tbuckley/cabot-search huggingface dataset:
Abstract 4707: Evaluation of efficacy and immune response to PD1 checkpoint inhibition in human immune-reconstituted mice using patient-derived xenograft models
Authors: Hooman Izadi, Tommy Broudy, Deborah Yan, Jayant Thatte
Journal: Cancer Research (2017)

Abstract Background: Human Immune-reconstituted Mice, generated by transplanting pre-validated human CD34+ hematopoietic stem cells (HSC) into immune-compromised mice, are extremely useful in basic and applied human disease research. Many cancer therapies, including immune checkpoint inhibitors such as the anti-PD-1 monoclonal antibody, rely on an intact immune system to release immunosuppression and destroy cancer cells. Material and methods: We evaluated the effects of anti-PD-1 in humanized mice in donor cohorts utilizing the cancer matrix of 5 HSC donor cohorts of humanized animals with PDX models from 7 small cell lung cancer (SCLC). We also tested anti-PD-1 in 1 triple negative breast cancer (TNBC) model and in 1 MDA-MB-231 study. Results: Here, we show that HSC derived human immune cell engraftment does not have significant effects on patient derived xenograft (PDX) tumor growth. However, humanization is required for anti-tumor response to anti-PD-1. In MDA-MB-231 study, tumors showed complete regression after the first round of treatment. Re-engraftment of same animals with MDA-MB-231 cells showed minor tumor growth before complete regression again. Aged match control naïve animals engrafted with same cells showed normal tumor growth. In SCLC studies anti-PD-1 efficacy varied between the models, which clearly underscores the inherent donor to donor variability in this humanized model system. Tumors from these studies were then analyzed to determine target engagement of anti-PD-1, tumor infiltrating lymphocytes (TILs) characterization and histology comparing anti-PD-1 responders vs non-responders. As expected, in this study, we demonstrate humanization of the animals is necessary to evaluate the efficacy of anti-PD-1 therapy and can elicit an immunotherapy mediated anti-tumor effect. Conclusion: Here we demonstrate the development of humanized mouse studies with ability to run multi point analysis to determine the outcome of treatment. Citation Format: Hooman Izadi, Tommy Broudy, Deborah Yan, Jayant Thatte. Evaluation of efficacy and immune response to PD1 checkpoint inhibition in human immune-reconstituted mice using patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4707. doi:10.1158/1538-7445.AM2017-4707
DETERMINATION OF THE LIFE SPAN OF HUMAN BLOOD PLATELETS USING LABELLED DIISOPROPYLFLUOROPHOSPHONATE
Authors: C. H. W. Leeksma, J. A. Cohen
Journal: Journal of Clinical Investigation (1956)

Recently we have reported a method for the de- termination of platelet survival time using diiso- propylfluorophosphonate (DFP) as the labelling agent (1).The present communication presents full details of this method.Hitherto, no satisfactory method for the deter- mination of platelet survival time has been de- scribed.Most data on this subject have been
Abstract 5258: Benzyl isothiocyanate prevents breast cancer-induced bone erosion <i>in vivo</i>
Authors: Subrata K. Pore, Shivendra V. Singh
Journal: Cancer Research (2017)

Abstract Bone is one of the metastatic sites for advanced breast cancer. Nearly 70% of breast cancer patients experience metastasis to bone due to enhanced osteoclastogenesis and formation of osteoclasts leading to bone resorption. We have shown previously that benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables such as garden cress, is a potent inhibitor of breast cancer cells in vitro and in vivo. The present study was designed to determine the effect of BITC on breast cancer-induced osteoclastogenesis. Co-culture of murine RAW 264.7 macrophages with human breast cancer cells resulted in genesis of osteoclasts in vitro that was suppressed significantly in the presence of BITC. Runx2, a transcription factor, is abnormally expressed in breast cancer and contributes to osteoclastogenesis by regulating receptor activator of NF-κB ligand (RANKL). BITC treatment downregulated expression of Runx2 in breast cancer cells at the mRNA and protein levels. Osteoclastogenesis was increased in Runx2 overexpressing MDA-MB-231 cells, whereas conditional knockdown of Runx2 in T47D cells attenuated this process. To determine the in vivo efficacy of BITC, MDA-MB-231-Luc cells were injected into the left ventricle of nude mice. BITC was administrated orally at 10 mg per kg body weight. Micro-CT X-ray analysis showed that bone metastases and erosion was decreased by about 50% upon BITC treatment when compared with vehicle control. Cathepsin K and total RANKL levels were lower in the plasma of BITC-treated mice when compared to the control group. Altogether, this study demonstrates, for the first time, that BITC is a potent inhibitor of breast cancer-induced osteoclastogenesis in vivo. This study was supported by the grant RO1 CA129347-09 awarded by the national Cancer Institute. Citation Format: Subrata K. Pore, Shivendra V. Singh. Benzyl isothiocyanate prevents breast cancer-induced bone erosion in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5258. doi:10.1158/1538-7445.AM2017-5258
Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis
Authors: Chengping Wen, Zhijun Zheng, Tiejuan Shao, Lin Liu, Zhijun Xie, Emmanuelle Le Chatelier, Zhixing He, Wendi Zhong, Yongsheng Fan, Linshuang Zhang, Haichang Li, Chunyan Wu, Changfeng Hu, Qian Xu, Jia Zhou, Shunfeng Cai, Dawei Wang, Yun Huang, Maxime Breban, Nan Qin, Stanislav Dusko Ehrlich
Journal: Genome biology (2017)

The assessment and characterization of the gut microbiome has become a focus of research in the area of human autoimmune diseases. Ankylosing spondylitis is an inflammatory autoimmune disease and evidence showed that ankylosing spondylitis may be a microbiome-driven disease. To investigate the relationship between the gut microbiome and ankylosing spondylitis, a quantitative metagenomics study based on deep shotgun sequencing was performed, using gut microbial DNA from 211 Chinese individuals. A total of 23,709 genes and 12 metagenomic species were shown to be differentially abundant between ankylosing spondylitis patients and healthy controls. Patients were characterized by a form of gut microbial dysbiosis that is more prominent than previously reported cases with inflammatory bowel disease. Specifically, the ankylosing spondylitis patients demonstrated increases in the abundance of Prevotella melaninogenica, Prevotella copri, and Prevotella sp. C561 and decreases in Bacteroides spp. It is noteworthy that the Bifidobacterium genus, which is commonly used in probiotics, accumulated in the ankylosing spondylitis patients. Diagnostic algorithms were established using a subset of these gut microbial biomarkers. Alterations of the gut microbiome are associated with development of ankylosing spondylitis. Our data suggest biomarkers identified in this study might participate in the pathogenesis or development process of ankylosing spondylitis, providing new leads for the development of new diagnostic tools and potential treatments.
Abstract 5850: Salicylate sensitizes prostate cancer (PrCa) to radiotherapy; activation of AMPK and suppression of lipogenesis
Authors: Theodoros Tsakiridis, Katarina Marcinko, Linsday Broadfield, Linda Villani, Carrie Gerdes, Danitra Maharaj, Tom Farell, James Wright, Gregory Steinberg
Journal: Cancer Research (2017)

Abstract Radiotherapy (RT) is a key therapeutic modality for PrCa that achieves reasonable disease control rates in localized disease. However, this requires dose-escalated RT, which is associated with increased toxicity to surrounding tissues and leads to deterioration of patient quality of life. Improving the therapeutic ratio in PrCa RT is of high clinical importance. Aspirin has an established role in cancer prevention and studies suggested association with improved PrCa outcomes. It was shown that its metabolite salicylate (SAL) binds directly and activates the metabolic stress sensor AMP-activated kinase (AMPK). This is likely achieved through direct binding to the AMPK β1 subunit, leading to enhanced AMPK activity through suppression of AMPK α-subunit T172 de-phosphorylation. In this study we examined the ability of SAL to sensitize PrCa to RT. Hormone insensitive (PC3) and sensitive (LnCap) human PrCa cells, as well as PC3 xenografts grown in immunocompromised nude mice were subjected to SAL and RT treatments. SAL mediated a dose-dependent inhibition of proliferation and clonogenic survival in both PrCa cell lines and suppressed de novo lipogenesis (DNL). This was detected at μM concentrations of the drug, which can be safely achieved in human circulation. SAL (100-500 μM) radio-sensitized PC3 and LnCap cells, and enhanced the ability of SAL to inhibit DNL. In animals treated with conformal RT (10Gy) to the tumor xenografts, Salsalate feeding (chow diet containing 2.5gr/kg) enhanced the cytotoxicity of RT detected as reduced tumor growth kinetics and weight and volume at sacrifice. Salicylate treatment of cells or salsalate feeding of mice led to increased AMPK activity in cells and tumors, inhibitory phosphorylation of Acetyl-CoA Carboxylase and reduction of AktThr308 phosphorylation. These results indicate that SAL could improve radiation response in PrCa through a mechanism involving the suppression of DNL. This is achieved at clinically attainable doses of SAL. This work supports prospective investigation of SAL as a radio-sensitizer in early phase clinical trials of localized PrCa. Note: This abstract was not presented at the meeting. Citation Format: Theodoros Tsakiridis, Katarina Marcinko, Linsday Broadfield, Linda Villani, Carrie Gerdes, Danitra Maharaj, Tom Farell, James Wright, Gregory Steinberg. Salicylate sensitizes prostate cancer (PrCa) to radiotherapy; activation of AMPK and suppression of lipogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5850. doi:10.1158/1538-7445.AM2017-5850
Abstract 3114: The role of prostaglandin signaling in human glioblastoma cell activities and growth in vitro and in vivo
Authors: Jiange Qiu, Yifeng Du, Qianqian Li, Zhi Shi, Jianxiong Jiang
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) constitutes the most frequent and aggressive form of malignant brain primary tumors. Despite current combined treatment involving surgery, chemotherapy and radiation therapy, the median survival of GBM patients is only about one year, with less than 3-5% of patients surviving over 5 years. Cyclooxygenase-2 (COX-2) is overexpressed in glioblastoma, and its expression level is highly positively correlated with the tumor grade. As a major enzymatic product of COX-2, prostaglandin E2 (PGE2) mediates inflammatory processes within the brain and facilitates progression of many chronic inflammation-associated neurological diseases via its four downstream receptors - EP1-EP4. We hypothesize that selectively targeting these receptors might provide an alternative therapeutic strategy for GBM with more specificity than generic blockade of the entire COX-2 cascade. In this study, two engineered human GBM cells with or without activated COX-2 were used to explore the PGE2 signaling involved in the development and progression of GBM. COX-2 activation by LPS or its overexpression facilitated migration, invasion, and transformation of these GBM cells in vitro. Moreover, the COX-2-mediated GBM cell activities were substantially suppressed by selective antagonists of PGE2 receptors that are highly expressed in these cells. Furthermore, the tested PGE2 receptor selective antagonists also suppressed the growth of GBM cells in vivo. In sum, our results suggested the inflammatory PGE2 signaling is involved in human GBM cell inflammation, migration, invasion and transformation through its downstream receptors, and should be explored as alternative molecular targets for novel GBM therapies. Citation Format: Jiange Qiu, Yifeng Du, Qianqian Li, Zhi Shi, Jianxiong Jiang. The role of prostaglandin signaling in human glioblastoma cell activities and growth in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3114. doi:10.1158/1538-7445.AM2017-3114
Abstract 2983: Tumor induced stromal STAT1 deregulates mammary tissue homeostasis and accelerates breast cancer
Authors: Victoria R. Zellmer, Patricia M. Schnepp, Sarah L. Fracci, Xuejuan Tan, Erin N. Howe, Siyuan Zhang
Journal: Cancer Research (2017)

Abstract The tumor microenvironment (TME) – the dynamic tissue space in which the tumor exists – plays a significant role in tumor initiation and is a key contributor in cancer progression. Little is known about the tumor-induced changes in the adjacent tissue stroma. Herein, we sought to explore tumor-induced changes in the TME at the morphological and molecular level to further characterize cancer progression. We show that tumor-adjacent mammary glands (TAGs) display altered branch morphology, increased expression of αSMA particularly in myofibroblasts, and an increased capacity to form mammospheres in 2D suspension culture. FACS analysis showed that TAGs contain an increased number of Lin-CD24+/CD49+ enriched mammary gland stem cell (MaSCs) population, suggesting deregulated tissue homeostasis in TAGs. We conducted comparative transcriptomics on TAGs and contralateral control glands. Meta-analysis on differentially expressed genes from our RNA-seq dataset plus two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1, which we verified in tumor-adjacent tissues. Knockdown of STAT1 in caveolin-deficient mouse embryonic fibroblasts (CAFs) cocultured with human breast cancer cells altered cancer cell proliferation, further suggesting the role of STAT1 as a stromal contributor of tumorigenesis. Furthermore, in our proof-of-concept in vivo experiment, co-treatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Our results demonstrate that stromal STAT1 expression could promote tumor progression and is a potential therapeutic target for breast cancer. Citation Format: Victoria R. Zellmer, Patricia M. Schnepp, Sarah L. Fracci, Xuejuan Tan, Erin N. Howe, Siyuan Zhang. Tumor induced stromal STAT1 deregulates mammary tissue homeostasis and accelerates breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2983. doi:10.1158/1538-7445.AM2017-2983
Abstract 5329: Glycyl-tRNA Synthetase is a novel target for cancer therapeutics
Authors: Zhongying Mo, Ze Liu, Xiang-Lei Yang
Journal: Cancer Research (2017)

Abstract Neddylation, an ubiquitination-like, post-translational modification that controls cell cycle and proliferation, is strongly associated with cancer. Interestingly, we recently identified that glycyl-tRNA synthetase (GlyRS) as a critical chaperone for neddylation1. GlyRS is also an essential enzyme for protein synthesis, which is required for tumor growth. Therefore, the dual functional GlyRS may be a novel target for anti-cancer therapy. Consistent with this idea, we found strong positive correlation between the level of GlyRS and tumor progression in breast cancer. A proof-of-concept inhibitor of GlyRS for aminoacylation was able to suppress neddylation in breast cancer cells, and reduce their lung metastasis in a mouse model. Taken together, we propose that GlyRS is a novel and promising target for cancer treatment. Reference:1. ZY Mo, Q Zhang, J Laurer, Z Liu, LT Sun, Y Shi, P Griffin, XL Yang. Nature Structural and Molecular biology. 2016 Jun 27. doi: 10.1038/nsmb.3250. Citation Format: Zhongying Mo, Ze Liu, Xiang-Lei Yang. Glycyl-tRNA Synthetase is a novel target for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5329. doi:10.1158/1538-7445.AM2017-5329
Author Correction: Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours
Authors: Suping Li, Yinlong Zhang, Jing Wang, Ying Zhao, Tianjiao Ji, Xiao Zhao, Yanping Ding, Xiaozheng Zhao, Ruifang Zhao, Feng Li, Xiao Yang, Shaoli Liu, Zhaofei Liu, Jianhao Lai, Andrew K. Whittaker, Gregory J. Anderson, Jingyan Wei, Guangjun Nie
Journal: Nature Biomedical Engineering (2017)
Does This Child Have Pneumonia?
Authors: Sonal N. Shah, Richard G. Bachur, David L. Simel, Mark I. Neuman
Journal: JAMA (2017)

<h3>Importance</h3> Pneumonia is a leading cause of morbidity and mortality in children. It is important to identify the clinical symptoms and physical examination findings associated with pneumonia to improve timely diagnosis, prevent significant morbidity, and limit antibiotic overuse. <h3>Objective</h3> To systematically review the accuracy of symptoms and physical examination findings in identifying children with radiographic pneumonia. <h3>Data Sources and Study Selection</h3> MEDLINE and Embase (1956 to May 2017) were searched, along with reference lists from retrieved articles, to identify diagnostic studies of pediatric pneumonia across a broad age range that had to include children younger than age 5 years (although some studies enrolled children up to age 19 years); 3644 unique articles were identified, of which 23 met inclusion criteria. <h3>Data Extraction and Synthesis</h3> Two authors independently abstracted raw data and assessed methodological quality. A third author resolved disputes. <h3>Main Outcomes and Measures</h3> Likelihood ratios (LRs), sensitivity, and specificity were calculated for individual symptoms and physical examination findings for the diagnosis of pneumonia. An infiltrate on chest radiograph was considered the reference standard for the diagnosis of pneumonia. <h3>Results</h3> Twenty-three prospective cohort studies of children (N = 13 833) with possible pneumonia were included (8 from North America), with a range of 78 to 2829 patients per study. The prevalence of radiographic pneumonia in North American studies was 19% (95% CI, 11%-31%) and 37% (95% CI, 26%-50%) outside of North America. No single symptom was strongly associated with pneumonia; however, the presence of chest pain in 2 studies that included adolescents was associated with pneumonia (LR, 1.5-5.5; sensitivity, 8%-14%; specificity, 94%-97%). Vital sign abnormalities such as fever (temperature &gt;37.5°C [LR range, 1.7-1.8]; sensitivity, 80%-92%; specificity, 47%-54%) and tachypnea (respiratory rate &gt;40 breaths/min; LR, 1.5 [95% CI, 1.3-1.7]; sensitivity, 79%; specificity, 51%) were not strongly associated with pneumonia diagnosis. Similarly, auscultatory findings were not associated with pneumonia diagnosis. The presence of moderate hypoxemia (oxygen saturation ≤96%; LR, 2.8 [95% CI, 2.1-3.6]; sensitivity, 64%; specificity, 77%) and increased work of breathing (grunting, flaring, and retractions; positive LR, 2.1 [95% CI, 1.6-2.7]) were signs most associated with pneumonia. The presence of normal oxygenation (oxygen saturation &gt;96%) decreased the likelihood of pneumonia (LR, 0.47 [95% CI, 0.32-0.67]). <h3>Conclusions and Relevance</h3> Although no single finding reliably differentiates pneumonia from other causes of childhood respiratory illness, hypoxia and increased work of breathing are more important than tachypnea and auscultatory findings.
Abstract 4999: Stress, spiritual wellbeing and cancer risk among diverse racial faith-based communities: Elevated levels of stress proteomic biomarkers in breast cancer patients
Authors: Padma P. Tadi Uppala, Gretchen Krivak, Sherine Brown-Fraser, Dixon Anjejo, Alfredo Mejia, Dominique wakefield, Kumar Kolli
Journal: Cancer Research (2017)

Abstract Spiritual wellbeing is associated with decreased risk for cancer. Stress and depression are common among cancer patients and may be inversely associated with spiritual wellbeing. The purpose of the study is to examine if stress and depression as indicators of cancer risk are lower in a racially diverse faith-based community. Methods: 752 individuals from a faith-based community completed a behavioral assessment survey that mapped the current patterns of behavior in key categories that include: stress, depression, exercise and nutrition using the E-wellness platform FitThumb. To identify stress biomarkers in cancer patients we examined levels of stress serum proteomic biomarkers that were previously identified in our study by proteomic profiling using 2D-DIGEMS analysis and a subset of samples by shotgun LCMS technology. The serum proteomic study included serum samples from 15 African American breast cancer patients and 12 healthy controls who were from a faith-based community. Results: The behavioral assessment surveys that included 752 individuals who were racially diverse showed a low stress risk of 47.74% vs 8.24 % of high stress risk for chronic disease; and low depression risk of 85.11% vs 1.99% high risk for chronic disease. Elevated levels of stress and inflammatory serum proteomic biomarkers such as ceruloplasmin known to increase in stressed animals and humans; heptaglobin, apolipoproteins, and heat shock proteins were significantly elevated in breast cancer patients compared to healthy controls. Conclusions: Our results indicate that spiritual well-being is associated with significantly low stress and depression in a faith-based community regardless of race or ethnicity, posing a low risk for cancer as shown in previous Adventist Health Cohort studies. Future efforts will focus on validating and identifying panel of biomarkers from this cohort to gain insight into their role(s) in the mechanisms of stress hormones and cancer risk. Funded by Susan G Komen for the cure. Citation Format: Padma P. Tadi Uppala, Gretchen Krivak, Sherine Brown-Fraser, Dixon Anjejo, Alfredo Mejia, Dominique wakefield, Kumar Kolli. Stress, spiritual wellbeing and cancer risk among diverse racial faith-based communities: Elevated levels of stress proteomic biomarkers in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4999. doi:10.1158/1538-7445.AM2017-4999