tbuckley/cabot-search huggingface dataset:
Abstract C33: Effects of curcumin on pancreatic ductal adenocarcinoma
Authors: Adrianna M. Vaskas, Joseph A. Fraietta, Kristen B. Long
Journal: Cancer Research (2019)

Abstract Without an early method of diagnosis or effective treatment plan, the prognosis for pancreatic ductal adenocarcinoma (PDAC) is grim, which begs for the development of additional treatment options. The plant-derived chemical, curcumin, has recently shown some promise as a potential therapy when tested in xenograft models of PDAC, glioblastoma, lung, breast, cervical, and colon tumors and is currently being tested in early clinical trials of certain cancers. However, efficacy studies against PDAC have not included preclinical mouse models with an intact immune system. To address the potential complication of a fully functional immune system on curcumin effectiveness, we assessed the effects of curcumin on murine PDAC cell lines both in vitro and in vivo. Murine PDAC lines were previously derived from genetically engineered KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) mice, which spontaneously produce metastatic PDAC that closely mimics human disease. The dose- and time-dependent toxicity of curcumin was assessed using various cell lines in vitro, and our findings support previously published results. To assess effectiveness in vivo, tumor cells were implanted subcutaneously into syngeneic, C57Bl/6J mice. Once tumors were established, curcumin (or vehicle alone) was administered via intraperitoneal (i.p.) or intratumoral injection. Treatment efficacy was assessed by measuring tumor growth and the overall survival of mice. We found that curcumin treatment had no impact on tumor growth or overall survival of immunocompetent mice. To circumvent potential solubility issues common to curcumin and illustrate the importance of the immune system in treatment resistance, we repeated our in vivo studies using curcumin encapsulated in liposomes. In addition, we used T cell-depleting antibodies for a subset of mice to mimic athymic mice used in previously published xenograft models. T-cell depletion was verified prior to tumor cell implantation by flow cytometry. Once tumors were established, liposomal curcumin or mock treatment was administered via i.p. injection. For T cell-depleted mice, we found that treatment with liposomal curcumin stalled tumor growth and increased overall survival compared to mock treated mice. For T cell-replete mice, we found that treatment with liposomal curcumin had no impact on tumor growth or overall survival compared to mock treated mice, which agrees with our findings. Taken together, our data suggest that the presence of T cells causes a difference in responsiveness to curcumin in vivo. This finding warrants additional studies in order to understand this mechanism and enhance its potential success in the clinic. Citation Format: Adrianna M. Vaskas, Joseph A. Fraietta, Kristen B. Long. Effects of curcumin on pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C33.
Distribution of Mediastinal Lesions Across Multi-Institutional, International, Radiology Databases
Authors: Anja C. Roden, Wentao Fang, Yan Shen, Brett W. Carter, Darin B. White, Sarah M. Jenkins, Grant M. Spears, Julian R. Molina, Eyal Klang, Mattia D. Segni, Jeanne B. Ackman, Edward Z. Sanchez, Nicolas Girard, Engjellush Shumeri, Marie-Pierre Revel, Guillaume Chassagnon, Ami Rubinowitz, Demetrius Dicks, Frank Detterbeck, Jane P. Ko, Conrad B. Falkson, Samantha Sigurdson, Sabrina Segreto, Silvana Del Vecchio, Giovanella Palmieri, Margaret Ottaviano, Mirella Marino, Robert Korst, Edith M. Marom
Journal: Journal of Thoracic Oncology (2019)
High incidence of HCV in HIV-negative men who have sex with men using pre-exposure prophylaxis
Authors: Elske Hoornenborg, Liza Coyer, Anders Boyd, Roel Christiaan Alfons Achterbergh, Maarten Franciscus Schim van der Loeff, Sylvia Bruisten, Henry John Christiaan de Vries, Jelle Koopsen, Thijs J.W. van de Laar, Maria Prins, J.E.A.M. van Bergen, G.J. de Bree, P. Brokx, F. Deug, M. Heidenrijk, M. Prins, P. Reiss, M. van der Valk, J.E.A.M. van Bergen, G.J. de Bree, P. Brokx, U. Davidovich, S.E. Geerlings, E. Hoornenborg, A. Oomen, A. van Sighem, W. Zuilhof, M.L. Groot Bruinderink, R.C.A. Achterbergh, M. van Agtmael, J. Ananworanich, D. Van de Beek, G.E.L. van den Berk, D. Bezemer, A. van Bijnen, W.L. Blok, S. Bogers, M. Bomers, C.A.B. Boucher, W. Brokking, D. Burger, K. Brinkman, N. Brinkman, M. de Bruin, S. Bruisten, L. Coyer, R. van Crevel, C.G. Daans, L. Dellemann, M. Dijkstra, Y.T. van Duijnhoven, A. van Eeden, L. Elsenburg, M.A.M. van den Elshout, C. Ester, E. Ersan, P.E.V. Felipa, P.H.J. Frissen, T.B.H. Geijtenbeek, M.H. Godfried, J. van Gool, A. Goorhuis, M. Groot, C.A. Hankins, A. Heijnen, M.M.J. Hillebregt, A. Hogewoning, M. Hommenga, J.W. Hovius, Y. Janssen, K. de Jong, V. Jongen, N.A. Kootstra, R.A. Koup, F.P. Kroon, T.J.W. van de Laar, F. Lauw, M.M. van Leeuwen, K. Lettinga, I. Linde, D.S.E. Loomans, J.T. van der Meer, T. Mouhebati, B.J. Mulder, J. Mulder, F.J. Nellen, A. Nijsters, H. Nobel, P. Oostvogel, E.L.M. Op de Coul, E. Peters, I.S. Peters, T. van der Poll, O. Ratmann, C. Rokx, M.S. van Rooijen, M.F. Schim van der Loeff, W.E.M. Schoute, G.J. Sonder, J. Veenstra, A. Verbon, F. Verdult, J. de Vocht, H.J. de Vries, S. Vrouenraets, M. van Vugt, W.J. Wiersinga, F.W. Wit, L.R. Woittiez, S. Zaheri, P. Zantkuijl, M.C. van Zelm, A. Żakowicz, H.M.L. Zimmermann
Journal: Journal of Hepatology (2019)
US researchers’ conflicts of interest are still widespread and under-reported, investigations find
Authors: Owen Dyer
Journal: BMJ (2019)

Industry payments that could skew research results are still commonplace in the United States and frequently go unnoticed despite years of effort to police such practices better, two investigations by the non-profit public interest journalism group ProPublica have found.

Federally funded health researchers reported more than 8000 significant financial conflicts of interest worth at least $188m in total (£143m; €169m) since 2012, said ProPublica’s review of data held by the National Institutes of Health.1 The institutes’ database has never been publicly seen before, and the findings were obtained through a freedom of information request.

A second investigation found that dozens of researchers at the University of California (UC), including influential heads of medical departments, had reported to their employer only a fraction of the payments that drug companies reported having given them on the government’s Open Payments database.2

Two thirds of nearly 90 UC health faculty members whose …
In vivo fluorescence imaging of Noggin-mediated tumor growth arrest in MV522 xenograft model.
Authors: Hye-Won Kang, Alexei Bogdanov
Journal: Cancer Research (2008)

4544  Noggin is a secreted cysteine-knot protein, which antagonizes BMP signaling by direct binding to TGFbeta superfamily members BMP-7 and BMP-4 and is involved in negative regulation of vasculogenesis. We previously demonstrated that noggin overexpression in endothelial cells abrogated migration, blocked endothelial transmigration in basal membrane inserts and caused abrogation of endotubular formation in vitro and in vivo. Therefore, we hypothesized that noggin effects could be anti-angiogenic and investigated whether noggin expression could potentially disrupt tumor growth in vivo. Wild-type MV522 lung carcinoma cells or MV522 overexpressing DsRed2 protein (MV522-DsRed2) were transduced by using bicistronic GFP/noggin lentiviral vectors. The expression of noggin in MV522 was confirmed by RT-PCR. Five groups of mice harboring ectopic MV522 tumors were studied: MV522-GFP (G), MV522-GFP-Noggin (GN), MV522-DsRed2 (R), tumors grown using mixed MV522-GFP and MV522-DsRed2 cells (GR), as well as MV522-GFP-Noggin and MV522-DsRed2 cells (GNR). GR and GNR tumors were grown using the same numbers of GFP+ and GFP-noggin+ cells mixed with DsRed2+ cells. The control group included wild-type MV522 (W) tumors. Tumors were implanted ectopically in the flank of nu/nu mice either subcutaneously, or in the muscle. Tumor growth was monitored using in vivo fluorescence imaging system. Ten days after the implantation there was visible tumor formation in the intramuscularly injected mouse groups W, G, R and GR and green, red and green/red fluorescence signals, respectively, were detected in G, R and GR tumors. Tumors in those groups grew rapidly and at 3 weeks after the implantation exceed the volumes of 2.5 cm3. In contrast, GN and GNR mice showed no tumor growth and no fluorescent signal was detectable during 4 weeks of observation. In the subcutaneously implanted mice (groups G, R and GR) the initial tumor growth was detectable only by fluorescence imaging. Twenty days after implantation tumor growth was present in the abdomen of these mice and the whole abdominal region was fluorescent. In the GNR mice slowly growing subcutaneous tumors were detected by using the fluorescence imaging system. However, these tumors consisted mainly of DsRed2-positive cells and their total signal area and intensity were less than 10% of G, R and GR groups. Therefore, the effect of noggin was inhibitive not only to the growth of tumors that were overexpressing it (i.e. MV522-GFP-Noggin), but also inhibited tumor growth in mixed populations of cells (i.e. MV522-DsRed2 implanted together with MV522-GFP-Noggin) suggesting that the tumor formation by tumorigenic MV522-DsRed2 cells was inhibited as a result of noggin secretion by neighboring cells. Taken together, our study demostrated that tranduced or secreted noggin protein shows strong inhibition of the invasive growth of MV522 tumors and has a potential for antiangiogenic treatment of cancer.
Cardiac monocytes and macrophages after myocardial infarction
Authors: Claire Peet, Aleksandar Ivetic, Daniel I Bromage, Ajay M Shah
Journal: Cardiovascular Research (2019)

Abstract Improvements in early interventions after acute myocardial infarction (AMI), notably, the increased use of timely reperfusion therapy, have increased survival dramatically in recent decades. Despite this, maladaptive ventricular remodelling and subsequent heart failure (HF) following AMI remain a significant clinical challenge, particularly because several pre-clinical strategies to attenuate remodelling have failed to translate into clinical practice. Monocytes and macrophages, pleiotropic cells of the innate immune system, are integral in both the initial inflammatory response to injury and subsequent wound healing in many tissues, including the heart. However, maladaptive immune cell behaviour contributes to ventricular remodelling in mouse models, prompting experimental efforts to modulate the immune response to prevent the development of HF. Seminal work in macrophage biology defined macrophages as monocyte-derived cells that are comprised of two populations, pro-inflammatory M1 macrophages and reparative M2 macrophages, and initial investigations into cardiac macrophage populations following AMI suggested they aligned well to this model. However, more recent data, in the heart and other tissues, demonstrate remarkable heterogeneity and plasticity in macrophage development, phenotype, and function. These recent insights into macrophage biology may explain the failure of non-specific immunosuppressive strategies and offer novel opportunities for therapeutic targeting to prevent HF following AMI. Here, we summarize the traditional monocyte-macrophage paradigm, experimental evidence for the significance of these cells in HF after AMI, and the potential relevance of emerging evidence that refutes canonical models of monocyte and macrophage biology.
Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions
Authors: Steffen Rickelt, Charlene Condon, Miyeko Mana, Charlie Whittaker, Christina Pfirschke, Jatin Roper, Deepa T. Patil, Ian Brown, Anthony R. Mattia, Lawrence Zukerberg, Qing Zhao, Runjan Chetty, Gregory Y. Lauwers, Azfar Neyaz, Lieve G.J. Leijssen, Katherine Boylan, Omer H. Yilmaz, Vikram Deshpande, Richard O. Hynes
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma–associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. Experimental Design: Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC. Results: Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs. Conclusions: Muscularis mucosae–based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.
Abstract C46: Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms
Authors: Dayana Reverón, Francisca Beato, Gina DeNicola, Antonio Ortiz, Barbara Centeno, Kun Jiang, Daniel Jeong, Mokenge Malafa, Pamela Hodul, Kaleena Deszi, Jennifer Permuth, Jason Fleming
Journal: Cancer Research (2019)

Abstract Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect pancreatic cancer at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic pancreatic cancer precursors that comprise nearly 50% of pancreatic cysts detected incidentally via computed tomography (CT) scans. Since IPMNs can progress from low- and moderate-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish the first living biobank of IPMN tumor organoids. IPMN tumors and adjacent normal pancreatic tissues were harvested from 15 patients undergoing pancreatic surgical resection at Moffitt Cancer Center &amp; Research Institute (Tampa, FL) between 2017 and 2019. Following immunohistopathologic analysis of primary tissues, organoid cultures were generated, expanded, and cryopreserved. Furthermore, organoid cultures were generated from cryopreserved tissues as well. Count and size of the organoids over time was determined via the Image-Pro Premier 3D Version digital platform. Genomic characterization of the organoids was performed through DNA fingerprinting, and a subset of cases were sequenced. The success rates of organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different IPMN subtypes tissues showed different morphologies in vitro, with the low- and moderate-grade pancreatobiliary subtypes showing the highest proliferation rates. This model has potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for detection and targets for chemoprevention. Citation Format: Dayana Reverón, Francisca Beato, Gina DeNicola, Antonio Ortiz, Barbara Centeno, Kun Jiang, Daniel Jeong, Mokenge Malafa, Pamela Hodul, Kaleena Deszi, Jennifer Permuth, Jason Fleming. Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C46.
The majority of A-to-I RNA editing is not required for mammalian homeostasis
Authors: Alistair M. Chalk, Scott Taylor, Jacki E. Heraud-Farlow, Carl R. Walkley
Journal: Genome biology (2019)

Adenosine-to-inosine (A-to-I) RNA editing, mediated by ADAR1 and ADAR2, occurs at tens of thousands to millions of sites across mammalian transcriptomes. A-to-I editing can change the protein coding potential of a transcript and alter RNA splicing, miRNA biology, RNA secondary structure and formation of other RNA species. In vivo, the editing-dependent protein recoding of GRIA2 is the essential function of ADAR2, while ADAR1 editing prevents innate immune sensing of endogenous RNAs by MDA5 in both human and mouse. However, a significant proportion of A-to-I editing sites can be edited by both ADAR1 and ADAR2, particularly within the brain where both are highly expressed. The physiological function(s) of these shared sites, including those evolutionarily conserved, is largely unknown.To generate completely A-to-I editing-deficient mammals, we crossed the viable rescued ADAR1-editing-deficient animals (Adar1E861A/E861AIfih1-/-) with rescued ADAR2-deficient (Adarb1-/-Gria2R/R) animals. Unexpectedly, the global absence of editing was well tolerated. Adar1E861A/E861AIfih1-/-Adarb1-/-Gria2R/R were recovered at Mendelian ratios and age normally. Detailed transcriptome analysis demonstrated that editing was absent in the brains of the compound mutants and that ADAR1 and ADAR2 have similar editing site preferences and patterns.We conclude that ADAR1 and ADAR2 are non-redundant and do not compensate for each other's essential functions in vivo. Physiologically essential A-to-I editing comprises a small subset of the editome, and the majority of editing is dispensable for mammalian homeostasis. Moreover, in vivo biologically essential protein recoding mediated by A-to-I editing is an exception in mammals.
Abstract B15: Therapeutic potential of targeting amino acid metabolism in pancreatic cancer
Authors: Martin Fernandez-Zapico, Dae Won Kim, Philip Philip, Alexander Vandell, Jonathan Eckard, Ron Korn, Giuseppe Del Priore, Diane Simeone
Journal: Cancer Research (2019)

Abstract Background: A wide range of cancers, including pancreatic cancer, display altered expression of amino acid transporter LAT-1. LAT-1 overexpression has been shown to be an important prognostic factor and predicts chemo resistance in pancreatic cancer (Kaira K, 2012; Altan B, 2018). Radiolabeled amino acids for PET imaging, including 3-18F-l-α-methyl-tyrosine ([18F] FAMT), have successfully leveraged cancer’s aberrant LAT1 expression and amino acid uptake for decades. SM-88 is a denatured D/L racemic form of α-methyl-tyrosine designed for selective uptake and disruption of protein synthesis in cancer cells, as well as disruption of catecholamine production via inhibition of tyrosine hydroxylase. Catecholamines have been reported to potentially have a role in driving pancreatic cancer progression and changes in the tumor immune status (Renz B, Cancer Cell 2018; Calvani M, Oncotarget 2014). Initial clinical and preclinical results with SM-88 indicate that this agent could pose a novel approach in the treatment of pancreatic cancer. Methods and Results: Initial xenograft models of human gastrointestinal cancers using monotherapy SM-88 showed a &amp;gt;50% decrease in tumor growth at three weeks of treatment (p&amp;lt;0.05). Ongoing preclinical experiments are testing the full pharmacodynamic effects of SM-88 on pancreatic cancer cells, as well as potential effects on the tumor microenvironment due to catecholamine interruption. In results from the ongoing phase 2 trial of SM-88 in heavily pretreated metastatic pancreatic cancer patients, SM-88 has shown monotherapy antitumor activity based on RECIST 1.1 criteria. Additionally, 16/24 patients demonstrated a reduction in circulating tumor cells, with the median nadir decline of 63%. LAT1 has been reported to be important in EMT transition and mesenchymal cell survival (Holldorsson S, Cancer letters 2017); examination of the impact of SM-88 on this important emerging biomarker is ongoing. Conclusion: Altered amino acid (LAT1) metabolism has been shown to be a negative prognosticator in pancreatic cancer outcomes and progression. Targeting LAT1 and amino acid pathways has been identified as a therapeutic approach in multiple cancers (Fuchs BC, Semin Ca Biol 2005). Initial and ongoing studies of SM-88 may clarify the potential utility of this approach in the treatment of pancreatic cancer. Citation Format: Martin Fernandez-Zapico, Dae Won Kim, Philip Philip, Alexander Vandell, Jonathan Eckard, Ron Korn, Giuseppe Del Priore, Diane Simeone. Therapeutic potential of targeting amino acid metabolism in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B15.
Intestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis: results from the TRUST&amp;UC study
Authors: Christian Maaser, Frauke Petersen, Ulf Helwig, Imma Fischer, Alexander Roessler, Stefan Rath, Dorothee Lang, Torsten Kucharzik
Journal: Gut (2019)

Prospective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice.TRansabdominal Ultrasonography of the bowel in Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography.At baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%-38.6%; descending colon 83.0%-42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001).IUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.