function of the TP53-273H is dictated by the cell microenvironment, especially the presence/absence of the wild type TP53 through dominant-negative effects in lung tissues. Mutant TP53-273H exerts oncogenic/tumor suppressor effects through specific miRNAs and their target gene networks. Citation Format: Christopher Yin, Li Gao, Miguel A. Villalona-Calero, Wenrui Duan. Mutant TP53 action in lung dictated by the cell microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2539.
Abstract 5713: Reprogramming of serine metabolism during breast cancer progression
Authors: Albert Mao Li, Gregory S. Ducker, Yang Li, Jose A. Seoane, Yiren Xiao, Stavros Melemenidis, Yiren Zhou, Ling Liu, Sakari Vanharanta, Edward E. Graves, Erinn B. Rankin, Christina Curtis, Joan Massague, Joshua D. Rabinowitz, Craig B. Thompson, Jiangbin Ye
Journal: Cancer Research (2020)

Abstract The causes and consequences of metabolic reprogramming during human breast cancer metastasis remain largely unknown. We performed metabolomics in the human triple-negative breast cancer cell line MDA-MB-231 (231-Parental) and its metastatic subclones that display tissue-tropism towards the brain (831-BrM), the bone (1833-BoM), and the lung (4175-LM). Using molecular and metabolic flux analysis, we uncovered that the mitochondrial serine and one-carbon (1C) unit pathway is upregulated in the metastatic subclones. Inhibition of the first rate-limiting enzyme of the pathway, serine hydroxymethyltransferase (SHMT2), potently suppresses proliferation of metastatic subclones in culture and impairs growth of lung metastatic subclones at both primary and metastatic sites in mice. In addition to breast cancer, a few other cancer types, such as adrenocortical carcinoma (ACC) and kidney chromophobe cell carcinoma (KICH), also display increased SHMT2 expression during disease progression. Moreover, we found that metastatic cells are exquisitely adapted to low serine conditions by synthesizing serine de novo from glucose to generate 1C units, and blocking serine catabolism abrogates metastatic growth under serine deprivation. How do metastatic breast cancer cells acquire new metabolic properties such as de novo serine synthesis? We observed that 231-Parental cells grown in media lacking serine for up to ten passages exhibited metastatic cell-like metabolic properties. Subsequent RNA-sequencing revealed dramatic global gene expression changes during serine starvation in more primary tumor-like cells. Several pathways involved in metastasis such as TNFα signaling, mTOR1 signaling, and Ras signaling were modulated upon serine starvation. These data suggest that the availability of the nonessential amino acid serine may play a key regulatory role in breast cancer progression and metastasis, and highlight the potential for metabolite supplementation to block or halt these transformations. Citation Format: Albert Mao Li, Gregory S. Ducker, Yang Li, Jose A. Seoane, Yiren Xiao, Stavros Melemenidis, Yiren Zhou, Ling Liu, Sakari Vanharanta, Edward E. Graves, Erinn B. Rankin, Christina Curtis, Joan Massague, Joshua D. Rabinowitz, Craig B. Thompson, Jiangbin Ye. Reprogramming of serine metabolism during breast cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5713.
Are we underestimating seroprevalence of SARS-CoV-2?
Authors: Stephen Burgess, Mark J Ponsford, Dipender Gill
Journal: BMJ (2020)

<h3>Background</h3> Sexually transmitted infections (STIs) and Human immunodeficiency virus and acquired immune-deficiency syndrome (HIV/AIDS) are global problems and currently over 100 million STIs occur each year in people within the 15–24 age bracket. Young people between ages 15 and 24 also account for more than fifty (50) percent of all HIV infections throughout the world. <h3>Methods</h3> A survey research questionnaire made up of three trajectories including sexual behaviour scale, attitude towards STI/HIV/AIDS scale and knowledge of STI/HIV/AIDS scale was used in this study (n = 226, mean = 18.3years). The study made use of frequency counts, percentage and regression analysis. The SPSS software was used to analyse the data. <h3>Results</h3> The study indicates a fairly high knowledge level of STI/HIV (89.4%) with more males (87%) and younger participants (88%) possessing good knowledge of STI/HIV. Majority of the participants are sexually active (63.3%) and of this are more males (61.3%) and younger participants (60%). Findings show that age (β = 0.025; t = 0.04; p &gt; 0.05) of the three predictor variables was not a predictor of attitude towards STI/HIV. However, knowledge of STI/HIV (β = 0.459; t = 5.032; p &lt; 0.05) and sexual behaviour (β = 0.341; t = 4.278; p &lt; 0.05) were strong predictors of attitude towards STI/HIV. <h3>Conclusion</h3> This study shows the need for strong advocacy, enlightenment and community mobilisation for improved awareness of STI/HIV. Local, community and religious leaders, including youth leaders should be incorporated into the drive to increase awareness and knowledge of STI/HIV/AIDS among young people in Nigeria.
Abstract 17222: Safety, Tolerability and LDL-C Reduction With LIB003 a Novel Anti-PCSK9 Recombinant Fusion Protein: Results of Open-Label Extension Phase 2B Study
Authors: Evan A Stein, Traci Turner, Dean J Kereiakes, Bain Butcher, Padma Mangu, Rong Zhou
Journal: Circulation (2019)

Introduction: LIB003 (LIB) is a recombinant fusion protein of a PCSK9-binding domain (adnectin) and human serum albumin which offers small injection volumes for monthly (Q4W) dosing. We evaluated l...
Abstract 2780: <i>In vivo</i> quantitative molecular imaging for receptor-specific contrast and image guided surgery of glioblastoma
Authors: Shazia Bano
Journal: Cancer Research (2020)

Abstract Quantitative, noninvasive imaging utilizing the full potential of antibody targeted nanomedicines has recently emerged as a new paradigm in cancer therapeutics. However, the specificity of these nanomedicines to the molecular targets in in vivo is much controversial. We have leveraged a molecular-specific approach for the simultaneous imaging and quantitation of in vivo EGFR expression levels, using NIR-activable cetuximab targeted nanomedicine. Using quantitative molecular imaging, the EGFR specificity of these targeted nanomedicines is measured, following i.v. administration in glioblastoma tumors bearing mice. For the first time we demonstrate, that in vivo specificity of ligand targeted nanomedicines correlates positively with cellular expression levels of EGFR established by flow cytometry (Pearson's r = 0.93, p &amp;lt; 0.0003).Importantly, we show that the EGFR concentrations in glioblastoma (with varying expressions of EGFR) closely match with those previously derived from dual-reporter imaging using fluorescent conjugates. This first demonstration of non-invasive quantitation of targeted nanomedicine binding introduces an unexplored approach to leverage targeted nanomedicines as a critical component in the design and validation process of cancer therapeutics. Such an informed methodology promises to expedite translation and minimize failures that often occur after substantial investment. Citation Format: Shazia Bano. In vivo quantitative molecular imaging for receptor-specific contrast and image guided surgery of glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2780.
The Impact of the COVID-19 Pandemic on Genitourinary Cancer Care: Re-envisioning the Future
Authors: Christopher J.D. Wallis, James W.F. Catto, Antonio Finelli, Adam W. Glaser, John L. Gore, Stacy Loeb, Todd M. Morgan, Alicia K. Morgans, Nicolas Mottet, Richard Neal, Tim O’Brien, Anobel Y. Odisho, Thomas Powles, Ted A. Skolarus, Angela B. Smith, Bernadett Szabados, Zachary Klaassen, Daniel E. Spratt
Journal: European Urology (2020)
Abstract PR01: Assessment of PARPi and cisplatin resistance in <i>BRCA1</i> exon 11 mutant patient -derived xenografts
Authors: John J Krais, Emma Clausen, Vladimir Khazak, Igor Astsaturov, Clare L Scott, Neil Johnson
Journal: Clinical Cancer Research (2020)

Abstract Introduction: The BRCA1 protein contributes to homologous recombination (HR) repair of DNA breaks. BRCA1 mutations often result in dysfunction or absence of BRCA1 proteins. Consequently, BRCA1 mutations induce PARP inhibitor (PARPi) and cisplatin sensitivity. BRCA1 exon 11 is the largest exon and harbors a plethora of germline mutations. BRCA1 exon 11 is subject to alternative splicing and can generate the BRCA1-Δ11q isoform. This isoform is a hypomorphic variant that removes germline exon 11 mutations allowing for translation through to the end of the protein. In this study we examined PARPi and cisplatin sensitivity and resistance in a panel of BRCA1 exon 11 mutant PDX tumors. Experimental Procedures: Wild-type BRCA1 PDX036, exon 13 truncating BRCA1 mutant PDX1126, and BRCA1 exon 11 mutants PDX017, PDX056, and PDX124 were utilized. Using these models, we developed several isogenic sets of cisplatin and PARPi sensitive/resistant PDX using serial passaging and treatments. Additionally, we developed a method for lentiviral manipulation of PDX models to study resistance mechanisms. We assessed tumors for cisplatin and PARPi sensitivity and examined BRCA1 and 53BP1 expression by Western blotting and immunohistochemistry. Results: We observed variable responses to cisplatin and PARPi treatments among PDX models despite the presence of BRCA1 mutations that abrogated expression of full-length BRCA1. PDX196 expressed an abundance of BRCA1-Δ11q and exhibited resistance to both PARPi and cisplatin treatments. Interestingly, exon 11 mutant PDX017, 056, and 124 initially responded to both cisplatin and PARPi treatments. Serial passaging and treatments ultimately elicited resistance in each of these models and in some tumors coincided with an increase in BRCA1-Δ11q expression. Additionally, PARPi and cisplatin-resistant PDX017 tumors exhibited a simultaneous reduction of 53BP1 and increased BRCA1-Δ11q expression. In contrast to the BRCA1 exon 11 mutant PDX models, exon 13 mutant PDX1126 failed to develop resistance after multiple rounds of serial passaging with either cisplatin or PARPi treatments. However, when PDX1126 cells were transduced with lentivirus containing BRCA1-Δ11q cDNA, a rapid acquisition of cisplatin resistance occurred. Conclusions: Our data indicate BRCA1-Δ11q expression is variable in BRCA1 exon 11 mutant tumors, but nevertheless, when abundantly expressed, supports resistance to cisplatin and PARPi. This abstract is also being presented as Poster A46. Citation Format: John J Krais, Emma Clausen, Vladimir Khazak, Igor Astsaturov, Clare L Scott, Neil Johnson. Assessment of PARPi and cisplatin resistance in BRCA1 exon 11 mutant patient -derived xenografts [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR01.
Response to: ‘Correspondence on ‘Interleukin-6 blockade with subcutaneous tocilizumab in severe COVID-19 pneumonia and hyperinflammation: a case–control study’ by Potere<i>et al’</i>by Buckley
Authors: Nicola Potere, Marcello Di Nisio, Donatella Cibelli, Rosa Scurti, Antonella Frattari, Ettore Porreca, Antonio Abbate, Giustino Parruti
Journal: Annals of the Rheumatic Diseases (2020)

We thank Dr Buckley1 for the interest in our report on interleukin-6 receptor blockade with subcutaneous tocilizumab in patients with severe COVID-19 pneumonia receiving supplemental oxygen without mechanical ventilation and hyperinflammation.2 We acknowledge that the recently published results from the RECOVERY trial showed reduced mortality in patients treated with dexamethasone (6 mg daily up to 10 days) in addition to usual care, with the benefits being greater in critically ill patients receiving mechanical ventilation (41% vs 29%), while considerably reduced in severe patients on supplemental oxygen without mechanical ventilation (18% vs 14%).3 We also read with interest the results of the CHIC study showing that high-dose intravenous tocilizumab (8 mg/kg body weight, single infusion) may increase the benefits of high-dose methylprednisolone (250 mg on day 1, followed by 80 mg on days 2–5) in patients with severe COVID-19 pneumonia and cytokine storm syndrome requiring supplemental oxygen, mostly through nasal cannulas or mask.4 It is therefore of utmost …
Abstract B17: Modeling ovarian cancer in mice using in vivo electroporation and CRISPR-mediated genome editing
Authors: Keerthana Harwalkar, Katie Teng, Jocelyn Arceneau, Yifan Zhao, Dave Farnell, Matt Ford, Tuyet Nhung Tun Nu, David Huntsman, Yojiro Yamanaka
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer is the fifth largest cause of cancer-related deaths in women. The vast majority of ovarian cancers are epithelial ovarian cancers, and high-grade serous carcinoma (HGSC) is the most common and most lethal epithelial ovarian cancer. In the last 10 years, it has been recognized that the cell of origin of most HGSCs is within the fallopian tube epithelium, instead of the ovarian surface epithelium. However, the early events in disease progression still remain poorly defined, because HGSC is usually diagnosed at advanced stages and there is a lack of proper animal models recapitulating human disease progression. My group has recently developed a unique strategy for generating mouse ovarian cancer models, which is a combination of in vivo fallopian tube electroporation, Cre-mediated lineage tracing and CRISPR-mediated gene modifications. As proof of principle, we generated a highly metastatic HGSC model by targeting four tumor suppressor genes. The female mice targeted these four genes generated ovarian tumors within 5 months after electroporation and peritoneal metastasis within 6 months. After 6 months, ascites formation was observed in two third of those females. Interestingly, similar to human ovarian cancer patients, we observed two metastatic patterns, miliary and nonmiliary. Our unique strategy has several advantages over the current mouse cancer models: 1) high flexibility permitting many gene combinations/modifications and host genetic backgrounds to be tested; 2) control over the size and area of targeted cells (the low-frequency mosaic transfection pattern better recapitulates the sporadic nature of human tumorigenesis); 3) the ability to track genetically modified cells by fluorescent reporters, permitting analysis of tumor initiation and early metastasis; and 4) highly metastatic mouse models with immune competency. Citation Format: Keerthana Harwalkar, Katie Teng, Jocelyn Arceneau, Yifan Zhao, Dave Farnell, Matt Ford, Tuyet Nhung Tun Nu, David Huntsman, Yojiro Yamanaka. Modeling ovarian cancer in mice using in vivo electroporation and CRISPR-mediated genome editing [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B17.
Drug delivery in intervertebral disc degeneration and osteoarthritis: Selecting the optimal platform for the delivery of disease-modifying agents
Authors: Fabio Colella, João Pedro Garcia, Marco Sorbona, Andrea Lolli, Bernardo Antunes, Domenico D'Atri, Florian P.Y. Barré, Jacopo Oieni, Maria Letizia Vainieri, Luana Zerrillo, Serdar Capar, Sonja Häckel, Yunpeng Cai, Laura B. Creemers
Journal: Journal of Controlled Release (2020)

Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) as major cause of chronic low back pain represent the most common degenerative joint pathologies and are leading causes of pain and disability in adults. Articular cartilage (AC) and intervertebral discs are cartilaginous tissues with a similar biochemical composition and pathophysiological aspects of degeneration. Although treatments directed at reversing these conditions are yet to be developed, many promising disease-modifying drug candidates are currently under investigation. Given the localized nature of these chronic diseases, drug delivery systems have the potential to enhance therapeutic outcomes by providing controlled and targeted release of bioactives, minimizing the number of injections needed and increasing drug concentration in the affected areas. This review provides a comprehensive overview of the currently most promising disease-modifying drugs as well as potential drug delivery systems for OA and IVDD therapy.
Abstract 5237: High-throughput slide preparation for spatially-resolved, multiplexed quantification of protein or mRNA in tumor tissues with automation of GeoMx™ DSP Assays on Leica Biosystems BOND RX
Authors: Daniel R. Zollinger, Sarah Ketting, Kristina Sorg, Oliver Appelbe, Danielle Aaker, Damian Cockfield, Chris Merritt, Joseph M. Beechem
Journal: Cancer Research (2020)

Abstract Characterization of the spatial distribution and abundance of proteins and mRNAs with morphological context within tissues enables a better understanding of biological systems in many research areas, including immunology and oncology. The GeoMxTM Digital Spatial Profiler (DSP) enables the highly-multiplexed detection of mRNA or protein targets within distinct regions of tissues, including FFPE. This assay utilizes in situ hybridization (ISH) probes or antibodies linked to indexing oligo barcodes via a photo-cleavable linker. The GeoMx DSP enables profiling of RNA or protein targets by releasing and collecting these barcodes from user-defined regions-of-interest. Manual preparation of FFPE tissue uses conventional immuno-fluorescence (IF) and ISH reagents, however it requires greater than two hours of hands-on-time over 2 days. Protocols have been developed to enable the automation of these tissue preparation protocols using the Leica Biosystems BOND RX and BOND RXm Fully Automated Research Stainers. Here we describe protocols for the semi-automated preparation of GeoMx RNA and protein assays as well as the fully-automated preparation of GeoMx RNA assays. These protocols reduce the hands-on time of performing the assay to 72 minutes and 35 minutes for the semi- and fully-automated protocols, respectively. Signal-to-noise ratios (SNR) are highly concordant between serial sections processed manually and processed on the Leica BOND RXm using the GeoMx Immune Cell Profiling Panel for protein (58-plex) and GeoMx Immune Pathways Panel for RNA (84-plex). Furthermore, automated assays show high concordance between the BOND RX and BOND RXm instruments. Lastly, we demonstrate the use of the fully automated slide preparation protocol with the GeoMx Cancer Transcriptome Atlas, a panel that targets &amp;gt;1,600 key cancer mRNAs that are read out by next-generation sequencing. GeoMx Assays are for RESEARCH USE ONLY. Not for use in diagnostic procedures. Citation Format: Daniel R. Zollinger, Sarah Ketting, Kristina Sorg, Oliver Appelbe, Danielle Aaker, Damian Cockfield, Chris Merritt, Joseph M. Beechem. High-throughput slide preparation for spatially-resolved, multiplexed quantification of protein or mRNA in tumor tissues with automation of GeoMx™ DSP Assays on Leica Biosystems BOND RX [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5237.
Abstract 6595: Targeting T cell lymphomas with CRISPR/Cas9-generated anti-CD70 allogeneic CAR-T cells
Authors: Sushant Karnik, Minh Thu Pham, Pooja Keerthipati, Zinkal Padalia, Julie Carson, Tony Ho, Ewelina Morawa, Matthias Will, Jonathan Terrett, Mary-Lee Dequeant
Journal: Cancer Research (2020)

Abstract T cell lymphomas account for 10% to 15% of non-Hodgkin lymphomas and are diverse biologically and clinically. Unlike B-cell lymphomas, T cell lymphomas are rather resistant to conventional therapies, such as chemotherapy and antibody-based therapeutics. This resistance coupled with the diversity of the T cell diseases means that there is a significant unmet need across the T cell lymphoma subtypes. CD70 (CD27 ligand) is a candidate target antigen for T cell lymphomas and has been is the subject of clinical trials using an enhanced ADCC antibody (ARGX-110). Using flow cytometry and immunohistochemistry (IHC) methods, we analyzed the expression of CD70 in cell lines and clinical samples representing T cell lymphomas and found significant expression of CD70 in multiple types of T cell lymphoma, but at highly variable antigen density. CAR-T cells targeting CD70 may thus be a potent new therapy to tackle these diseases. However, the use of autologous CAR-T therapy against T cell lymphomas is complicated by the likelihood of creating lymphoma cells carrying the CAR construct. Thus, we sought to examine the potency of our allogeneic anti-CD70 CAR-T cells (CTX130) against T cell lymphoma cells. CTX130 has previously been shown to be active across a range of CD70 expression levels in other cell types representing other malignancies. Consistent with these prior observations, CTX130 exhibited high potency in vitro and in vivo against T cell lymphoma cells across a range of CD70 antigen density and representing different types of T cell lymphomas such as Sezary syndrome and cutaneous T cell lymphoma (CTCL). CTX130 may thus be a valid therapeutic to evaluate in T cell lymphoma patients. Citation Format: Sushant Karnik, Minh Thu Pham, Pooja Keerthipati, Zinkal Padalia, Julie Carson, Tony Ho, Ewelina Morawa, Matthias Will, Jonathan Terrett, Mary-Lee Dequeant. Targeting T cell lymphomas with CRISPR/Cas9-generated anti-CD70 allogeneic CAR-T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6595.