tbuckley/cabot-search huggingface dataset:
Abstract 773: Analysis of oncogene affected networks in tumorigenesis of lung cancer
Authors: Adwait Sathe, Yong Chen, Hyuntae Yoo, Michael Q. Zhang
Journal: Cancer Research (2016)

Abstract Genetic abnormality is one of major causes of tumorigenesis by driving the progressive transformation of normal human cells into highly malignant derivatives. Tracing the downstream pathways through which and how the effects of the oncogenic-activating mutations are transmitted is an important and challenging problem in studying disease mechanisms, diagnoses and treatments. In this study, we designed a network-based computational method, called MAXMAP, to not only predict mutation downstream affected pathways, but also quantitatively measure the dynamics of the pathway genes. We first constructed a heterogeneous network by integrating protein-protein interaction networks and signaling and regulatory networks from available up-to-date curated databases, as well as RNASeq expression data. The RNAseq dataset of these mutated cell lines has 18,096 genes whereas the Protein Protein Interaction and Signalling, regulation dataset has 14,864 genes. We then used the maximal information flow method to globally optimize the effects from the mutations to target downstream genes. The method was applied to analyze the biological network dynamics that is caused by single (TP53), double (TP53+KRAS) and triple (TP53+KRAS+STK11) mutations of HBEC30KT, an immortalized lung cell line, and revealed the core dynamical subnetworks of these mutations. Only the triple mutant is known to have tumor-like properties and as shown in earlier studies these sequential mutation accumulations lead to tumorigenesis in mouse xenograft models. The experimental validation of a small subnetwork was performed using transient knock down of the pathway genes and expression was verified using qPCR. We showed the dynamical subnetworks through which a gene, SLC7A5 was affected by sequential single, double or triple mutations. We have experimentally validated the predicted small subnetwork for SLC7A5 which is an important transporter of neutral amino acids. It is associated with bladder and bile duct adeno carcinomas and overexpressed in lung cancers. We selected the subnetwork affected due to the single mutation (TP53) for validation, including THBS1, TNFRSF11B and MAPK1 and SLC7A5. Hence, using the MAXMAP method we have successfully identified a dynamical subnetwork affected by changes in the known network of genes. These results suggest that this computational method may allow us to predict drug targets or biomarkers or to study interesting alternative paths and predict the most likely path leading to certain phenotypic outcomes. Citation Format: Adwait Sathe, Yong Chen, Hyuntae Yoo, Michael Q. Zhang. Analysis of oncogene affected networks in tumorigenesis of lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 773.
Abstract 938: Activation of ATR/CHK1 checkpoint is critical for mediating p53-dependent autophagy and pro-inflammatory VEGF production in human bronchial epithelial cells under fine particulate matters (PM2.5) exposure
Authors: Lun Song
Journal: Cancer Research (2016)

Abstract The epidemiological and clinical studies have increasingly shown that fine particulate matters (PM2.5) exposure is associated with exacerbation of airway inflammation, which might results in the occurrence of lung cancer. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is a crucial issue for the study of PM2.5 toxicity. In the current study, we found that exposure of human bronchial epithelial cells (Beas-2B) to the winter PM2.5 collected in Wuhan, the south city of China, induced an significant up-regulation of VEGF production, a typical signaling event functionally in controlling chronic airway inflammation and vascular remodeling. Further investigations showed that autophagy was induced upon PM2.5 exposure and then mediated VEGF up-regulation by activating Src/STAT3 pathway in the Beas-2B cells. When exploring the upstream signaling events responsible for autophagy induction, we disclosed the requirement of p53 activation and its downstream target DRAM expression for the induction of autophagy, which results thus have extended the role of p53/DRAM-dependent autophagy beyond cell fate determination under genotoxic stresses and to the control of pro-inflammatory cytokine production. Moreover, PM2.5 exposure strongly induced activation of ATR/CHK1 axis, which subsequently triggered p53-dependent autophagy and VEGF production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genome integrity and the airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure. Citation Format: Lun Song. Activation of ATR/CHK1 checkpoint is critical for mediating p53-dependent autophagy and pro-inflammatory VEGF production in human bronchial epithelial cells under fine particulate matters (PM2.5) exposure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 938.
Abstract 4615: eIF4B is a key effector of oncogenic Pim and PI3K/Akt/mTOR signaling pathways during Abl-mediated cellular transformation
Authors: Ke Chen, Jianning Li, Jilong Chen
Journal: Cancer Research (2016)

Abstract Abl oncoproteins, including v-Abl, Bcr-Abl and Tel-Abl, are activated non-receptor tyrosine kinases that are associated with various malignant transformations of hematopoietic cells. Expression of Abl kinase constitutively activates multiple signaling pathways that are critically involved in the regulation of cell proliferation and survival. Despite extensive studies, the precise mechanism by which these Abl oncoproteins induce hematopoietic malignances is not fully elucidated. eIF4B plays a critical role in Abl-mediated cellular transformation, but the precise mechanisms are largely unknown. Here we show that eIF4B is a convergent substrate of JAK/STAT/Pim and PI3K/Akt/mTOR pathways in Abl transformants. Both pathways regulated the phosphorylation of eIF4B in Abl-transformed cells, and such redundant regulation was responsible for the limited effect of single inhibitor on Abl oncogenicity. Surprisingly, persistent inhibition of one signaling pathway induced the activation of the other pathway and thereby restored the phosphorylation levels of eIF4B. Simultaneous inhibition of the two pathways impaired eIF4B phosphorylation more effectively, and synergistically induced apoptosis in Abl transformed cells and inhibited the growth of engrafted tumors in nude mice. Similarly, the survival of Abl transformants exhibited a higher sensitivity to the pharmacological inhibition, when combined with the shRNA-based silence of the other pathway. Interestingly, such synergy was dependent on the phosphorylation status of eIF4B on Ser422, as overexpression of eIF4B phosphomimetic mutant S422E in the transformants greatly attenuated the synergistic effects of these inhibitors on Abl oncogenicity. In contrast, eIF4B knockdown sensitized Abl transformants to undergo apoptosis induced by the combined blockage. Collectively, the results indicate that eIF4B integrates the signals from Pim and PI3K/Akt/mTOR pathways in Abl-expressing leukemic cells, and is a promising therapeutic target for such cancers. Citation Format: Ke Chen, Jianning Li, Jilong Chen. eIF4B is a key effector of oncogenic Pim and PI3K/Akt/mTOR signaling pathways during Abl-mediated cellular transformation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4615.
Abstract 1700: Novel microfluidic blood-brain niche to study breast cancer metastasis to the brain
Authors: Megan Altemus, Brendan Leung, Aki Morikawa, Michele Dziubinski, Maria Castro, Sofia Merajver
Journal: Cancer Research (2016)

Abstract Metastasis from the primary tumor site to the brain is the most lethal complication of advanced cancer. Once a patient has developed brain metastasis, treatment involves surgical resection or radiation and is often only palliative. Poor prognosis following these therapies as well as the presence of concurrent disease outside of the nervous system emphasize the need for new systemic therapies that can reach and are active within the brain. In order to study the process of brain metastasis and develop potential therapies, models that mimic the human blood-brain niche must be used. Models currently utilized are murine in vivo models and various in vitro methods that do not accommodate all the biophysical characteristics of a blood-brain barrier. In vivo murine models are costly, time intensive, very slow to manifest metastases, and the metastatic process is seldom amenable to monitoring in real time. Current in vitro models are faster and more cost effective; however the models currently used do not have the same micro-environment complexity as “live” models. Here we describe a novel microfluidic device that accurately mimics the physical and cellular components of the human blood-brain niche to study the brain metastatic process. This device is composed of two chambers separated by a porous membrane. The top chamber and apical side of the membrane is seeded with human brain endothelial cells with and uses flow to mimic shear stress encountered within the vasculature. Cancer cells are introduced into this chamber in which they adhere to and migrate through the endothelium into the bottom chamber. The bottom chamber contains astrocytes suspended in a collagen gel to mimic the brain stroma and provide room for invading cancer cells to colonize and grow. Barrier integrity is monitored using TEER (trans-endothelial electrical resistance), and fluctuates as the tight junctions of the endothelium are compromised by invading cancer cells. Throughout all time points, from introduction into the flow chamber, adherence to the endothelium, extravasation through the barrier, migration into the stroma, and proliferation the cancer cells can be monitored via microscopy or TEER. This device provides a powerful novel tool to study the brain metastatic process and can be used to determine differences in brain metastatic potential of various cell lines or patient derived material, study the molecular mechanisms that promote brain metastasis, and test potential new therapies. Citation Format: Megan Altemus, Brendan Leung, Aki Morikawa, Michele Dziubinski, Maria Castro, Sofia Merajver. Novel microfluidic blood-brain niche to study breast cancer metastasis to the brain. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1700.
Abstract 4525: Distinctive chromatin organization of p53 binding sites in normal and cancer cells
Authors: Feng Cui, Peter LoVerso, Feifei Bao
Journal: Cancer Research (2016)

Abstract The tumor suppressor p53 is arguably one of best known proteins in humans, which induces or represses hundreds of genes to prevent tumor development. Now, it becomes clear where p53 binds across the human genome and how it regulates gene expression. Recent studies have established that p53 can access its target sites on the nucleosomal DNA and the rotational positioning of a nucleosome is critical to determine the accessibility of p53 sites. We have found that p53 response elements (REs) associate with cell cycle arrest such as p21 REs are likely to be exposed on the nuclesomal surface. However, it remains unclear if other chromatin elements such as histone modifications and DNA methylation affect p53 in vivo binding and if such chromatin organization differs in normal cells versus cancer cells. We analyzed the pre-existing chromatin landscape of thousands of p53 binding sites identified so far in normal (GM12878) and cancer (K562) cells. The p53 sites derived from the normal cells are often found in the vicinity of the transcription start sites (TSSs) of nearby genes, characterized with relative low nucleosome occupancy, high levels of transcriptionally active histone marks such as H3K4me3 and low levels of DNA methylation. By contrast, the p53 sites found in the cancer cells are located remotely from TSSs, with relatively high nucleosome occupancy, low levels of H3K4me3 and DNA methylation. The shift in p53 genomic binding patterns in the normal and cancer cells reflects the cancer-associated epigenetic dysregulation. Overall, in contrast to most of DNA-binding transcriptional factors, p53 binding sites occur in nucleosome-enriched regions. These findings indicate that p53 belong to a set of transcription factors including the pluripotency factors Oct4, Sox2 and Klf4 that can directly interact with nucleosomes in the context of chromatin. Citation Format: Feng Cui, Peter LoVerso, Feifei Bao. Distinctive chromatin organization of p53 binding sites in normal and cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4525.
The parental brain: A neural framework for study of teaching in humans and other animals
Authors: Hesun Erin Kim, Adrianna Torres-Garcia, James E. Swain
Journal: Behavioral and Brain Sciences (2015)

Parenting, conceptualized as a specific form of teaching, may inform mentalistic, culture-based, and functional definitions. Combined brain-imaging, hormone-measurement, and cognitive-behavioral analyses indicate the importance of mentalization circuits. These circuits appear to function according to culture, and cross animal species. Further, these approaches shed light on sex differences through work on fathers as well as mothers, are affected by psychopathology, and may be amenable to treatment in ways that may be applied to optimize teaching.
Abstract LB-266: Large oncosomes reprogram prostate fibroblasts toward a pro-angiogenic phenotype
Authors: Valentina Minciacchi, Cristiana Spinelli, Mariana Reis-Sobreiro, Mandana Zandian, Rosalyn M. Adam, Edwin M. Posadas, Freeman R. Michael, Emanuele Cocucci, Neil Bhowmick, Dolores Di Vizio
Journal: Cancer Research (2016)

Abstract Introduction: Cancer cells communicate with different cells in the tumor microenvironment, establishing a supportive stroma that sustains tumor development and facilitates the first steps of metastasis. Extracellular vesicles (EVs) have emerged as key functional mediators of this process. Aim of this study was to determine the mechanism of intercellular communication mediated by the atypically large EVs produced by highly migratory and metastatic tumor cells, referred to as large oncosomes (LO), and prostate fibroblasts (NAF). Methods: Filtration, differential centrifugation followed by iodixanol gradient; flow cytometry and confocal imaging; RNA-seq; kinase assay; TF array; luciferase assay; tube formation; siRNA; RT-qPCR. Results: Active AKT1 is significantly more expressed and functional in LO than in exosomes (Exo). Patients with metastatic disease express abundant active AKT1 in plasma LO. Uptake of LO harboring active AKT1 by NAF results in AKT1 and c-MYC activation. Conditioned media from LO-treated NAF, but not from Exo-treated NAF, promoted endothelial morphogenesis. The Dynamin (DNM) inhibitor Dynasore (Dyn) inhibited LO-uptake, as well as MYC activation and tube formation. Transient silencing of DNM2 significantly reduced LO uptake, suggesting that uptake occurs by phagocytosis. LO treatment increased levels of MYC targets in NAF, suggesting that MYC is involved in LO-induced reprogramming of NAF. Accordingly, MYC expression was higher in activated fibroblasts than NAF, and MYC overexpression in NAF induced hyperplasia in normal prostate epithelium in mice, suggesting MYC activation is an early event in cancer development. Summary/Conclusion: Our results indicate that tumor-derived LO induce a novel, c-MYC mediated, pro-tumorigenic reprogramming of fibroblasts that can be reverted by selectively inhibiting LO uptake. Support: National Institutes of Health NCI NIH R00 CA131472; NIH UCLA SPORE in Prostate Cancer award P50 CA092131; Avon Foundation Fund 02-2013-043 (to DDV). Citation Format: Valentina Minciacchi, Cristiana Spinelli, Mariana Reis-Sobreiro, Mandana Zandian, Rosalyn M. Adam, Edwin M. Posadas, Freeman R. Michael, Emanuele Cocucci, Neil Bhowmick, Dolores Di Vizio. Large oncosomes reprogram prostate fibroblasts toward a pro-angiogenic phenotype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-266.
Abstract 1927: Myc-induced suppression of the RNA-binding protein ZAR2 in breast cancer cells
Authors: Smita Misra, Gautam Chaudhuri
Journal: Cancer Research (2016)

Abstract Our objective is to verify the hypothesis that c-Myc-regulated oncomiR miR-130a-5p suppresses the level of the RNA-binding tumor suppressor protein ZAR2 in the cMyc-high aggressive breast cancer cells. We experimentally validated the binding of miR130a-5p miRISC to ZAR2 mRNA in vivo and inhibition of the translation of this mRNA by this binding. We used three commercially available c-Myc-high ZAR2-low breast cancer cell lines BT549, MDA-MB-453 and MDA-MB-231 and two c-Myc-low ZAR2-high breast cancer cells MCF7 and HCC38 for our studies. We cloned the full length 3′-UTR (179 bp) of human ZAR2 mRNA immediately downstream of the firefly luciferase open reading frame sequence contained in the reporter plasmid. We also have created different mutants of the 3’-UTR, each having mutation in each of the putative miR130a-5p binding sites. We transiently transfected the recombinant plasmid and miR130a-5p miRNA mimic into breast cancer cells and assessed luciferase activity or fluorescence 24-48 hours after transfection. We also have transfected just the reporter construct into breast cancer cells which express the endogenous miR130a-5p miRNAs, along with vectors which express mutant versions of the miRNA binding sites. In this experimental system the wild-type reporters had less activity than their respective mutants. To evaluate the functional importance of miR130a-5p miRNA/ZAR2 mRNA pair, we transiently over-expressed a miR130a-5p miRNA mimic in the cMyc-low breast cancer breast cancer cells and subsequently analyzed the level of ZAR2 protein levels. Our data showed that ZAR2 protein levels are decreased by the mimic increasing the in vitro invasiveness of these cells. Our results thus reveal a novel mechanism for the induction of aggressiveness by cMyc in the breast cancer cells. This research is supported in part by DOD-CDMRP IDEA Expansion Grant# BC103645 and NIH/NCI grant 1R21CA181920-01 to GC and NIH grant 1U54RR026140 TO SM Citation Format: Smita Misra, Gautam Chaudhuri. Myc-induced suppression of the RNA-binding protein ZAR2 in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1927.
Quantitative image analysis of PD-L1, CD8, CD3, CD68 and FoxP3 protein expression in lung and bladder cancer specimens by fully automated multiplex fluorescence immunohistochemistry.
Authors: Wenjun Zhang, Mehrnoush Khojasteh, Nick Cummins, Antony Hubbard, John Hurley, Liping Zhang, Ehab Elgabry, Joerg Bredno, Dustin Harshman, William Day, Marcin Kowanetz, Sanjeev Mariathasan, Dustin Smith, J. Andrew Williams, Lidija Pestic-Dragovich, Larry E. Morrison, Lei Tang
Journal: Journal of Clinical Oncology (2016)

11590 Background: Expression of PD-L1 in tumor cells (TC) and infiltrating immune cells (IC) allows TCs to escape from host’s antitumor immunity by inducing tolerance among tumor-specific T cells. Treatment with the anti-PD-L1 agent atezolizumab has been shown to result in significantly improved outcomes in patients with advanced urothelial bladder cancer (UBC) and non-small cell lung cancer (NSCLC). Higher levels of PD-L1-expression have been associated with a greater efficacy. An ideal assessment of TCs and ICs in patients with anti-PD-L1 treatment requires simultaneous immunohistochemistry (IHC) detection of multiple biomarkers. Methods: A fully automated 5-Plex fluorescence IHC assay was developed on the BenchMark ULTRA automated slide stainer using rabbit monoclonal antibodies PD-L1 (SP142), CD3, CD8, CD68 and FoxP3 by tyramide signal amplification. The stained slides were scanned with Zeiss AXIO Z1, and analyzed with in-house digital image analysis tools. Results: A cohort of archived NSCLC and UBC specimens were evaluated for PD-L1 positive staining in tumor areas or on tumor infiltrating immune cells. The workflow consisted of spectral unmixing to determine marker colocalization, and followed by detection of individual cells within the tumor region and classifying them into tumor or one of the immune phenotypes through a supervised machine learning algorithm trained on expert-provided examples. The spatial relationship of immune and PD-L1-positive tumor cells was quantitatively explained using descriptive statistics of the distances of immune cells to the closest PD-L1 positive tumor and PD-L1 positive immune cells, and density of different immune cell phenotypes within the tumor and peri-tumoral regions. Hot and cold spots of immune cell makeup were also identified in the heat maps of immune cells within the tumor region. Conclusions: The fully automated 5-Plex IHC assay together with its respective digital analysis could serve as a tool for further characterizing tumors and their microenvironment and provide a better understanding of which patients may benefit from immune-therapies.
Imaging of Hepatic Ectopic Pregnancy by 18F-FDG PET/CT
Authors: Jingwen Hao, Zhen Cheng, Na Hu, Lizhi Xiao, Yunhua Wang
Journal: Clinical Nuclear Medicine (2016)

Hepatic ectopic pregnancy is an uncommon form of extrauterine pregnancy. A 31-year-old woman had acute abdominal pain and distention. Laboratory examination showed significantly increased serum β-human chorionic gonadotropin level. Both ultrasound and MRI identified a lesion located at the right lobe of the liver. FDG PET/CT was performed to determine whether the other causes of elevated β-human chorionic gonadotropin level, which showed an oval mass with mid peripherally increased FDG activity. After surgery, pathological results confirmed a diagnosis of hepatic ectopic pregnancy.
Implementation of an Infection Prevention Bundle to Reduce Surgical Site Infections and Cost Following Spine Surgery
Authors: Joseph Featherall, Jacob A. Miller, E. Emily Bennett, Daniel Lubelski, Hannah Wang, Tagreed Khalaf, Ajit A. Krishnaney
Journal: JAMA Surgery (2016)

This study compares surgical site infections and costs of care for patients undergoing spinal surgery before and after implementation of an infection prevention bundle in the neurosurgical unit of the Cleveland Clinic.