tbuckley/cabot-search huggingface dataset:
Abstract 1033: NANOG-HSP90A axis confers immunotherapeutic resistance by blocking anti-tumor immunity cycle
Authors: Se Jin Oh, Tae Woo Kim, Kwon-Ho Song, Suyeon Kim
Journal: Cancer Research (2020)

Abstract T cell-based immunotherapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to presence of immune-refractory tumor cells that limits its clinical success by blocking amplification of anti-tumor immunity cycle. Previously, we found that immune selection by T-cell based immunotherapy drives the evolution of tumors toward immunotherapeutic refractoriness including multimodal resistant and stem-like phenotype via activation of NANOG-TCL1A-AKT axis. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and the refractoriness of immune-edited tumor cells by identifying HSP90AA1 as a novel NANOG transcriptional target. Furthermore, we found that TCL1A is a novel client of HSP90A, and demonstrated that HSP90A potentiates AKT activation through TCL1A stabilization and thereby contributes to refractoriness in NANOGhigh immune-edited tumor cells. Importantly, inhibition of HSP90A sensitizes immune-refractory tumor cells to T cell-based immunotherapy and elicits effective anti-tumor response by re-invigorating anti-tumor immune cycle of tumor-reactive T cells. Our findings implicate that the NANOG-HSP90A pathway is a central molecular axis and a potential target for immune-refractory tumor. Citation Format: Se Jin Oh, Tae Woo Kim, Kwon-Ho Song, Suyeon Kim. NANOG-HSP90A axis confers immunotherapeutic resistance by blocking anti-tumor immunity cycle [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 1033.
Mothers of Preterm Infants Have Individualized Breast Milk Microbiota that Changes Temporally Based on Maternal Characteristics
Authors: Michelle R. Asbury, James Butcher, Julia K. Copeland, Sharon Unger, Nicole Bando, Elena M. Comelli, Victoria Forte, Alex Kiss, Lauren LeMay-Nedjelski, Philip M. Sherman, Alain Stintzi, Christopher Tomlinson, Pauline W. Wang, Deborah L. O’Connor
Journal: Cell Host & Microbe (2020)
Abstract 6294: Absolute, quantitative and high throughput measurement of tissue biomarkers in FFPE specimens using QDB method
Authors: Jiandi Zhang
Journal: Cancer Research (2020)

Abstract Absolute quantitation of tissue biomarkers in FFPE samples to aid drug discovery efforts. Tissue protein biomarkers play irreplaceable role in clinical diagnosis, prognosis and prediction. It is also heavily used in drug discovery to evaluate the effectiveness of a drug candidate, or to monitor its potential side effects at both preclinical stage and during clinical trials. In recent years, several tissue protein biomarkers are used as companion diagnostics to identify right patients for the right treatment. However, while the consistency and objectivity are the prerequisites for any assays to be used in scientific studies, the current prevailing method for tissue biomarker assessment, immunohistochemistry (IHC), is known to be associated with inconsistency and subjectivity. For example, there were studies demonstrating as much as 20% inaccuracy in Her2 assessment for breast cancer patients using IHC method. Conceivably, this practice leads to significantly increased cost and efforts in drug discovery. In this study, we demonstrated the usage of Quantitative Dot Blot (QDB) method to achieve absolute and quantitative measurements of tissue biomarkers in Formalin Fixed Paraffin Embedded (FFPE) samples in high throughput format. We were able to develop multiple QDB-based immunoassays using clinically validated antibodies for IHC in several types of cancers including breast cancer, lung cancer and prostate cancer. In the case of Her2, when the quantitatively measured results were converted into dichotomous variables using Receiver Operative Characteristics, we were able to achieve concordance with IHC at 94.8% (n=748), and 94.2% with Fluorescence in situ hybridization (FISH) (n=141). QDB-based assays also require minimum amount of total protein lysates, ranging from 0.1 to 0.5 μg per sample. Total protein lysates extracted from 2X5μm is sufficient to measure at least 5 to 10 protein biomarkers in triplicate. The introduction of QDB method in drug discovery promises significantly increased objectivity and consistency of the results. The high throughput aspect of QDB method also suits well the daily activity in drug development. We believe the adoption of this method should significantly speed up the drug discovery process while reduce the related costs and efforts. Citation Format: Jiandi Zhang. Absolute, quantitative and high throughput measurement of tissue biomarkers in FFPE specimens using QDB method [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 6294.
Abstract 6001: 6-Phosphofructo-2-kinase inhibition to increase the efficacy of ER and CDK4/6 inhibitors against ER+ breast cancer
Authors: Lilibeth Lanceta, Nadiia Lypova, Jasson Chesney, Yoannis Imbert-Fernandez
Journal: Cancer Research (2020)

Abstract Deregulation of the estrogen receptor (ER)-cyclin D1-CDK4/6 pathway is a hallmark of ER+ breast cancer that has prompted the development of CDK4/6 inhibitors. Although administration of CDK4/6 inhibitors to patients with ER+ advanced breast cancers have resulted in an improvement in progression free survival, almost all patients invariable develop resistance and relapse over time. Activation of glucose metabolism upon CDK4/6 inhibition is becoming increasingly evident. A key stimulator of glycolysis is the PFKFB3 enzyme which synthesizes fructose 2,6-bisphosphate (F2,6BP), a potent allosteric activator of the rate-limiting 6-phosphofructo-1-kinase (PFK1). F2,6BP controls flux throughout the entire glycolytic pathway and, as a result is required for the proliferation of cancer cells. In preliminary studies, we provide evidence that PFKFB3 expression and activity is increased in response to CDK4 inhibition in ER+ breast cancer cells and that a PFKFB3 inhibitor, PFK-158, increases the anti-tumor activity of anti-CDK4 targeted therapy in vitro. Importantly, we found that ER+ cancer cells with acquired resistance to palbociclib have increased levels of PFKFB3 and are highly susceptible to the effects of PFK-158. Our studies provide a clear rationale to propose the use of PFKFB3 inhibitors in combination with CDK4/6 inhibitors as an effective strategy to increase the efficiency and/or overcome resistance to CDK4/6 inhibition. Citation Format: Lilibeth Lanceta, Nadiia Lypova, Jasson Chesney, Yoannis Imbert-Fernandez. 6-Phosphofructo-2-kinase inhibition to increase the efficacy of ER and CDK4/6 inhibitors against ER+ breast 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 6001.
Abstract 293: Heat shock factor 1 directly suppresses AMP-activated protein kinase to promote tumorigenesis
Authors: Kuo-Hui Su, Siyuan Dai, Zijian Tang, Meng Xu, Chengkai Dai
Journal: Cancer Research (2020)

Abstract Heat shock factor 1 (HSF1), a master transcriptional regulator of the evolutionarily conserved proteotoxic stress response, preserves proteomic stability upon environmental insults. HSF1 is also a potent pro-oncogenic factor, suggesting that proteomic stability enables oncogenesis. AMP-activated protein kinase (AMPK), a key cellular metabolic sensor and downstream effector of the tumor suppressor LKB1, activates catabolic pathways but suppresses anabolic pathways, including fatty acid and cholesterol biosynthesis, thereby maintaining energy homeostasis. We previously showed that upon activation by metabolic stressors, AMPK interacts with and phosphorylates HSF1 to inactivate it and cause proteomic instability, leading to tumor suppression. Intriguingly, we also discovered that HSF1 suppresses AMPK and controls body fat mass. This study is to investigate the mechanisms by which HSF1 reciprocally suppresses AMPK and the roles of this suppression in lipid metabolism and tumorigenesis. By utilizing recombinant proteins, HSF1 peptide libraries and transcription-deficient HSF1 mutants, our in vitro studies reveal that through physical interactions HSF1 imposes multilayer regulations on AMPK, including blocking AMP binding to γ subunits, impairing LKB1-mediated Thr172 phosphorylation, promoting Thr172 de-phosphorylation by PP2A, and impeding ATP binding to catalytic α subunits. Results from circular dichroism spectroscopy reveal that HSF1 induces global AMPK conformational changes. Biologically, Hsf1 deficiency suppresses lipogenesis and decreases lipid content via AMPK activation. Moreover, Hsf1-deficient cells and mice display reduced cholesterol levels. Interestingly, this defect leads to impaired cholesteroylation of sonic hedgehog (SHH). Consequently, the oncogenic SHH signaling is impaired in HSF1-deficient cells. In vivo, Hsf1 deficiency reduces body fat mass in mice, which can be markedly rescued by either pharmacological or genetic inhibition of AMPK. Importantly, the transcription-deficient HSF1 mutant, through AMPK suppression, enhances the lipid content and SHH cholesteroylation, and promotes the in vivo growth of xenografted human melanomas. In conclusion, HSF1 is a direct AMPK antagonist. This transcription-independent interaction of HSF1 with AMPK epitomizes a reciprocal kinase-substrate regulation whereby lipid metabolism and proteomic stability intertwine and promotes cancer anabolism and oncogenesis. Citation Format: Kuo-Hui Su, Siyuan Dai, Zijian Tang, Meng Xu, Chengkai Dai. Heat shock factor 1 directly suppresses AMP-activated protein kinase to promote tumorigenesis [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 293.
Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome
Authors: Luke Y.C. Chen, Ryan L. Hoiland, Sophie Stukas, Cheryl L. Wellington, Mypinder S. Sekhon
Journal: European Respiratory Journal (2020)

<b>Hypercytokinaemic immune dysregulation in COVID-19 is known as cytokine storm syndrome. Interleukin-6 levels ≥80 pg·mL<sup>−1</sup> predict an increased risk of respiratory failure and death, and immunomodulatory therapy is an area of urgent investigation.</b>https://bit.ly/3jq3uJ4
Abstract 150: Establishment of diagnostic criteria for upper urinary tract urothelial carcinoma based on genome-wide DNA methylation analysis
Authors: Mao Fujimoto, Eri Arai, Koji Tsumura, Takuya Yotani, Yuriko Yamada, Yoriko Takahashi, Akiko Miyagi Maeshima, Hiroyuki Fujimoto, Teruhiko Yoshida, Yae Kanai
Journal: Cancer Research (2020)

Abstract For diagnosis of upper urinary tract urothelial carcinoma (UTUC), retrograde ureteropyelography and ureteroscopy are invasive, and selective urine cytology has insufficient sensitivity and specificity. The aim of this study was to establish a less invasive and more accurate method for UTUC diagnosis based on genome-wide DNA methylation profiling. Single-CpG resolution genome-wide DNA methylation screening was performed using the Infinium assay, and DNA methylation quantification was verified using pyrosequencing. We analyzed 26 samples of normal control urothelial tissue (C), an initial cohort of 62 samples (31 samples of non-cancerous urothelium [N] from UTUC patients and 31 samples of the corresponding UTUCs), a validation cohort of 82 samples (41 N and 41 UTUC samples), and 14 samples of urinary bladder urothelial carcinoma (BUC). In the initial cohort, we identified 2,448 CpG sites showing significant differences in DNA methylation levels between both C and UTUC and N and UTUC, but not showing differences between C and N. Among these CpG sites, 10 were located within CpG islands or their shores and shelves included in genomic domains where DNA methylation levels are stably controlled, allowing discrimination of UTUC even from BUC. Receiver operating characteristic curve analysis for discrimination of UTUC from N in these 10 CpG and neighboring sites (37 diagnostic panels in total) yielded area under the curve values of 0.959-1.000, with a sensitivity and specificity of 86.6-100% and 93.5-100%, respectively. The reliability of the established criteria was successfully confirmed in the validation cohort. Application of our criteria to voided urine samples will ultimately allow non-invasive and reliable DNA methylation diagnosis of UTUC using an appropriate DNA methylation quantification system such as high-performance liquid chromatography. Citation Format: Mao Fujimoto, Eri Arai, Koji Tsumura, Takuya Yotani, Yuriko Yamada, Yoriko Takahashi, Akiko Miyagi Maeshima, Hiroyuki Fujimoto, Teruhiko Yoshida, Yae Kanai. Establishment of diagnostic criteria for upper urinary tract urothelial carcinoma based on genome-wide DNA methylation analysis [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 150.
SEP-1 Septic Shock Bundle Guidelines Not Applicable to Inpatients
Authors: Jason Stankiewicz, Maniraj Jeyaraju, Michael T. McCurdy
Journal: JAMA Internal Medicine (2020)

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Abstract 5474: Identification of novel druggable fusions enabled through the use of an automated RNA fusion prioritization pipeline
Authors: Sumaiya A. Islam, Robert Huether, Emily Kudalkar
Journal: Cancer Research (2020)

Abstract Gene fusions can serve as key drivers in the development of various cancers and represent important therapeutic targets and diagnostic biomarkers. Due to high detection of candidate fusions from RNA-sequencing data, there is a recognized need to build tools that will make reasonable and automated predictions to identify clinically or biologically relevant fusion events in a tumor sample. We developed a computational pipeline which scores and prioritizes all detected fusion transcripts within a sample to determine which fusions are likely driver events in the tumor. Specifically, the pipeline implements a categorization scheme that bins all scored fusion events into Low, Medium and High Confidence levels based on threshold read support levels and a DriverScore metric, which is derived from a binary classification algorithm using specific features, such as reading frame, breakpoint region, kinase domain and transcript isoform. We systematically analyzed 3200 fusion candidates from a previously published cohort of 500 paired tumor-normal samples sequenced with the Tempus xT assay. We found that 1.7% and 20.1% of fusion candidates were categorized in the High and Medium Confidence levels, respectively, while 78.2% of fusion events were deprioritized as Low Confidence calls. Of the 35 clinically-relevant fusions, 27 (77.1%) were captured in our prioritized set (High/Medium Confidence), including National Comprehensive Cancer Network actionable gene rearrangements involving RET, STAT6 and FUS, while the remaining 8 were assigned as Low Confidence due to an out of frame fusion transcript and insufficient read support. The frequency of prioritized fusions varied by cancer type, with prostate and breast cancer having the highest frequency of prioritized fusions. In addition to well-established canonical fusions, we also sought to characterize novel fusions, identifying a subset of 21 novel prioritized fusions which were also observed in The Cancer Genome Atlas tumor samples. Within this subset, 3% of fusion candidates contained a druggable domain such as a tyrosine kinase or Ras-binding domain, signifying the potential of categorization to enable novel fusion drug target discovery. Overall, our analysis highlights the utility of using an automated prioritization tool to detect known canonical fusion drivers and explore novel fusion drug targets and biomarkers. Citation Format: Sumaiya A. Islam, Robert Huether, Emily Kudalkar. Identification of novel druggable fusions enabled through the use of an automated RNA fusion prioritization pipeline [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 5474.
Abstract 6394: Combined FLT3 and PARP inhibition induces synthetic lethality in non-small cell lung cancer cells
Authors: Hwani Ryu, Hyo Jeong Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn
Journal: Cancer Research (2020)

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Fms-like receptor tyrosine kinase 3 (FLT3), a member of class III receptor tyrosine kinase, targeted inhibitors have not been well studied in lung cancer including NSCLC. Since recent studies have been reported that FLT3 inhibitors can suppress DNA repair activities, we investigated the antitumor activities of quizartinib, an FLT3 inhibitor, in NSCLC cells to expand the use of FLT3 inhibitors. Quizartinib inhibited the growth of NSCLC cells in a concentration-dependent manner, and induced DNA damage and reactive oxygen species (ROS) generation in A549 and H1299 cells. We found that quizartinib suppressed DNA damage repair genes through the downregulation of STAT5, resulting in the ‘BRCAness' or ‘DNA-PKness' phenotype in A549 and H1299 cells. As quizartinib-induced ‘BRCAness/DNA-PKness' and poly(ADP-ribose) polymerase inhibitors (PARP) inhibition can induce synthetic lethality, combined treatment with quizartinib and olaparib, a PARP inhibitor, showed synergistic inhibitory proliferation and apoptotic cell death in A549 and H1299 cells compared with either drug alone. Taken together, our findings suggest that quizartinib may be a synthetic lethal partner of PARP inhibitors to enhance therapeutic efficacy in NSCLC cells. Citation Format: Hwani Ryu, Hyo Jeong Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn. Combined FLT3 and PARP inhibition induces synthetic lethality in non-small cell lung cancer 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 6394.
Abstract 5044: Integrin-linked kinase gene knockdown results in decreased growth of ovarian cancer xenograft models
Authors: Tiffany Redfern, Benjamin Wilson, Michael Ulm, Adam ElNaggar, Suriyan Ponnusamy, Yinan Wang, Sarah Asemota, Ramesh Narayanan
Journal: Cancer Research (2020)

Abstract Integrin-linked kinase (ILK) is overexpressed in ovarian cancer cells. In the present study, we sought to assess the effect of ILK silencing on ovarian cancer cell proliferation using shRNA. Our lab previously demonstrated that phosphorylation of ILK acts as a proliferative signal in a variety of ovarian cancer cell lines. Cytotoxicity of ILK knockdown using shRNA was analyzed in vitro using SKOV3 cell lines. Transfected cells were incubated in Incucyte®, which allowed for simultaneous assessment of viable cells at the end of the incubation period using CellTiter glo assay. Knockdown of ILK using shRNA significantly inhibited the proliferation of SKOV3 cells. SKOV3 cells were then infected with lentivirus expressing ILK shRNA to obtain stable knockdown of ILK, which was confirmed with Western blot. Both parental and ILK shRNA infected cells were injected subcutaneously in NOD SCID Gamma immunocompromised mice. Tumor growth was assessed by sequential tumor measurements and final weights. Xenograft data indicated significantly decreased tumor volume over multiple time points in the transfected cells (p &amp;lt;0.0001) (Figure 1). Average final volume for the ILK-shRNA group (n = 15) and control group (n = 13) was 660mm3 (SD = 366.7, range 271 - 1667 mm3) and 1165 mm3 (SD = 668.7, range 506 - 2664 mm3), respectively. Similarly, average tumor weight was less for the ILK-shRNA group (404.4mg [range 226.1 - 801mg]) relative to control (584.3mg [range 293.2 - 1033.4mg]). Our findings demonstrate that knockdown of ILK in ovarian cancer cell lines results in decreased cell proliferation, as well as decreased tumor growth in xenograft models. This supports the role for further investigation into ILK as a potential therapeutic target in ovarian cancer. Days From Tumor Implantation1214161921232628313438VectorAverage Tumor Volume (mm^3)142.4151.6203274.7379.3482.1671.4741.2845.11083.81164.6Standard Error26.983.430.835.759.682112.3110.7133.9172.2185.5ILK-shRNAAverage Tumor Volume (mm^3)45.9107.282.4113150.9177263.4345.2397.3568.8659.9Standard Error6.39.99.915.225.822.841.558.455.19994.7 Citation Format: Tiffany Redfern, Benjamin Wilson, Michael Ulm, Adam ElNaggar, Suriyan Ponnusamy, Yinan Wang, Sarah Asemota, Ramesh Narayanan. Integrin-linked kinase gene knockdown results in decreased growth of ovarian cancer xenograft models [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 5044.
Revisiting Rate versus Rhythm Control in Atrial Fibrillation — Timing Matters
Authors: T. Jared Bunch, Benjamin A. Steinberg
Journal: New England Journal of Medicine (2020)

Bunch and Steinberg comment on the findings of EAST-AFNET 4, an international randomized trial comparing early rhythm control with usual care among patients with atrial fibrillation and other cardiovascular risk factors. They note the need to treat atrial fibrillation with comprehensive management.