tbuckley/cabot-search huggingface dataset:
Multiplexed non-invasive tumor imaging of glucose metabolism and receptor-ligand engagement using dark quencher FRET acceptor
Authors: Alena Rudkouskaya, Nattawut Sinsuebphon, Marien Ochoa, Sez-Jade Chen, Joseph E Mazurkiewicz, Xavier Intes, Margarida Barroso
Journal: Theranostics (2020)

Following an ever-increased focus on personalized medicine, there is a continuing need to develop preclinical molecular imaging modalities to guide the development and optimization of targeted therapies. Near-Infrared (NIR) Macroscopic Fluorescence Lifetime Förster Resonance Energy Transfer (MFLI-FRET) imaging offers a unique method to robustly quantify receptor-ligand engagement in live intact animals, which is critical to assess the delivery efficacy of therapeutics. However, to date, non-invasive imaging approaches that can simultaneously measure cellular drug delivery efficacy and metabolic response are lacking. A major challenge for the implementation of concurrent optical and MFLI-FRET
Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway
Authors: Yuhong Lu, Yanfeng Liu, Sebastian Oeck, Gary J. Zhang, Alexander Schramm, Peter M. Glazer
Journal: Cancer Research (2020)

Abstract Development of resistance remains the key obstacle to the clinical efficacy of EGFR tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the non–small cell lung cancer (NSCLC) cell line H1975, which harbors two EGFR mutations including T790M. Hypoxia-induced resistance was associated with development of epithelial–mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827, and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the proapoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small-molecule inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC. Significance: Hypoxia-induced resistance to EGFR TKI is driven by overexpression of FGFR1 to sustain ERK signaling, where a subsequent combination of EGFR TKI with FGFR1 inhibitors or MEK inhibitors reverses this resistance.
Abstract 321: Novel bone microenvironment model of prostate cancer with chitosan fiber matrix and osteoblast in 3D culture
Authors: Masahiro Samoto, Hiroaki Matsumoto, Hiroshi Hirata, Sho Ozawa, Junichi Mori, Ryo Inoue, Seiji Yano, Yoshiaki Yamamoto, Hideyasu Matsuyama
Journal: Cancer Research (2020)

Abstract BACKGROUND: The interaction between prostate cancer cells and osteoblast is essential for the development of bone metastasis. Recently, novel androgen receptor signal inhibitors (ARSi) have been approved for metastatic castration naïve (mCNPC), or non-metastatic castration resistant prostate cancer (nmCRPC), both of which should be pivotal to investigate the association between bone microenvironment and tumor. We established a novel 3D in vitro culture method reflecting bone microenvironment and evaluated the drug susceptibility of ARSi including enzalutamide, apalutamide, darolutamide, and abiraterone (Abi) with/without dutasteride (Duta). METHODS: GFP-transferred C4-2 (CRPC cell line) and RFP-transferred human osteoblast differentiated from human-mesenchymal stem cell was co-cultured in chitosan nanofiber, a mimicry of 3D scaffold of bone microenvironment, coated culture plate (Cosmo bio Co., LTD). The growth of C4-2 cell was quantified using live-cell imaging and analysis system, Cell3 iMager duos (SCREEN). Abi metabolites including delta-4 abiraterone (D4A) and 3-keto-5-alfa abiraterone in C4-2 cells were measured by ESI-TOF-MS method. RESULTS: We could non-invasively quantify the sustained growth of C4-2 cells at maximum of 30 days. IC50 of each drugs and combination effect of Abi and Duta was evaluated using this model. Combination treatment synergistically inhibited the growth of C2-4 cells compared with each drug alone. D4A, the strongest anti-proliferative metabolite of Abi under the CRPC-specific backdoor pathway, was detected from the treated C4-2 cell. These results were coincided with the effective cases of pharmacokinetics of Abi metabolites in our ongoing phase II clinical trial of combination therapy of Abi with Duta for CRPC (UMIN000027795). Furthermore, combination of abiraterone and dutasteride was most potent cell growth inhibitor than other ARis tested in this model. This model is applying for international patent (C12N 5/09). CONCLUSIONS: Our bone microenvironment model is unique and useful to evaluate the new drug susceptibility testing in prostate cancer cells. This model may help in disclose unknown mechanisms from micro- to clinical bone metastasis in prostate cancer. Citation Format: Masahiro Samoto, Hiroaki Matsumoto, Hiroshi Hirata, Sho Ozawa, Junichi Mori, Ryo Inoue, Seiji Yano, Yoshiaki Yamamoto, Hideyasu Matsuyama. Novel bone microenvironment model of prostate cancer with chitosan fiber matrix and osteoblast in 3D culture [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 321.
Abstract 4751: Brain and plasma choline compounds altered by cancer and cancer-induced cachexia
Authors: Santosh K. Bharti, Paul T. Winnard, Raj Kumar Sharma, Marie-France Penet, Balaji Krishnamachary, Zaver M. Bhujwalla
Journal: Cancer Research (2020)

Abstract Introduction: Cancer-induced cachexia has lethal consequences. Cachexia results in lower tolerance to chemotherapy1. Cachectic patients experience a wide range of symptoms affecting the function of organs such as muscle, liver, brain, and heart, causing significant morbidity 2. An altered choline metabolism is one of the hallmarks of cancers. Here, for the first time, we identified changes in brain choline metabolism induced by cachexia-inducing pancreatic cancer xenografts and related these changes to plasma choline levels. Methods: Panc1 or Pa04C cells were implanted in the flank of SCID mice. Snap frozen brains were powdered under liquid nitrogen, weighed, and dual phase extraction was performed3. All 1H MR spectra were acquired on a Bruker Avance III 750 MHz MR spectrometer. Mouse plasma choline was quantified using a fluorometric assay (Choline Assay Kit, BioAssay Systems). Brain and plasma studies were performed with normal mice (n=10), mice with cachexia-inducing Pa04C tumors (n=9) and mice with non cachexia-inducing Panc1 tumors (n=10). Results and Discussion: Cachexia-inducing Pa04C tumors induced significant weight loss in mice compared to Panc1 tumor bearing mice or normal mice3. A significant decrease of brain choline was observed in Pa04C tumor bearing mice compared to control mice as well as Panc1 tumor bearing mice, whereas brain phosphocholine (PC) levels were significantly lower compared to normal mice. Brain glycerophosphocholine (GPC) was significantly lower in both tumor bearing groups compared to normal mice. We observed a significant decrease of plasma choline in Pa04C tumor bearing mice. Plasma choline in Panc1 tumor bearing mice also decreased but not as drastically. The changes in plasma choline levels most likely contributed to the reduction of brain choline, PC and GPC. Reduced plasma choline may represent a risk factor for cancer as choline deficiency is known to result in lymphocyte apoptosis and DNA damage 4 that may compromise the immune response. Normalization of plasma choline using metabolic supplements merits investigation in reducing cancer morbidity and the onset of cachexia. Acknowledgement: This work was supported by NIH R35CA209960 and R01CA193365. References 1. Argiles JM et al., Nature reviews Cancer. 14(11):754-762. 2. Inui A. 2002. CA Cancer J Clin. 52(2):72-91. 3. Winnard PT, Jr., et al., Cancer Res. 76(6):1441-1450. 4. da Costa KA, et al., The American journal of clinical nutrition. 84(1):88-94. Citation Format: Santosh K. Bharti, Paul T. Winnard, Raj Kumar Sharma, Marie-France Penet, Balaji Krishnamachary, Zaver M. Bhujwalla. Brain and plasma choline compounds altered by cancer and cancer-induced cachexia [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 4751.
Abstract B30: The effect of OCP use on the incidence of precancerous p53 lesions in fallopian tube fimbria
Authors: Kendall Greening, Anthony Karnezis, Dawn Cochrane, David Farnell, Lien Hoang, Gillian Hanley, David Huntsman
Journal: Clinical Cancer Research (2020)

Abstract Background: High-grade serous ovarian carcinoma (HGSOC) accounts for &amp;gt;70% of ovarian cancer-related deaths and is the most common ovarian cancer histotype, most originating from precancerous p53 lesions in the fallopian tube (FT) fimbria. Use of oral contraceptive pills (OCPs) for 5 years or more is associated with a &amp;gt;40% reduction in risk of HGSOC, but the mechanism is unknown. We hypothesize that OCP use reduces the incidence of p53 lesions. Our preliminary data show higher incidence of p53 lesions in post- compared to premenopausal women; therefore we aim to quantify p53 lesions in postmenopausal women who previously did or did not use OCPs. This will provide insight into the protective effects of OCPs against HGSOC. Preliminary Results: We determined the presence of p53 lesions by immunohistochemistry (IHC) in FT of women up to 40 years old (n=27) and &amp;gt;60 years old (n=24) who underwent salpingectomies for noncancer reasons. p53 lesions were identified in 3/27 cases of the younger cohort (11%) and in 10/24 of the older cohort (42%). Thus, we conclude an increased incidence of p53 lesions in older compared to younger women. Proposed Design: IHC for p53 will be performed on FT fimbria of women &amp;gt;55 years old who received salpingectomy for noncancer reasons. Based on an assumed reduction in p53 lesions of 35% in women who used OCPs for 5 years or more compared to nonusers (25 vs. 42%), analysis of 190 cases from each group will provide &amp;gt;80% power (p&amp;lt;0.05). Cases will be identified through Population Data BC and blind analysis by p53 IHC will be performed at the Vancouver General Hospital. Data will be flowed back to Pop Data BC to compare to OCP data. Conclusion: Our preliminary study found that 42% of postmenopausal women had p53 lesions, informing this study design. The study registered through this abstract will be the first to examine the impact of OCPs on the earliest known precursors of HGSOC. Citation Format: Kendall Greening, Anthony Karnezis, Dawn Cochrane, David Farnell, Lien Hoang, Gillian Hanley, David Huntsman. The effect of OCP use on the incidence of precancerous p53 lesions in fallopian tube fimbria [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 B30.
A combined microRNA and target protein-based panel for predicting the probability and severity of uraemic vascular calcification: a translational study
Authors: Chia-Ter Chao, Hsiang-Yuan Yeh, You-Tien Tsai, Chih-Kang Chiang, Huei-Wen Chen
Journal: Cardiovascular Research (2020)

Abstract Aims Vascular calcification (VC) increases the future risk of cardiovascular events in uraemic patients, but effective therapies are still unavailable. Accurate identification of those at risk of developing VC using pathogenesis-based biomarkers is of particular interest and may facilitate individualized risk stratification. We aimed to uncover microRNA (miRNA)-target protein-based biomarker panels for evaluating uraemic VC probability and severity. Methods and results We created a three-tiered in vitro VC model and an in vivo uraemic rat model receiving high phosphate diet to mimic uraemic VC. RNAs from the three-tiered in vitro and in vivo uraemic VC models underwent miRNA and mRNA microarray, with results screened for differentially expressed miRNAs and their target genes as biomarkers. Findings were validated in original models and additionally in an ex vivo VC model and human cells, followed by functional assays of identified miRNAs and target proteins, and tests of sera from end-stage renal disease (ESRD) and non-dialysis-dependent chronic kidney disease (CKD) patients without and with VC. Totally 122 down-regulated and 119 up-regulated miRNAs during calcification progression were identified initially; further list narrowing based on miRNA–mRNA pairing, anti-correlation, and functional enrichment left 16 and 14 differentially expressed miRNAs and mRNAs. Levels of four miRNAs (miR-10b-5p, miR-195, miR-125b-2-3p, and miR-378a-3p) were shown to decrease throughout all models tested, while one mRNA (SULF1, a potential target of miR-378a-3p) exhibited the opposite trend concurrently. Among 96 ESRD (70.8% with VC) and 59 CKD patients (61% with VC), serum miR-125b2-3p and miR-378a-3p decreased with greater VC severity, while serum SULF1 levels increased. Adding serum miR-125b-2-3p, miR-378a-3p, and SULF1 into regression models for VC substantially improved performance compared to using clinical variables alone. Conclusion Using a translational approach, we discovered a novel panel of biomarkers for gauging the probability/severity of uraemic VC based on miRNAs/target proteins, which improved the diagnostic accuracy.
Abstract 781: Methylation-based liquid biopsy of meningioma primary and recurrent samples
Authors: Thais S. Sabedot, Tathiane M. Malta, Ruicong She, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, James Ewing, AnaValeria Castro, Houtan Noushmehr
Journal: Cancer Research (2020)

Abstract Meningiomas are mostly benign CNS tumors however, a subset of these tumors may become atypical or malignant. The standard of care to monitor patients after diagnosis requires serial MRI assessments, which have limited value in distinguishing malignant tumors from benign disease. Therefore the discovery of non-invasive methodologies that reflect meningioma tumor burden and its dynamic evolution in real-time is highly desirable. Liquid biopsy (LB) could be used to fine-tune surveillance and treatment with minimal risk to patients. Evidence of circulating tumor cells and cell-free (cf) tumor DNA in the blood has been shown in several tumor types however, limited progress has been made for brain tumors with known biomarkers; possibly due to the unlikelihood of capturing point mutations in circulating DNA fragments. On the other hand, DNA methylation signatures are maintained even in small DNA fragments, which suggests that DNA methylation is an attractive biomarker to be studied in liquid biopsy of brain cancers. In order to identify DNA methylation-based biomarkers using archival serum and tissue specimens, we generated and analyzed the epigenome (Illumina Human EPIC array) of patients with meningioma (including primary (n=6); recurrent (n=8)) and non-meningioma (including non-tumor patients (n=5), pituitary tumor (n=13), colorectal cancer (n=2) and other CNS diseases (n=6), such as inflammatory tissue and radiation necrosis). cfDNA fragment size distribution revealed peaks with 150~200bp on average. By randomly selecting 70% of our cohort as a discovery set, we identified 500 CpGs (FDR&amp;lt;0.05) differentially methylated between meningiomas and non-meningiomas, which show a DNA methylation profile similar to the matched meningioma tissue. Then, we trained a random-forest machine learning using the same signature and applied the model to the remaining 30% samples (validation set) from our cohort. The model was able to correctly classify samples into meningioma and non-meningiomas with a sensitivity of 100% and specificity of 100%. From this pilot data, we were able to investigate the LB methylome of meningioma patients and identify potential markers to detect tumor cells in the serum of these patients, which could eventually allow clinicians to monitor impending disease progression and recurrence. Citation Format: Thais S. Sabedot, Tathiane M. Malta, Ruicong She, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, James Ewing, AnaValeria Castro, Houtan Noushmehr. Methylation-based liquid biopsy of meningioma primary and recurrent samples [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 781.
Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency
Authors: Craig D. Platt, Fatima Zaman, Wayne Bainter, Kelsey Stafstrom, Abuarahman Almutairi, Margot Reigle, Sabrina Weeks, Raif S. Geha, Janet Chou
Journal: Journal of Allergy and Clinical Immunology (2020)
TRPM8-regulated calcium mobilization plays a critical role in synergistic chemosensitization of Borneol on Doxorubicin
Authors: Haoqiang Lai, Chang Liu, Liyuan Hou, Wenwei Lin, Tianfeng Chen, An Hong
Journal: Theranostics (2020)

Lung cancer has a high mortality rate and is resistant to multiple chemotherapeutics. Natural Borneol (NB) is a monoterpenoid compound that facilitates the bioavailability of drugs. In this study, we investigated the effects of NB on chemosensitivity in the A549 human lung adenocarcinoma cell line and to elucidate therapeutic molecular target of NB.
Reproductive factors, hormone use and melanoma risk: an Australian prospective cohort study
Authors: C. M. Olsen, N. Pandeya, J. C. Dusingize, B. S. Thompson, A. C. Green, R. E. Neale, P. M. Webb, D. C. Whiteman
Journal: British Journal of Dermatology (2020)

Despite many epidemiologic studies in the past two decades investigating whether hormonal and reproductive factors increase risk of melanoma, the issue remains unresolved. Findings appear to differ according to study design, with positive findings generally limited to case-control studies, which are prone to selection and recall bias. Given the relative paucity of prospective data on the topic, we aimed to assess the relationship between hormonal and reproductive factors and subsequent risk of melanoma in a large population-based cohort of Australian women.
Abstract 14289: High Flow Oxygen to Improve Cardiac Autonomic Dysfunction During Exercise in Advanced Cancer: A Pilot Study
Authors: Tushar Ramesh, Conrad J Fernandes, Michelle Seymour, Kara Thompson, Juan Lopez-Mattei, David Hui
Journal: Circulation (2019)

Introduction: Supplemental High-flow Oxygen (HFO2) has been observed to increase exercise time (ET) in advanced cancer patients by an unclear mechanism. We propose that HFO2 may increase ET by impr...
Abstract A45: Quinacrine induces necrosis of ovarian high-grade serous carcinoma cells by breaking the mitochondria ROS balance
Authors: Ching-I Huang, Tang-Yuan Chu, Hsuan-Shun Huang
Journal: Clinical Cancer Research (2020)

Abstract Ovarian high-grade serous ovarian carcinoma (HGSC) was found to be initiated and promoted by repeated exposure of fimbrial epithelium to ovulatory ROS with resultant intolerable stress of oxidative damages and DNA repair load. Consequential cell apoptosis is overcome on the one hand by quenching excessive ROS by hemoglobin contributed by retrograde menstruation and on the other by upregulation of antioxidant machinery. A dangerous balance is achieved between the oxidative stress and antioxidation and between DNA damage stress and repair. Breaking of this balance on the stress side such as by DNA chelating agent such as cisplatin or inhibitors targeting on DNA repair enzyme such as PARP leads to therapeutic cell killing. In this report, we show ROS enhancing drug such as quinacrine effectively kill HGSC cells and its tubal precursor cells with p53 and Rb defect. Quinacrine is a traditional antimalarial drug with wide antitumor effect in either a single agent or combined with chemotherapy drugs. We show here that quinacrine has a cytotoxic effect in two HGSC cell lines (KURAMOCHI, OVSAHO) and in an HPV E6/E7-immortalized human fimbrial epithelial cells, which are readily fully transformed by ovulatory follicular fluid. Cytotoxicity was observed dose-dependently at concentrations ranging from 2.5μM to 25μM. Flow cytometry analysis indicated a cell necrosis (PI +, annexin V-) 48hr post-treatment. We further found a significant induction of the mitochondrial ROS upon quinacrine treatment, and ROS inhibitor N-acetyl-l-cysteine considerably reversed this cytotoxic effect. The study proves the concept of breaking the balance of mitochondria-ROS is a feasible strategy for the development of a new drug for ovarian HGSC. Note: This abstract was not presented at the conference. Citation Format: Ching-I Huang, Tang-Yuan Chu, Hsuan-Shun Huang. Quinacrine induces necrosis of ovarian high-grade serous carcinoma cells by breaking the mitochondria ROS balance [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 A45.
A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy
Authors: Shannon K. Oda, Kristin G. Anderson, Pranali Ravikumar, Patrick Bonson, Nicolas M. Garcia, Cody M. Jenkins, Summer Zhuang, Andrew W. Daman, Edison Y. Chiu, Breanna M. Bates, Philip D. Greenberg
Journal: The Journal of Experimental Medicine (2020)

Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor–positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies.
Evaluation of functional pulmonary response to gonadotrophin realeasing hormone agonist (GOSERELIN) in the treatment of lynphangioleiomyomatosis (LAM)
Authors: P. Medeiros Junior, R. I. Lopes, C. N. Chaves, Ronaldo Adib Kairalla, Carlos Roberto Ribeiro de Carvalho
Journal: American Journal of Respiratory and Critical Care Medicine (2002)