tbuckley/cabot-search huggingface dataset:
Abstract 4304: Radio-chemotherapy efficacy is predicted by intra-tumor CD8+FoxP3+ double positive T cell density in locally advanced non-small cell lung carcinoma
Authors: Yoan Velut, Geoffroy Boulle, Audrey Mansuet Lupo, Laure Gibault, Hélène Blons, Jean Tredaniel, Ludovic Fournel, Aurélie Boni, Isabelle Cremer, Marie Wislez, Veronique Duchatelle, Scott Hammond, Marco Alifano, Philippe Giraud, Diane Damotte
Journal: Cancer Research (2020)

Abstract Background: radiotherapy is a standard of care for locally advanced stage III (N2) non-small cell lung cancer (NSCLC) combined with surgery and/or chemotherapy. Radiotherapy is hypothesized to induce intra-tumoral immune infiltration via neoantigen release from dying tumor cells sometimes resulting in an abscopal effect. However, intra-tumoral immune cell characteristics that predict radiotherapy efficacy have not been identified. Patients and Methods: we retrospectively analyzed tumor samples and clinical data from 113 patients, 89 resected) and 24 non-resected stage III (N2) NSCLC treated within the same radiotherapy department (2002 to 2015). We performed multiplex staining (CD8, FoxP3, PD-L1, pan-keratin) in order to correlate immune environment (density and location) to overall survival (OS) and disease free survival (DFS). Results: high density of CD8+ T cells was associated with DFS (p=0.0036, HR=2.42 [1.31 - 4.47]) and OS (p=0.049, HR=1.93 [0.99 - 3.78]) in resected group only. High density of CD8+/FoxP3+ double positive T cells was associated with OS (p=0.017, HR= 1.97 [1.11 - 3.48]) in the global population; and in resected group for OS (p=0.05, HR=1.92 [0.98 - 3.74]) and PFS (p=0.03, HR=1.83 [1.03 - 3.23]), with a trend of significance for OS and PFS in the non-resected group (p=0.06, HR=2.84 [0.88 - 9.13] and p=0.05, HR=3.03 [0.91 - 10.10], respectively). Intermediate PD-L1 expression in tumor cells (TPS=1-49%) was associated with a higher survival in the resected group. Conclusions: we demonstrated that intra-tumoral CD8+ T cell and particularly the CD8+/FoxP3+ cell density predict radiotherapy efficacy and survival in stage III N2 NSCLC. Thus, it suggests that radiotherapy rather improves than promotes tumor immunogenicity. Citation Format: Yoan Velut, Geoffroy Boulle, Audrey Mansuet Lupo, Laure Gibault, Hélène Blons, Jean Tredaniel, Ludovic Fournel, Aurélie Boni, Isabelle Cremer, Marie Wislez, Veronique Duchatelle, Scott Hammond, Marco Alifano, Philippe Giraud, Diane Damotte. Radio-chemotherapy efficacy is predicted by intra-tumor CD8+FoxP3+ double positive T cell density in locally advanced non-small cell lung carcinoma [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 4304.
Abstract 5169: Tissue analysis of NAD(P)H: quinone oxidoreductase (NQO1) and catalase expression in patients with germ cell tumors (GCT)
Authors: Neda Hashemi Sadraei, Nabil Adra, Constance Temm, Kenneth A. Kesler, Muhammad T. Idrees, David A. Boothman, Lawrence Einhorn
Journal: Cancer Research (2020)

Abstract Background: Testicular germ cell tumor (GCT) is the most common cancer in young men between 15 and 35 years of age. Cisplatin-based combination chemotherapy will cure 70% of patients with metastatic GCT. Patients who relapse can still be cured with salvage standard-dose or high-dose chemotherapy. However, about 15% of patients with relapsed/refractory GCT are incurable. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase elevated in several tumor types compared to normal tissue. NQO1 detoxifies quinones and reduces oxidative stress. NQO1 bioactivatable drugs induce DNA damage in cells overexpressing NQO1, but not in cells lacking it, hence delivering tumor-selective damage and cell death. Alterations in catalase expression can cause cytoprotection. The ratio of NQO1:catalase activities is presumed to be a predictive marker for therapeutic activity of NQO1 bioactivatable drugs. There is no existing data on NQO1 or catalase expression in GCTs. Methods: Patients with testicular or extra-gonadal GCT who had surgery between January 2016 and December 2018 were identified from the Indiana University Melvin and Bren Simon Cancer Center Tissue Bank database. Patients with non-seminomatous GCT (NSGCT) of testis or primary mediastinal NSGCT were selected and specimens obtained. Immunohistochemistry staining was performed on tumor tissue to determine the quantity and intensity of NQO1 and catalase expression. Results: NQO1 and catalase expression were determined in 16 patients. Thirteen specimens stained moderately to strongly positive for NQO1. Only 1 specimen stained negative. Conversely, no specimen stained strongly positive for catalase, and only 2 stained moderately positive. Fourteen specimens were catalase deficient or only mildly positive for catalase. The details of the immunostaining is summarized in the table below. Immunohistochemistry staining for NQO1 and catalase in GCTImmunostainNegative(0)Mildly positive (&amp;lt;10%)Moderately positive (10-50%)Strongly positive (&amp;gt;50%)NQO1Quantity01114Intensity0547Combined score1267CatalaseQuantity3472Intensity31120Combined score7720 Conclusions: NSGCTs appear to have high levels of NQO1 and deficiency of catalase. NQO1 bioactivatable agents could serve as a potential therapeutic approach in patients with refractory testicular GCTs. Citation Format: Neda Hashemi Sadraei, Nabil Adra, Constance Temm, Kenneth A. Kesler, Muhammad T. Idrees, David A. Boothman, Lawrence Einhorn. Tissue analysis of NAD(P)H: quinone oxidoreductase (NQO1) and catalase expression in patients with germ cell tumors (GCT) [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 5169.
Abstract 6252: Development and validation of an LC/MS/MS method for the determination of celastrol in rat plasma and its application to the pharmacokinetic evaluation of celastrol-encapsulated silk fibroin nanoparticles
Authors: Shuyu Zhan, Amy Paik, Felicia Onyeabor, Baoyue Ding, Sunil Prabhu, Jeffrey Wang
Journal: Cancer Research (2020)

Abstract Celastrol (CL), a compound isolated from Tripterygium wilfordii, possesses various bioactivities such as anti-tumor, anti-inflammatory and anti-obesity effects. Many new drug delivery systems of CL have been designed to overcome its poor water solubility and low bioavailability. However, few studies are available concerning its in vivo pharmacokinetics. In this study, a simple and sensitive LC-MS/MS method was developed and validated to determine CL in rat plasma using 18α-glycyrrhetinic acid as the internal standard. The separation of CL was performed on a Phenomenex Gemini C18 column (150 mm × 2 mm, 5 µm) following sample preparation using liquid-liquid extraction with the optimized extraction solvent of tert-butyl methyl ether and a small plasma sample volume of 50 μL. The analyte was quantitated under positive electrospray ionization and multiple reactions monitoring mode. The assay exhibited a good linearity in the concentration range of 0.5-500 ng/mL. The lower limit of quantification (LLOQ) was 0.5 ng/mL. The method was fully validated to meet the requirements for bioassay with accuracy of 91.1-110.0%, precision (RSD %) of less than 9.1 %, extraction recovery of 63.5-74.7%, and matrix effect of 87.3-101.2%. The developed method was successfully applied to the pharmacokinetic evaluation of CL-encapsulated silk fibroin nanoparticles (CL-SFNP). The results show, after intravenous (IV) and oral (PO) administration of equivalent CL (1 mg/kg and 3 mg/kg, respectively) in rats, the AUC values of CL were 8646.1±1998.9 ng/mL·h after IV dosing and 1065.5±494.6 ng/mL·h after PO dosing for CL-SFNP, which were significantly (P&amp;lt;0.05) higher than those for pure CL (4697.7±723.0 ng/mL·h and 441.9±82.6 ng/mL·h, respectively). The dose-normalized oral bioavailability of CL significantly (P&amp;lt;0.05) increased from 3.1% for pure CL to 7.6% for CL-SFNP. Citation Format: Shuyu Zhan, Amy Paik, Felicia Onyeabor, Baoyue Ding, Sunil Prabhu, Jeffrey Wang. Development and validation of an LC/MS/MS method for the determination of celastrol in rat plasma and its application to the pharmacokinetic evaluation of celastrol-encapsulated silk fibroin nanoparticles [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 6252.
Social distancing and COVID-19: an unprecedented active transport public health opportunity
Authors: John H M Brooks, Richard Tingay, Justin Varney
Journal: British Journal of Sports Medicine (2020)

Social distancing measures to control the spread of COVID-19 are themselves likely to have had a negative impact on health and inequalities,1 but they could be an unprecedented public health opportunity in other ways.

Social distancing is likely to limit public transport capacity for the foreseeable future. Staggered work times and flexible working may alleviate some public transport crowding, but travel will still be necessary. Alternatives to increase transport capacity will be required, particularly in crowded cities where increased personal car use is unfeasible and potentially environmentally unfriendly.

Up to 90% of active commuters walking or cycling have been shown to meet the minimum physical activity guidelines, with evidence of a consequential lower risk of CVD and mortality, all-cause mortality and cancer outcomes.2 Other benefits include environmental change and improvements in mood and self-esteem.3 However, commuters may choose to increase personal car use, potentially reducing physical activity levels with negative health and environmental impacts.

More than 80% of journeys into London in the morning peak used rail-based services in 2019, only 11% of the UK adult population is thought to cycle at least once per week (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/870647/tsgb-2019.pdf) and 59% of car …
Abstract 5723: Loss of stemness and lineage commitment in the intestinal crypt
Authors: Amber Habowski, Jessica Flesher, Jennifer Bates, Anand Ganesan, Robert Edwards, Yongsheng Shi, Klemens Hertel, Marian Waterman
Journal: Cancer Research (2020)

Abstract The stem cell niche in intestinal crypts maintains multi-potent stem cells that constantly replenish all cell types in the mucosal lining of normal tissue. As daughter cells exit this niche, a loss of high Wnt signaling triggers rapid differentiation and lineage commitment to secretory or absorptive trajectories. Although signaling pathways such as Wnt and Notch are known to play a role in this differentiation and commitment, the mechanism that allows for such rapid action is not well understood. To investigate this, we used a novel flow sorting protocol to sort mouse colon crypt cells and then performed deep bulk RNA-sequencing. During differentiation we uncovered a gradual loss of stem cell markers and a sharp increase in alternatively spliced and alternatively polyadenylated genes. This indicates mRNA processing may be one of the first loss-of-stemness signals in the intestine. We also were able to find lineage specific activity for the unfolded protein response and further resolution on other signaling pathways. This unique sorting procedure will aid further study of crypt dynamics and this rich dataset provides an unprecedented resolution of the intestinal crypt processes including differentiation and lineage commitment along with a baseline plasticity potential of crypt cells. Citation Format: Amber Habowski, Jessica Flesher, Jennifer Bates, Anand Ganesan, Robert Edwards, Yongsheng Shi, Klemens Hertel, Marian Waterman. Loss of stemness and lineage commitment in the intestinal crypt [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 5723.
Abstract 4689: Co-treatment of MEKi and BRD4 inhibitors lead to synergistic repression of MYC-associated enhancer RNAs
Authors: Joseph Azofeifa, Joel Basken, Maria Lai, Ryan Langendorf, Laura Norris, Tim Read, Adam Robbins-Pianka
Journal: Cancer Research (2020)

Abstract Recent evidence suggests that co-treatment with BRD4 and MEK inhibitors can lead to synergistic suppression of MAPK signaling, however, little is known about the mechanism of action of this synergy. In a triple negative breast cancer cell line model, we harvested nascent RNA at 45 minutes following repression of BRD4 and MEK via a variant of the precision run-on followed by sequencing (PRO-seq) assay. We noted dose-dependent repression of enhancer RNAs over MYC binding sites as well as enhancer RNAs upstream known ERK targets such as DUSP6. Using new machine learning techniques, we were able to link synergy-specific enhancer RNAs to their target genes. This work will inform on new methods for patient stratification and biomarker selection of the BETi and MEKi treatment regimes. Citation Format: Joseph Azofeifa, Joel Basken, Maria Lai, Ryan Langendorf, Laura Norris, Tim Read, Adam Robbins-Pianka. Co-treatment of MEKi and BRD4 inhibitors lead to synergistic repression of MYC-associated enhancer RNAs [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 4689.
Abstract 844: RNA binding domains of nucleolin exhibit specificity in driving nucleolin-miRNA interactions: An <i>in silico</i> modeling and RNA-protein docking study
Authors: Avdar San, Anjana Saxena, Shaneen Singh
Journal: Cancer Research (2020)

Abstract Nucleolin (NCL) is a stress responsive multifunctional RNA binding protein (RBP) that plays important roles in gene transcription and RNA metabolism. NCL levels and similarly many of NCL RNA targets are dysregulated in multiple human cancers. NCL- RNA interactions are driven by its four RNA binding domains (RBDs). Despite the myriad NCL functions that involve its RNA-binding properties, the mechanisms driving these interactions are poorly understood. Partial three-dimensional structural information available on NCL RBDs in the RCSB PDB database, is not sufficient to provide a comprehensive understanding of NCL- RNA interactions. To get a better insight into RNA binding specificity for its diverse targets, we have built upon the existing NCL-RBDs structures to generate multiple combinations of RBDs in tandem, using in silico modeling approaches. In this study, we analyze NCL-miRNA interactions in depth with a focus on a subset of miRNAs that are implicated in breast cancer. Using both template-based and ab initio approaches, we have generated complete and robust structural models of all 4 NCL RBDs in tandem and in combinations of two different RBDs in sequence. All models were then tested using a variety of structural quality evaluation programs. Models with top validation scores were used in RNA-protein docking algorithms and assessed for interaction with specific miRNA. Our docking analyses have generated a comprehensive map of the miRNA-NCL protein interface sites for each individual miRNA and consistently predict specific RBDs in NCL-miRNA binding. We have also identified critical residues on the NCL-RBDs that may drive the miRNA binding in an RBD-type specific manner. Our results corroborate previous studies on RBDs from other RBPs. Structural information derived from this study provides a valuable perspective for future experiments. Identification of consensus on RNA binding motifs on NCL RBDs is critical in elucidating RNA target specificity by NCL. Computational analyses provide time and cost-effective benefits over experimental techniques; the in silico predictions are important in designing rational experiments for the future investigations confirming the NCL-miRNA interactions. Our study provides the foundational steps for establishing consensus motifs on NCL-RBDs that potentially direct RNA target specificity. Targeting these specific binding sites will provide new approaches to regulate NCL functions in gene expression during tumorigenesis. Citation Format: Avdar San, Anjana Saxena, Shaneen Singh. RNA binding domains of nucleolin exhibit specificity in driving nucleolin-miRNA interactions: An in silico modeling and RNA-protein docking study [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 844.
Abstract 291: Functionalizing novel modulators in lung cancer
Authors: Yi Fei Lee, Ju Yuan, Edwin Lim, Jianbin Chen, Weiwei Zhai, Nguan Soon Tan, Wai Leong Tam
Journal: Cancer Research (2020)

Abstract Lung cancer is the leading cause of cancer mortality globally, with lung adenocarcinoma being the most prevalent subtype. The discovery of driver mutations has paved the way for the use of targeted therapy, notably EGFR inhibitors, in the management of advanced disease. However, the effectiveness of targeted therapy is limited firstly by the eventual development of treatment resistance, and secondly by the sizeable percentage of cases in which the driver mutations remain unknown. Furthermore, lung adenocarcinoma (LUAD) in Asians is known to exhibit a molecular profile distinct from that in Caucasians, yet the majority of existing cohort studies have been focused on the latter. To address this gap, we and our collaborators have spearheaded the largest Asian LUAD cohort study, comprising genomic and transcriptomic data from 305 patients. The MutSigCV and 20/20+ driver prediction algorithms were applied to whole exome sequencing data from our cohort and yielded seven novel candidate drivers that had not been previously implicated in LUAD. We proceeded to functionally validate these drivers by overexpressing or knocking them down in patient-derived transformed lung cell lines and observing their effects on tumorigenicity via a number of in vitro and in vivo tumorigenicity assays. We have identified a poly (ADP-ribose) polymerase (PARP) gene, which was mutated at a relatively high frequency within our cohort, and show that PARP is crucial for modulating the tumorigenicity of lung cancer cells. In LUAD patients, reduced PARP expression levels were correlated with poorer prognosis, suggesting a putative tumor suppressor role. We further observed a loss of PARP copy number both within our cohort as well as the Caucasian The Cancer Genome Atlas (TCGA) LUAD cohort. We are now working to dissect the underlying mechanisms and explore PARP's clinical utility. This work illustrates the use of a platform to systematically model genetics in patient-derived models to study novel driver functions. Citation Format: Yi Fei Lee, Ju Yuan, Edwin Lim, Jianbin Chen, Weiwei Zhai, Nguan Soon Tan, Wai Leong Tam. Functionalizing novel modulators in lung cancer [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 291.
Abstract 5345: Heterogeneous tumor PSMA expression represents a resistance mechanism to PSMA-targeted radioligand therapy
Authors: Katharina Lueckerath, Kyle Current, Catherine Meyer, Clara Magyar, Christine E. Mona, Joel Almajano, Roger Slavik, Andreea D. Stuparu, Chloe Cheng, David Dawson, Caius Radu, Johannes Czernin
Journal: Cancer Research (2020)

Abstract Radioligand therapy (RLT) with prostate-specific membrane antigen (PSMA)-targeting ligands is effective in ~50% of patients with advanced prostate cancer (PC). Causes for RLT failure are not well understood. The prevalent PSMA heterogeneity in PC might contribute to RLT failure. Here we investigate the relationship between RLT efficacy and PSMA levels per cell, and PSMA heterogeneity. PC cells expressing different levels of PSMA (RM1-PSMA low, medium, high, or RM1-YFP that do not express PSMA), or a mix of PSMA− and PSMA+ cells (RM1-YFP/ RM1-PSMA-high; PC3/ PC3-PIP) at various ratios were subcutaneously injected into NSG mice. Mice were treated with 177Lu- or 225Ac-PSMA617 (RLT) and tumor growth was monitored. In a subset of mice, radioligand uptake (γ-counting), DNA damage and PSMA expression (anti-53BP1 and -PSMA immunohistochemistry, respectively) were quantified in tumors resected 2 days after RLT. Increasing PSMA levels and fractions of PSMA+ cells improved RLT efficacy in both, the RM1 and PC3 model. PSMA expression correlated with radioligand uptake into the tumor and the degree of DNA damage and. Treatment with 225Ac-PSMA617 (vs. 177Lu-PSMA617) improved RLT outcomes and tended to enhance the differences in therapeutic efficacy between experimental groups. Taken together, we demonstrate in mouse models of PC that optimal anti-tumor efficacy of RLT hinges on homogenously high target expression. Although PSMA-RLT is effective even in tumors with low PSMA levels or with a small number of PSMA+ cells, low or heterogeneous PSMA expression might result in undertreatment and selection of treatment resistant clones. Systematic assessment of intra- and inter-lesion PSMA heterogeneity is currently not feasible clinically; however, this issue might be addressed by individual patient dosimetry to optimize safely delivered maximal tumor doses. Clinical studies designed to determine intra- and inter-lesion PSMA heterogeneity and to optimize PSMA-RLT for each patient are highly warranted. Citation Format: Katharina Lueckerath, Kyle Current, Catherine Meyer, Clara Magyar, Christine E. Mona, Joel Almajano, Roger Slavik, Andreea D. Stuparu, Chloe Cheng, David Dawson, Caius Radu, Johannes Czernin. Heterogeneous tumor PSMA expression represents a resistance mechanism to PSMA-targeted radioligand therapy [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 5345.