tbuckley/cabot-search huggingface dataset:
Inhibition of BMP and of TGFβ receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death
Authors: Dave J. Augeri, Elaine Langenfeld, Monica Castle, John A. Gilleran, John Langenfeld
Journal: Molecular Cancer (2016)

Bone morphogenetic proteins (BMP) are embryonic proteins that are part of the transforming growth factor (TGFβ) superfamily, which are aberrantly expressed in many carcinomas. Inhibition of BMP receptors with small molecule inhibitors decreases growth and induces death of lung cancer cells, which involves the downregulation of Id1 and Id3 by a Smad dependent mechanism. Developmentally, BMP and TGFβ signaling utilizes Smad-1/5 independent mechanisms to stabilize the expression of X-linked inhibitor of apoptosis protein (XIAP) and activate TGFβ activated kinase 1 (TAK1), which are known to be potent inhibitors of apoptosis. The role of BMP signaling in regulating XIAP and TAK1 in cancer cells is poorly understood. Furthermore, the interaction between the BMP and TGFβ signaling cascades in regulating the activation of TAK1 in cancer cells has not been elucidated.Feedback regulation between the BMP and TGFβ signaling pathways and their regulation of XIAP, TAK1, and Id1 were examined in lung cancer cells utilizing siRNA and inhibitors targeting BMP type I receptors, inhibitors of BMP and TGFβ type I receptors, and an inhibitor of BMP and TGFβ type I and type II receptors.We show that upon inhibition of BMP signaling in lung cancer cells, the TGFβ signaling cascade is activated. Both the BMP and TGFβ pathways activate TAK1, which then increases the expression of Id1. Inhibition of TGFβ signaling increased Id1 expression except when BMP signaling is suppressed, which then causes a dose-related decrease in the expression of Id1. Inhibition of both BMP and TGFβ signaling enhances the downregulation of TAK1. Our data also suggests that the blockade of the BMP type II receptor enhances the downregulation XIAP, which is important in decreasing the activity of TAK1. Knockdown studies demonstrate that both XIAP and TAK1 regulate the survival of lung cancer cells.This paper highlights that targeting the BMP and TGFβ type I and type II receptors causes a downregulation of XIAP, TAK1, and Id1 leading to cell death of lung cancer cells. Small molecule inhibitors targeting the BMP and TGFβ receptors represents a potential novel means to treat cancer patients.
Abstract 138: The effects of microRNA transfections on global patterns of gene expression are functionally coordinated
Authors: John F. McDonald, Shubin Shahab, Roman Mezencev, Lilya Matyunina, LiJuan Wang
Journal: Cancer Research (2012)

Abstract A current challenge in the application of miRNAs in cancer therapeutics is the inability to accurately predict the functional consequences of exogenous perturbations in the levels of potentially therapeutic miRNAs. To systematically address this issue, two miRNAs (miR-7 and miR-128) were separately transfected into a well characterized ovarian cancer cell line (HEY) and global changes in levels of gene expression were monitored. While ∼20% of the changes in expression patterns of hundreds to thousands of genes could be attributed to direct miRNA-mRNA interactions, the majority of the changes were indirect, involving the downstream consequences of miRNA-mediated changes in regulatory gene expression. The pathways most significantly affected by miR-7 transfection are involved with cell adhesion and other developmental networks previously associated with epithelial-mesenchymal transitions (EMT) and other processes linked with metastasis. In contrast, the pathways most significantly affected by miR-128 transfection are more focused on cell cycle control and other processes commonly linked with cellular replication. These computational predictions were experimentally verified. Our results indicate that changes in patterns of gene expression induced by exogenous expression of miRNAs are not random but functionally coordinated and that different families of miRNAs may regulate distinct cellular functions related to cancer. Our findings suggest that miRNAs may be of unique therapeutic value by providing clinicians with a strategy to treat cancer from a systems rather than a single gene perspective. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 138. doi:1538-7445.AM2012-138
Treatment of a Laboratory-Acquired Sabiá Virus Infection
Authors: Michele Barry, Mark Russi, Lori Armstrong, David Geller, Robert Tesh, Louise Dembry, Jean Paul Gonzalez, Ali S. Khan, Clarence J. Peters
Journal: New England Journal of Medicine (1995)

Arenaviruses are a group of RNA viruses several of which have the potential to cause a deadly syndrome of hemorrhagic fever. In humans these viruses are usually transmitted by exposure to infected rodent excreta; occasional laboratory or nosocomial infections have been reported.1 Sabia virus is an arenavirus that was first isolated in Sao Paulo, Brazil, in 1990 from an agricultural engineer who presented with a hemorrhagic fever syndrome and ultimately died. Necrosis of the liver was found at autopsy. The virus was subsequently characterized as a new member of the Tacaribe complex of the family Arenaviridae.2 A laboratory technician in . . .
P05.05 * RADIOSURGERY IN THE MANAGEMENT OF PEDIATRIC BRAIN TUMORS
Authors: M. E. Kusak, N. E. Martinez, J. Gutierrez, G. Rey, R. Martinez
Journal: Neuro-Oncology (2014)

BACKGROUND: Brain tumors are the most frequent solid tumors in the pediatric age. Their treatment is usually neurosurgical, followed by chemo and/or radiation therapy. Radiosurgery allows the administration of a high radiation dose to a well defined target in 1 to 5 fractions, with minimal dose to the surrounding tissues. This fact would make it especially indicated for certain situations of children with these tumors. There are scarce publications, all retrospective studies, with specific attention to this treatment in the pediatric population. METHOD: The aim of this study has been to review our experience of the pediatric patients with brain tumors treated at our Radiosurgery Unit from 1993 to 2013. Data were obtained retrospectively from a prospectively maintained database. We have reviewed 94 patients with central nervous system tumors below the age of 16 (range 8m- 15y, median 12y) with a complete follow-up in 71.7%, during a mean of 56.2 months. RESULTS: The treated tumors have a miscellanea of different diagnosis, the most frequent being 26 low grade gliomas (LGG), 19 craniopharyngiomas (CFG), 8 ependymomas (EP), 6 medulloblastomas-PNET (M-PNET) and 6 patients with tumors related to neurofibromatosis. Among the 21 followed LGG, control was achieved in 90.5%. In CFG, and as part of the multimodal treatment of these tumors, visual, hormonal and solid tumor stability was obtained in 14 out of 18, although in 3 patients stereotactic evacuation of the cystic component was necessary. As EP and M-PNET had already received radiotherapy, radiosurgery was a good option as a boost or salvage treatment, with good local control, but with outfield relapses, that could be further treated when necessary. CONCLUSION: This advanced technique of focalized radiation therapy, with high precision and accuracy, provides dosimeric characteristics especially relevant in children that are more susceptible to irradiation. It produces promising results in selected patients.
Abstract 1642: TIP-1 regulates sensitivity of glioma cells to radio- and chemotherapeutic agents through modulating p53 stability and activation
Authors: Miaojun Han, Hailun Wang, Zhaozhong Han
Journal: Cancer Research (2011)

Abstract Malignant gliomas represent one group of tumors that poorly respond to chemo- and radio-therapies because of the intrinsic or acquired resistance. Identification of novel molecules that are involved in the therapeutics resistance is critical to develop new therapeutic modalities. Our previous studies show that TIP-1 involves in tumor cells response to ionizing radiation (IR). In this study, we found that TIP-1 expression level correlates to the clinical staging and overall patient survival time after diagnosis of malignant gliomas. We hypothesized that TIP-1 is one novel predictive biomarker of glioma cell response to treatment, and targeting TIP-1 represents one novel strategy to combat the disease of high mortality. Studies on cell-based models indicated that TIP-1 deficiency resulted in the enhanced sensitivity of D54 and GL261 glioma cell lines to IR and chemotherapeutic agents, whereas ectopic expression of TIP-1 conferred resistance to the therapeutics in the cells. The data also showed that sensitivity of the glioma cell lines to IR correlates to stability and activation of p53 protein after IR treatment. Yeast two-hybrid screening identified C53/LZAP as one TIP-1 interacting protein within glioma cells. PDZ domain within TIP-1 binds to one classic type I PDZ-binding motif at the carboxyl terminus of C53/LZAP protein. C53/LZAP has been studied as one tumor suppressor and modulator of the cancer cell susceptibility to genotoxic stress including IR and several chemotherapeutic agents. C53/LZAP interacts with ARF and protects p53 from Mdm2-mediated protein degradation. Our data demonstrated that, after irradiation, presence of TIP-1 enhanced C53/LZAP interaction with ARF, thus promoted Mdm2-mediated p53 ubiquitination and resulted in less stable p53 protein. On the other hand, with absence of TIP-1 protein, IR treatment resulted in more stabilized and activated p53 protein that drives IR-induced apoptosis of the glioma cells. Taken together, our data suggests that TIP-1 is one novel modulator of p53 tumor suppressor and contributes to chemo- and radio-resistance of glioma cells. Therefore, targeting TIP-1 represents one novel approach for the improved therapy of malignant glioma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1642. doi:10.1158/1538-7445.AM2011-1642
The Role of F-18 FDG Positron Emission Tomography in Preoperative Assessment of the Liver in Patients Being Considered for Curative Resection of Hepatic Metastases from Colorectal Cancer
Authors: ERIC M. ROHREN, ERIK K. PAULSON, ROSALIE HAGGE, TERRENCE Z. WONG, JAMES KILLIUS, PIERRE-ALAIN CLAVIEN, RENDON C. NELSON
Journal: Clinical Nuclear Medicine (2002)

Purpose The authors' goal was to determine the sensitivity and specificity of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying patients with hepatic metastases from colorectal cancer and the accuracy of PET for determining the number and distribution of lesions within the liver. Intraoperative sonography and surgical inspection and palpation were used as the reference standard. Methods Twenty-three patients being evaluated for surgical resection of hepatic metastases from colorectal carcinoma underwent FDG PET before operation. Findings of the PET studies were reviewed in a blinded, retrospective manner, with the results compared with the findings of intraoperative sonography and surgical exploration. Lesions of all sizes were considered in the analysis. Results The FDG-PET results were positive in 21 of the 22 patients ultimately found to have metastatic disease to the liver, and they were negative in the single patient without metastases. Therefore, for identification of patients with hepatic metastatic disease, PET has a sensitivity of 95% and a specificity of 100%. In all, 48 metastatic lesions were identified in these patients, of which 38 (79%) were identified on PET images. The probability of lesion detection by PET was directly correlated with lesion size (P < 0.01). The assessment of lobar disease distribution in the liver was discordant between PET and surgery in 3 of 23 (13%) patients. Conclusions In patients being evaluated for potential curative resection of hepatic metastases from colorectal cancer, FDG PET is accurate for the identification of the presence or absence of metastatic disease to the liver. However, detection of individual lesions depends on their size, and determination of lesion number and distribution within the liver is more accurately accomplished with intraoperative sonography.
Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL)
Authors: H Harasawa, Y Yamada, M Kudoh, K Sugahara, H Soda, Y Hirakata, H Sasaki, S Ikeda, T Matsuo, M Tomonaga, T Nobori, S Kamihira
Journal: Leukemia (2002)
Abstract 3128: Mxd3 is required for proliferation of human neuroblastoma cells.
Authors: Gustavo Barisone, Noriko Satake, Carly Lewis, Connie Duong, Cathy Chan, Kit Lam, Jan Nolta, Elva Diaz
Journal: Cancer Research (2013)

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor in children. Up to 45% of the cases are high risk at diagnosis, representing very aggressive, usually metastasized tumors that are refractory or recurrent after all available therapies. Prognosis for these patients is very poor with only 30% survival. MXD3 is a transcription factor previously shown in our lab to be a novel member of the Hedgehog (Hh) pathway (Yun, Rust, Ishimaru, Diaz, Mol Cell Biol, 2007) in granule neuron precursors. In these cells, overexpression of MXD3 results in higher MYCN expression, suggesting a functional interaction between the two transcription factors. MXD3 phenocopies MYCN expression in mouse models of medulloblastoma; we have also shown that it is expressed in human medulloblastoma and that its knockdown reduces proliferation of human medulloblastoma cell lines (Barisone et al., PLoS One, 2012). More than 20% of NBs have MYCN amplification, which is considered a marker of poor prognosis. In the current study, we investigated a possible role for MXD3 in NB cell proliferation. Using qRT-PCR we observed high levels of MXD3 mRNA expression in 5 NB cell lines: SK-N-DZ, IMR-32, SH-SY5Y, SK-N-BE and SK-N-SH. Immunoblot analysis with anti-MXD3 monoclonal antibodies confirmed that the protein was present in these cells. Furthermore, immunohistochemistry analysis showed strong immunoreactivity in a cohort of 16 primary NB tissue specimens. We investigated the role of MXD3 in NB cell proliferation by silencing MXD3 in the SK-N-DZ cell line. We used lentiviral delivery to knockdown MXD3 using an RNA interference approach. Upon transduction by the viral vector, MXD3 knockdown was confirmed at both the RNA and protein level. Within 48 hours, MXD3 protein levels were reduced &amp;gt;90% in cells infected with the shMXD3 virus but not with the control virus. MXD3 knockdown resulted in decreased proliferation in NB cells, supporting our hypothesis that it may be involved in the maintenance of NB. We analyzed cell cycle progression after knockdown using flow cytometry. We observed no significant differences in the G0/G1, S or G2/M populations between experimental and control samples. Our results suggest that MXD3 is important for NB cell proliferation, possibly by acting as an anti-apoptotic factor. Therefore, MXD3 is a potential candidate for targeted therapies against neuroblastoma. Citation Format: Gustavo Barisone, Noriko Satake, Carly Lewis, Connie Duong, Cathy Chan, Kit Lam, Jan Nolta, Elva Diaz. Mxd3 is required for proliferation of human neuroblastoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3128. doi:10.1158/1538-7445.AM2013-3128
EXERCISE GAS EXCHANGE PHENOTYPES IN A POPULATION AT RISK AND REDUCED HEART RATE RECOVERY POST-EXERCISE: FINDINGS FROM THE EURO(PEAN) EX(ERCISE) POPULATION-BASED STUDY
Authors: Marta Pellegrino, Greta Generati, Francesco Bandera, Valentina Labate, Valeria Donghi, Eleonora Alfonzetti, Marco Guazzi
Journal: Journal of the American College of Cardiology (2015)
Abstract 4780: Discovery of novel checkpoint kinase 1 inhibitors by virtual screening based on multiple crystal structures
Authors: Yan Li, Dong Joon Kim, Weiya Ma, Ronald Lubet, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2012)

Abstract Checkpoint kinase 1 (Chk1) is activated in response to DNA damage through the ATM/ATR pathway, and plays an essential role in the regulation of the G2/M checkpoint. Inhibition of Chk1 should abrogate this checkpoint in a manner relevant to the treatment of cancer, and may induce apoptosis. Currently about 50 crystal structures of Chk1 are available in RCSB Protein Data Bank. The abundance of Chk1 structures offers the opportunity not only to discover new inhibitors with receptor-based drug design but also to explore the impact of receptor flexibility in ligand docking. Here we describe a successful application of the docking of multiple structures to discover novel and potent Chk1 inhibitors. Forty-six Chk1 structures were first compared in single structure docking by predicting the binding mode and recovering known ligands. Combinations of different protein structures were then compared by recovery of known ligands and an optimal ensemble of Chk1 structures were selected. The chosen structures were used in the virtual screening of over 60,000 diverse compounds for Chk1 inhibitors. Six compounds ranked at the top of the hits list were tested experimentally and two of these compounds inhibited Chk1 activity-the best with an IC50 value of 9.6 µM. Further study indicated that achieving a better enrichment and identifying more diverse compounds was more likely using multiple structures than using only a single structure even when protein structures were randomly selected. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4780. doi:1538-7445.AM2012-4780
Abstract 4698: Gene expression profiles of triple negative breast cancer epithelial and stromal cells are predictive of treatment response.
Authors: Bojana Jovanovic, Steven X. Chen, Brian D. Lehmann, Kimberly N. Johnson, Violeta Sanchez, Maria G. Kuba, Melinda E. Sanders, Ingrid A. Mayer, Harold L. Moses, Jennifer A. Pietenpol
Journal: Cancer Research (2013)

Abstract Lacking human epithelial growth factor receptor 2 (HER2) amplification as well as estrogen and progesterone receptors, TNBC is a heterogeneous collection of biologically diverse cancers that likely contributes to variable clinical outcomes for patients suffering from this disease. Since TNBC lacks well-defined molecular targets, we recently performed gene expression (GE) analyses and identified six distinct molecular TNBC subtypes with unique biologies. To further decipher the contribution of tumor epithelium and its adjacent stroma to the biology of TNBC and clinical response to treatments, we performed GE analysis on biopsy material from 20 TNBC patients enrolled in a phase II clinical trial [VICC-BRE0904; a neoadjuvant study of cisplatin and paclitaxel±RAD001 (mTOR inhibitor)]. We isolated RNA from both tumor epithelial and stromal cells using laser capture microdissection. Our goal is to determine if GE from tumor epithelial and/or stromal cells is predictive of response to treatment. Our preliminary results indicate that there is differential GE in both tumor epithelial as well as stromal cells in pretreatment biopsies of responders versus non-responders. Patients with higher expression of proliferation genes such as MKI67, KIFCI, AURKB, E2F3, and DNA damage response genes TP53BP2, CHEK1, RPA1, BLM were more responsive to treatment compared to non-responders. Upon completion of the phase II clinical trial and correlative molecular analyses, we anticipate identifying biomarkers of drug sensitivity that will provide insight to novel combination therapies for the different subtypes of TNBC. Citation Format: Bojana Jovanovic, Steven X. Chen, Brian D. Lehmann, Kimberly N. Johnson, Violeta Sanchez, Maria G. Kuba, Melinda E. Sanders, Ingrid A. Mayer, Harold L. Moses, Jennifer A. Pietenpol. Gene expression profiles of triple negative breast cancer epithelial and stromal cells are predictive of treatment response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4698. doi:10.1158/1538-7445.AM2013-4698
Recurrent Extrahepatic Hepatocellular Carcinoma Detected by 18F-Choline PET/CT
Authors: Constantin Lapa, Jan-Stefan Schmid, Johannes Weiss, Andreas Geier, Oliver Götze
Journal: Clinical Nuclear Medicine (2016)

Diagnosis of recurrent hepatocellular carcinoma (HCC) is sometimes challenging, especially when extrahepatic disease is present. Here, we report on a 49-year-old woman with a history of HCC who was referred to our institution with suspicion of tumor recurrence for further workup. Combined 18F-choline PET/CT revealed a soft tissue mass at the right thoracic wall highly consistent with HCC.
TM-07 * 13C MRS DETECTS METABOLIC FLUX ADAPTATION IN IDH MUTANT GLIOMA CELLS
Authors: J. Izquierdo-Garcia, P. Eriksson, L. Cai, M. Chaumeil, R. Pieper, J. Phillips, S. Ronen
Journal: Neuro-Oncology (2014)

The isocitrate dehydrogenase (IDH)1 mutation is associated with accumulation of 2-hydroxyglutarate (2-HG), but the metabolic fluxes associated with 2-HG production and cellular reprogramming of mutant IDH1 cells are not fully understood. The objective of this study was to use 13C magnetic resonance spectroscopy (MRS) to probe the fate of 13C-labeled metabolites (at thermal polarization and hyperpolarized by dynamic nuclear polarization) and to monitor the glycolytic pathway, the TCA cycle, and glutamine metabolism in wild-type and mutant IDH1 glioma cells. To achieve this goal, U87 cells expressing mutant IDH1 and wild-type IDH1 were generated by transduction with a lentiviral vector coding for mutant or wild-type IDH1 respectively. MRS studies were performed using a cell perfusion (bioreactor) system. Live cells were exposed to hyperpolarized 1-13C or 2-13C-labeled pyruvic acid, 1-13C glucose or 3-13C glutamine and cell metabolism was probed using 13C MRS. We found that in mutant IDH1 cells pyruvate flux to lactate was increased relative to wild-type cells, and pyruvate flux to glutamate and 2-HG was decreased compared to pyruvate flux to glutamate in wild-type IDH1 cell. Glutamine flux to glutamate in wild-type cells, or to glutamate and 2-HG in mutant IDH1 cells was comparable. Accordingly, the total intracellular glutamate pool was reduced in mutant IDH1 cells. The drop in pyruvate flux to the TCA cycle was mediated by a significant drop in pyruvate dehydrogenase (PDH) activity, which was due to significantly increased inhibitory PDH phosphorylation. When considering 2-HG synthesis, our data also indicate that, consistent with previous work, the majority of 2-HG is produced from glutamine (82%). However in our cells a significant portion (18%) was also derived from glucose. Our findings thus point to metabolic reprogramming in IDH1 mutant cells beyond 2-HG production and highlight the value of MRS for characterizing the metabolic changes associated with the IDH1 mutation.