tbuckley/cabot-search huggingface dataset:
Abstract 5465: Systematic interrogation of druggable pathways in pancreatic adenocarcinomas using pooled gene-knockdown lentiviral libraries
Authors: Edgar Ferrer-Lorenzo, Daniel P. Nussbaum, Peter Winter, Kris Wood
Journal: Cancer Research (2015)

Abstract Despite significant advances in the development of cancer treatment in the last 20 years the best available therapies have marginally improved the survival rate of treated pancreatic cancer patients (from 3% to 6% five-year survival), making it still one the deadliest malignancies. Single standard of care cytotoxic and targeted therapies demonstrate little to no effect on patient survival. Even though we now understand some of the main genetic factors that are mutatated in pancreatic tumors, their role in drug response remains poorly understood. To identify drug-sensitizing genetic targets in cancer cells we have developed a high-throughput screening platform. In this methodology, pooled lentiviral libraries containing hundreds of knockout constructs specific for cancer-related genes are used to infect cancer cells. By treating the infected populations with therapeutic agents we are able to identify genetic targets that when inhibited synergize with existing drugs to cause increased cell death. We piloted this type of screening platform in HCT-116 cells, a KRAS mutant, MEK inhibitor resistant colorectal cancer cell line, using the MEK-inhibitor AZD-2644 and a pooled shRNA library. This study identified 4-7 target genes that when knocked down sensitized the previously resistant HCT-116 cells to AZD-2644. To conduct a more robust and representative sensitization screen we developed a lentiviral CRISPR-Cas9 library. By performing screens in a panel of pancreatic cancer cell lines, we have identified both cell line dependencies and sensitizers to targeted and cytotoxic chemotherapies. The findings from these screens provide potential mechanistic insights into the key survival signaling programs in pancreatic cancer as well as new therapeutic strategies. Citation Format: Edgar Ferrer-Lorenzo, Daniel P. Nussbaum, Peter Winter, Kris Wood. Systematic interrogation of druggable pathways in pancreatic adenocarcinomas using pooled gene-knockdown lentiviral libraries. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5465. doi:10.1158/1538-7445.AM2015-5465
Abstract 3604: Targeting the PIM kinases in combination with BTK inhibition is synergistic in preclinical models of B-cell malignancies
Authors: Jeremiah J. Bearss, Brigham L. Bahr, Katie K. Soh, Peter W. Peterson, Clifford J. Whatcott, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner
Journal: Cancer Research (2015)

Abstract BTK inhibitors (e.g. ibrutinib) have significantly impacted the treatment of B-cell malignancies in a positive way. Single agent response rates with ibrutinib are 65% or higher in B-cell lymphomas and chronic lymphocytic leukaemia with the majority of patients enjoying a prolonged duration of response. Continued clinical development is needed, however, as most patients achieve only a partial response from their treatment and ultimately patients become refractory to ibrutinib leading to relapse and disease progression. Targeted combinations with ibrutinib could potentially increase the number of patients undergoing complete remission and combat emergent resistant mechanisms. The PIM family (1, 2, and 3) are serine/threonine kinases that have proven to be oncogenic in-part due to their ability to suppress c-Myc induced apoptosis. The PIM kinases have emerged as important regulators of drug resistance in multiple cancer types. Tolero Pharmaceutical's second generation PIM Kinase inhibitor, TP-3654 has exhibited favorable activity in preclinical models of prostate cancer, AML, and lymphoma. Due to the signaling crosstalk between BTK and PIM through the STAT transcription factors, we hypothesized that synergies may arise through the simultaneous targeting of both kinases. Here, we report a significant increase in drug activity when a BTK inhibitor (ibrutinib) was combined with TP-3654 in various lymphoma cell lines. In Granta-519 cells, the IC50 of ibrutinib decreased 3.5-fold, from 0.7 μM to 0.2 μM, when cultured in combination with a subtoxic concentration of TP-3654 (300 nM). Similarly, the IC50 of TP-3654 decreased 6-fold, from 2.4 μM to 0.4 μM, when cells were cultured in combination with a subtoxic concentration of ibrutinib (100 nM). BTK is known to attenuate the activity of the transcription factor STAT3, a major regulator of PIM kinase levels in cells. Due to this, mechanistic studies focused on analyzing the STAT3 pathway are ongoing to determine the downstream effects of using ibrutinib and TP-3654 in combination. Several lymphoma xenograft studies are also ongoing to further explore this combination in vivo. These results provide a strong rationale that inhibitors of PIM and BTK could be used in combination for the treatment of B-cell malignancies and other B-cell mediated diseases. Citation Format: Jeremiah J. Bearss, Brigham L. Bahr, Katie K. Soh, Peter W. Peterson, Clifford J. Whatcott, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner. Targeting the PIM kinases in combination with BTK inhibition is synergistic in preclinical models of B-cell malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3604. doi:10.1158/1538-7445.AM2015-3604
403. Toca Retroviral Replicating Vector in Tumor and Blood from Clinical Trial Subjects with Recurrent High Grade Glioma
Authors: Daniel Hogan
Journal: Molecular Therapy (2016)

Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector (RRV) based on an amphotropic murine gammaretrovirus, that encodes a cytosine deaminase transgene that allows infected cells to selectively convert the antifungal drug 5-fluorocytosine (5-FC) into the antineoplastic drug 5-fluorouracil (5-FU). Toca 511 can be delivered by multiple routes, selectively infects and spreads in tumor cells and through multiple mechanisms can elicit an anti-tumor immune response. Thus, clinically, treatment with Toca 511 and extended-release 5-FC (Toca FC) is expected to selectively destroy tumor cells within the body, while leaving healthy cells unharmed. Toca 511 and Toca FC have been administered to >120 high grade glioma subjects in three phase I studies (NCT01156584, NCT01470794, NCT01985256) and, based on results from these trials, a phase 2/3 trial (Toca 5) has recently started recruitment (NCT02414165). Although Toca 511 plus Toca FC has been well tolerated, we investigated potential off-target viral infection and integration, and whether such off-target events have potential toxicity; we also investigated the stability profile of the Toca 511 genome after infection of tumor targets and off-target tissue (blood). To date, few subjects (approximately 10-25%) show quantifiable viral signal (LOQ approximately 4000 copies/mL) in blood after initial clearance, following Toca 511 injection into the brain tumor or tumor bed. In all cases, quantifiable virus RNA and DNA signal was cleared from blood. In order to better understand interactions among Toca 511 and subjects' tumor and blood, we systematically mapped Toca 511 integration sites from subject samples with detectable virus and also sequenced, at high depth, integrated Toca 511 genomes, and in some cases RNA genomes, from these samples. Toca 511 integration profiles display a preference for integration near active transcription start sites, as has been seen generally for gammaretroviruses. There was no evidence for clonal expansion of Toca 511 integrated sites/cells or preferential retrieval of sites nearby oncogenes. Toca 511 sequences display an array of mutations in the tumor and blood, including transitions consistent with cytosine deaminase activity. The data provide a molecular correlate to the clinical safety profile of Toca 511 and Toca FC treatment as well as molecular characterization of RRV after infection, replication and therapeutic use in humans.
Abstract 508: Identification of FRA-1 as a potential driver of pro-invasive properties in pancreatic cancer in conjunction with MUC1
Authors: Ryan L. Hanson, Michael A. Hollingsworth
Journal: Cancer Research (2015)

Abstract The transmembrane mucin, MUC1, contributes to the progression of pancreatic cancer, in part by conducting signals from the cell surface that regulate expression of molecules associated with aggressive tumor behavior. We investigated transcriptional co-regulatory effects mediated by interactions of the MUC1 cytoplasmic tail with activator protein 1 (AP-1). Previous results suggest that MUC1 regulates the capacity of AP-1 to bind specific promoter elements and regulate genes that contribute to tumor progression. The DNA binding activity of AP-1 is controlled in several ways including composition of the protein dimer. The precise mechanism by which MUC1 alters transcriptional complexes remains unknown. We sought to determine how MUC1 influences the formation of AP-1 complexes and potential downstream effects. We found MUC1 increased c-Jun protein levels, the major component of AP-1, in a manner largely independent of transcriptional upregulation (mRNA upregulation was observed in only one cell line of several analyzed). Formation of the AP-1 dimer was assessed by quantitative and semi-quantitative assays. MUC1 promoted the association of c-Jun with the Fos protein, FRA-1. This association was promoted by enhanced ERK2 signaling in MUC1 expressing cell lines. In breast cancer, FRA-1 drives an invasive and metastatic phenotype. Overexpression of FRA-1 in pancreatic cancer cell lines promoted migratory and invasive behaviors in vitro. Blocking FRA-1 activity by shRNA knockdown or ERK inhibition decreased migration and invasion. Analysis of gene expression in pancreatic tumor samples and normal, uninvolved tissue [mined from the Gene Expression Omnibus (GEO)] revealed that tumor samples had significantly increased levels of FRA-1 mRNA. A subset of these samples exhibited gene expression patterns consistent with a FRA-1:EMT phenotype previously observed in colorectal cancer cells. We evaluated expression of FRA-1 protein in primary pancreatic tumors, liver metastases, and uninvolved non-malignant pancreas. Robust nuclear localization of FRA-1 was observed in primary and metastatic tumor cells whereas uninvolved pancreas showed lower levels of diffuse cytoplasmic staining. Based on these results, we hypothesize that FRA-1 plays an important role in a subset of pancreatic cancers by altering the binding profile of AP-1. Due to a dependence on ERK activity for FRA-1 function, we propose that cancers with activating mutations in the RAS-RAF-MEK-ERK cascade are the most likely candidates for utilization of FRA-1. Citation Format: Ryan L. Hanson, Michael A. Hollingsworth. Identification of FRA-1 as a potential driver of pro-invasive properties in pancreatic cancer in conjunction with MUC1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 508. doi:10.1158/1538-7445.AM2015-508
Industrial Pollution Threatens Millions in Developing World
Authors: MJ Friedrich
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Public health budgets “must be protected” to guarantee NHS’s long term future
Authors: Adrian O’Dowd
Journal: BMJ (2016)

National funding of public health should be protected to improve the population’s health and reduce future demand, allowing the NHS to be more sustainable in the long term, peers have been told.

England’s chief medical officer, Sally Davies, told the committee on the long term sustainability of the NHS that prevention was a good way of ensuring that the NHS had a long term future, during an evidence session on 20 December for the peers’ inquiry into the future of the NHS.

In the light of public health budget cuts nationally and locally, peers asked whether it was time to be more robust about protecting resources allocated to public health and prevention programmes.

Davies said, …
Abstract 4779: RUVBL1 and RUBVL2 are chromatin remodelers that represent prognostic and novel therapeutic targets for a subset of non-small cell lung cancers (NSCLCs)
Authors: Paul M. Yenerall, Rahul Kollipara, Ryan Carstens, Kenneth Huffman, Luc Girard, Jaime Rodriguez, Ignacio Wistuba, David Mangelsdorf, John Minna, Ralf Kittler
Journal: Cancer Research (2015)

Abstract RUVBL1 and RUVBL2 (collectively referred to as RUVBL1/2) are AAA+ ATPases that function in various chromatin remodeling complexes. We found that RUVBL1/2 are overexpressed (n = 224) and prognostic of patient outcome in NSCLC patients (n = 697) who undergo surgical resection (combined TCGA, KMPlot.com, and SPORE P50CA70907 dataset analyses). To assess the importance and biological functions of RUVBL1/2 in NSCLC, we measured cell growth following depletion of RUVBL1/2 in 24 NSCLC lines, representing a spectrum of oncogenotypes and histologies, and 2 normal human bronchial epithelial cell lines (HBECs) using two independent RNAi reagents. Growth inhibitory phenotypes ranged from 19-87% and were “rescued” by exogenous expression of an RNAi-resistant cDNA construct, indicating “on-target” siRNA effects. Four of the 23 NSCLCs were very sensitive (&amp;gt;75% growth inhibition), while 88% of NSCLCs were more growth inhibited than HBECs, indicating a therapeutic window. To establish molecular biomarkers of RUVBL1/2 dependency, we correlated whole exome mutation status, whole transcriptome mRNA levels, and a number of other parameters to sensitivity to RUVBL1/2 depletion. Sensitivity to RUVBL1/2 knockdown did not correlate with the mutation status or expression of any genes. However, sensitivity to RUVBL1/2 depletion did correlate with doubling time. Flow cytometry analysis in NSCLC lines sensitive to RUVBL1/2 KD revealed that RUVBL1/2 depletion resulted in a G2/M arrest (but not apoptosis), and a decrease in cell cycle related transcripts, such as CDKN3, AURKA, CIT and CDC20, whereas resistant cell lines do not exhibit these changes. Initial ChIP-seq analysis suggests that RUVBL1/2 preferentially occupies cell cycle related genes and are depleted in nucleosome free regions (i.e. transcription start sites). These results, combined with results from others demonstrating the necessity of ATP hydrolysis for RUVBL1/2's function(s), indicate that the chromatin remodelers RUVBL1/2 are potential therapeutic targets in a subset of NSCLCs. (Supported by UTSW Green Center Fellowship, CPRIT RP120732, SPORE P50CA70907) Citation Format: Paul M. Yenerall, Rahul Kollipara, Ryan Carstens, Kenneth Huffman, Luc Girard, Jaime Rodriguez, Ignacio Wistuba, David Mangelsdorf, John Minna, Ralf Kittler. RUVBL1 and RUBVL2 are chromatin remodelers that represent prognostic and novel therapeutic targets for a subset of non-small cell lung cancers (NSCLCs). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4779. doi:10.1158/1538-7445.AM2015-4779
Abstract 1031: Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src
Authors: Stephanie Guy, Patrick Magee, Mulu Geletu, Rozanne Arulanandam, Leda Raptis
Journal: Cancer Research (2015)

Abstract The signal transducer and activator of transcription-3 (Stat3) plays an important role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr-705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3: Engagement of cadherins such as cadherin-11 (cad11), a cell to cell adhesion protein known to be involved in metastasis, induces a dramatic increase in the levels of the Rac and Cdc42 small GTPases, and this leads to interleukin-6 transcription and Stat3 activation. Stat3 in turn, downregulates the p53 tumor suppressor and upregulates anti-apoptotic genes, thus offering a potent survival signal. A large number of oncogenes such as activated Src-527 activate the E2F transcription factor family, which induce the expression of genes involved in cell division. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for antiapoptotic signals. Since cad11 activates Stat3, a potent survival factor, we examined the effect of cad11 downregulation upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Forced expression of high levels of activated Src caused a dramatic reduction in cad11 levels. On the other hand, intermediate Src levels, which are the levels that are physiologically relevant, did allow cad11 expression, albeit at lower levels. Paradoxically, cells expressing high Src levels had actually lower Stat3 than cells expressing intermediate Src levels. This could be due to the observed downregulatory effect of Src upon cad11, and it demonstrates that cad11 is a more potent Stat3 activator than Src. Cad11 knockdown through shRNA expression in cells expressing intermediate Src levels, caused a dramatic reduction in Stat3 activity and induced apoptosis. That is, the residual amounts of cad11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Taken together, these findings indicate that cad11, despite its presumed structural role, and in addition to its known role in promoting metastasis, it is actually also necessary for full neoplastic transformation by the Src oncogene. Citation Format: Stephanie Guy, Patrick Magee, Mulu Geletu, Rozanne Arulanandam, Leda Raptis. Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1031. doi:10.1158/1538-7445.AM2015-1031
Abstract P025: Modulatory Effect of Angiotensin II on Endothelial Differentiation and Vasculogenic Capacity of Human MSCs
Authors: Michael Bellio, Cristina Sanina, Wayne Balkan, Claudia O Rodrigues, Samirah A Gomes, Ian McNiece, Joshua M Hare, Ivonne H Schulman
Journal: Circulation Research (2011)

Human bone marrow-derived mesenchymal stem cell (MSC)-based therapy holds great promise as a new approach for cardiovascular regeneration. In heart failure, there is activation of the renin-angiotensin system and increased formation of angiotensin (Ang) II. We tested the hypothesis that Ang II impairs endothelial differentiation and vasculogenic capacity of human MSCs. MSCs were cultured in endothelial growth media (EGM) and treated with vehicle, 1µM Ang II, or 10µM Ang II for 7 days to assess by real time RT-PCR the expression of two markers of endothelial differentiation, platelet endothelial cell adhesion molecule (PECAM) and von Willebrand factor (vWF). Expression of PECAM and vWF increased similarly in each treatment group at day 7, suggesting endothelial differentiation of MSCs. To assess vasculogenesis, MSCs were cultured in EGM for 7 days and then plated on growth factor reduced Matrigel for 5 hours under the following conditions: vehicle, Ang II (1µM), Ang II + type 1 receptor (AT1R) inhibitor (10µM losartan), or Ang II + type 2 receptor (AT2R) inhibitor (0.1µM PD123177). The vascular index (VI) was determined by multiplying the average number of endothelial tubes formed by the average tube length. MSCs treated for 5 hours with 1µM Ang II exhibited a reduced VI (84.5 ± 2.6% of vehicle treated cells, P&lt;0.05). Treatment with Ang II+AT1R inhibitor increased VI (115 ± 4.9% of vehicle, P&lt;0.05) whereas Ang II+AT2R inhibitor decreased VI (77.1 ± 4.1% of vehicle, P&lt;0.05). Chronic treatment for 7 days in EGM with 1µM or 10µM Ang II also showed decreased VI compared to vehicle (75.4 ± 5.4% and 60.7 ± 2% of vehicle, respectively, P&lt;0.01). These results reveal that both acute and chronic treatment with Ang II produces a negative effect on the vasculogenic potential of endothelial-differentiated human MSCs and suggests opposing effects of AT1R and AT2R on vasculogenesis. In conclusion, we propose that selective modulation of AT1R and AT2R mediated pathways may serve as a promising means for enhancing the regenerative capacity of human MSCs in cardiovascular disease.
DIETARY FISH OIL MODIFIES RENAL-FUNCTION DURING EARLY POSTOPERATIVE REJECTION EPISODES IN CYCLOSPORINE (CSA) TREATED RENAL-ALLOGRAFT RECIPIENTS
Authors: Jjh Vanderheide, Henk Bilo, Ajm Donker, Jm Wilmink, Willem Sluiter, Am Tegzess
Journal: Kidney International (1990)
Risk of unplanned presentations and hospital admission of metastatic breast cancer outpatients
Authors: C. Fontanella, V. Fanotto, E. De Carlo, D. Iacono, C. Bozza, M. Bonotto, M. Cinausero, L. Gerratana, M. Guardascione, K. Rihawi, S. Russo, C. Andreetta, A.M. Minisini, S. Moroso, M. Mansutti, R. Sottile, G. Aprile, G. Fasola, F. Puglisi
Journal: Annals of Oncology (2015)
Iron Chelation Therapy with Deferasirox (Exjade®, ICL670) or Deferoxamine Results in Reduced Hepatocellular Inflammation and Improved Liver Function in Patients with Transfusion-Dependent Anemia.
Authors: P. Brissot, B. Turlin, G.L. Forni, G. Alimena, G. Quarta, D. Selleslag, A. Thompson, F. Locatelli, A. Berretta, M. de Montalembert, C. Ressayre-Djaffer, B. Rabault, J. Ford, D. Alberti
Journal: Blood (2005)