tbuckley/cabot-search huggingface dataset:
TMOD-11. MODELING AND TARGETING KIAA1549-BRAF DRIVEN CNS TUMORS
Authors: Ram Kannan, Peter Cook, Zhan Yao, Jieun Lee, Chiara Mastroleo, Paul Ogrodowski, Neal Rosen, Robert Benezra, Andrea Ventura
Journal: Neuro-Oncology (2019)

Low-grade gliomas account for ~30% of primary central nervous system tumors arising in children. Although LGGs grow slowly, inoperable tumors can lead to morbidity and premature death. The most common oncogenic event observed in nearly 70% of cases of Pilocytic astrocytomas (PA) and diffuse leptomeningeal glioneuronal tumors (DLGT)—is a recurrent tandem duplication on chromosome 7. This complex rearrangement results in the fusion of BRAF C-Terminus comprising of the kinase domain with KIAA1549 N-Terminus, an uncharacterized gene. Apart from creating this fusion, the entire region between KIAA1549 and BRAF comprising of 17 protein coding genes is duplicated. Currently, there are no accurate preclinical models for KIAA1549-BRAF duplication which has hindered targeted therapy for this class of pediatric brain tumors. Although cDNA overexpression of KIAA1549-BRAF has been shown to activate the MAPK pathway, in vivo models overexpressing the fusion protein lack the physiological features of either PA or DLGT. Our hypothesis in this project is that generating the entire tandem duplication event in addition to the Kiaa1549-Braf fusion is necessary for modeling the patho-physiological characteristics of the pediatric brain tumors. We have employed CRISPR based somatic genome editing to generate the tandem duplication of Kiaa1549-Braf in p53-/- adult neural stem cells ex-vivo, which results in brain tumors predominantly growing in the subarachnoid/leptomeningeal space and displays histopathological features of human DLGT. Further, we have shown that the Kiaa1549-Braf driven tumor lines can be inhibited by next generation Braf dimer inhibitors. In summary, we have developed a new preclinical model for Kiaa1549-Braf driven brain cancer and demonstrated efficacy against a new preclinical Braf inhibitor.
Association of Checkpoint Inhibitor–Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non–Small Cell Lung Cancer
Authors: Fiamma Berner, David Bomze, Stefan Diem, Omar Hasan Ali, Mirjam Fässler, Sandra Ring, Rebekka Niederer, Christoph J. Ackermann, Petra Baumgaertner, Natalia Pikor, Cristina Gil Cruz, Willem van de Veen, Mübeccel Akdis, Sergey Nikolaev, Heinz Läubli, Alfred Zippelius, Fabienne Hartmann, Hung-Wei Cheng, Gideon Hönger, Mike Recher, Jonathan Goldman, Antonio Cozzio, Martin Früh, Jacques Neefjes, Christoph Driessen, Burkhard Ludewig, Ahmed N. Hegazy, Wolfram Jochum, Daniel E. Speiser, Lukas Flatz
Journal: JAMA Oncology (2019)

Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy.To gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer.This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year.Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations).Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P < .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy.These findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy.
A novel oral prodrug-targeting transporter MCT 1: 5-fluorouracil-dicarboxylate monoester conjugates
Authors: Yixin Sun, Dongyang Zhao, Gang Wang, Qikun Jiang, Mengran Guo, Qiming Kan, Zhonggui He, Jin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Monocarboxylate transporter 1 (MCT1) is responsible for oral absorption of short-chain monocarboxylic acids from small intestine, hence, it's likely to serve as an ideal design target for the development of oral prodrugs. However, potential application of MCT1 to facilitate the oral delivery is still unclear. Irregular oral absorption, poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil (5-FU). Herein, we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages. Interestingly, due to high MCT1 affinity and good gastrointestinal stability, 5-FU-octanedioic acid monoester prodrug exhibited significant improvement in membrane permeability (13.1-fold) and oral bioavailability (4.1-fold) compared to 5-FU. More surprisingly, stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells, which provides an ideal foundation for the improvement of oral bioavailability. In summary, good gastrointestinal stability, high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs, and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.
TMOD-14. INNOVATIVE 3D MODEL FOR THE ESTABLISHMENT OF PRIMARY PAEDIATRIC LOW-GRADE GLIOMA (LGG) CULTURES: NEW PLATFORM FOR ADVANCED PRECLINICAL STUDIES OF INNOVATIVE AND IMMUNOTHERAPEUTIC APPROACHES
Authors: Tamascia Belardinilli, Claudia Manuela Arnone, Angela Mastronuzzi, Giulia Ceglie, Antonella Cacchione, Andrea Carai, Evelina Miele, Francesca Diomedi Camassei, Vinicia Assunta Polito, Cristiano De Stefanis, Concetta Quintarelli, Biagio De Angelis, Franco Locatelli, Ignazio Caruana, Francesca Del Bufalo
Journal: Neuro-Oncology (2019)

Solid tumours are characterized by a high structural complexity that is difficult to reproduce with common bidimensional (2D) systems. We developed an innovative fibrin-based hydrogel 3D model and tested it as platform to establish primary LGG cultures, otherwise difficult to maintain owing to the activation of senescence pathways. To date, 37 samples were cultured in both 2D and 3D platforms (19 astrocytomas and 18 gangliogliomas), with an average culture duration of 177+13 days, showing that the 3D-culture enables the stabilization of LGG. Whereas in the 2D-culture the cells showed overtime a significant reduction in the average culture days between each passage (average P1-P3:35+6 days; P3-P6: 29+5; >P6: 17+5), suggesting the selection of a peculiar clone, in the 3D-setting, we observed a more regular growth (average P1-P3:44+5 days; P3-P6: 64+20;>P6: 48+16). Cell lines identity was confirmed by short tandem repeats (STRs) and the immunohistochemical characterization (H&E, Ki67, tumour and differentiation markers) in 3D cultures revealed phenotype, cellular organization and proliferative rates closer to those observed in the onset samples, as compared to the 2D. We then analyzed the methylation profile and preliminary results suggest that the 2D lines evolve towards different lineages. The analysis of cell senescence using ß-galactosidase assay revealed a lower senescence in the 3D cultures (3D:12,28%+4,3% of the cells vs 2D:50,69%+18,46%; p=0,008). Lastly, we evaluated the responses to radiotherapy by MTS assay, and showed that 2D-cultured cells are more sensitive to treatment than 3D (2D: untreated, 0,0232+0,023, 160 Gy 0,089+0,025; 3D: untreated 0,235+0,09, 160 Gy 0,169+0,08), suggesting an overestimation of the efficacy of such treatment by the 2D-setting, therefore reducing the predictive power. The response to chemotherapy and more innovative approaches (i.e. Oncolytic Adenovirus) is currently under evaluation, the preliminary results confirming a similar finding. Overall, the 3D-culture offers an innovative platform for biological and therapeutic studies.
Abstract 16267: NADPH Oxidase Nox4 Up-regulation Contributes to the Worsening of Pressure Overload-induced Cardiac Dysfunction in Angiopoeitin-like 2 Knockdown Mice
Authors: Cécile Martel, Adeline Raignault, Carol Yu, Marc-Antoine Gillis, Maya Mamarbachi, Nicolas Bousette, Natacha Duquette, Nathalie Thorin-Trescases, Christine Des Rosiers, Eric Thorin
Journal: Circulation (2015)

Background: Angiopoietin-like 2 (angptl2) is a circulating protein promoting vascular inflammation and endothelial dysfunction in mice, but little is known on its impact on cardiac function. Our previous results suggest that knocking down angptl2 in mice (KD) worsens pressure overload-induced cardiac dysfunction while preserving cerebral artery structure and endothelial function. As NADPH oxidase NOX4 is known to produce H2O2, a deleterious hypertrophic stimulus in cardiomyocytes but also a vasodilatory factor, we hypothesized that increased expression of NOX4 contributes to the aggravated cardiac dysfunction observed in KD mice. Methods/Results: Cardiac function was measured in vivo by Millar catheter in KD mice versus their wild-type (WT) littermates in response to a 6-week pressure overload induced by transverse aortic constriction (TAC). Concomitantly to a worsened cardiac remodeling and an aggravated cardiac dysfunction compared to WT-TAC mice, only KD-TAC mice displayed an increase in cardiac mRNA and protein expression of NOX4 (p&lt;0.05 vs. WT, n=8). To specifically decrease cardiac NOX4 expression, we performed, two weeks after TAC surgery, a single i.v. injection of cardiac specific associated adenovirus AAV9 expressing a NOX4-targeted shRNA or a scrambled shRNA. In KD-TAC mice, the AAV9-shNOX4 limited cardiac hypertrophy as evidenced by a smaller heart/tibia ratio (Table, * p&lt;0.05). Moreover, cardiac function in KD-TAC-AAV9-shNOX4 mice was partly prevented by maintaining contraction and relaxation maximal velocities and by limiting the abnormal rise of minimal pressure and end diastolic pressure caused by TAC (Table, * p&lt;0.05). Conclusion: Angptl2 knockdown worsens cardiac hypertrophy and contractile dysfunction induced by pressure overload: cardiac up-regulation of NOX4 could contribute to these deleterious effects in angptl2 KD mice.
Abstract 11902: Mitochondria-targeted Antioxidant Therapy Improves Age-related Collateral Development With Ischemia Through p53 and Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α)
Authors: Shunsuke Miura, Tomoki Kokubun, Shu-ichi Saitoh, Yasuchika Takeishi
Journal: Circulation (2016)

Background: Aging is a major factor to decline collateral growth with ischemia, however, the underlying mechanism remains unclear. Methods and Results: We investigated the pathophysiological role of mitochondrial oxidative stress (MOS) in hindlimb ischemia with femoral artery ligation in young mice [8 weeks old (W)] and old mice (80 W) with or without treatment of a mitochondria-targeted antioxidant, MitoTEMPO [180 μg/kg/day, from before operative day 7 to post operative day (POD) 21] infusion using a subcutaneously implanted mini-pump. The recoveries of cutaneous blood flow in hindlimb and capillary density on POD 21 were lower in old mice than in young mice, that were improved in MitoTEMPO-treated old mice. Mitochondrial DNA damage was appeared in ischemic skeletal muscles of old mice, that was eliminated by MitoTEMPO treatment. On POD 2, treatment of MitoTEMPO suppressed the level of p53, the ratio of Bax/Bcl-2 and upregulated the levels of HIF-1α and VEGF in ischemic skeletal muscles of old mice. On POD 21, treatment of MitoTEMPO preserved the level of PGC-1α and its transcriptional factor, estrogen-related receptor α, in ischemic skeletal muscles of old mice. Ischemic soleus of old mice showed lower mitochondrial respiratory control ratio (state 3 respiration/state 4 respiration) on POD 21 than that of young mice, that was recovered in MitoTEMPO-treated old mice (young mice: 3.36±0.08, Old mice: 2.15±0.24 vs. MitoTEMPO-treated old mice: 3.37±0.03, P&lt;0.01). Conclusion: These data suggest that scavenging of MOS recovers collateral growth with ischemia through suppression of p53 and preservation of PGC-1α.
Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients
Authors: Jean-François Timsit, Romain Sonneville, Andre C. Kalil, Matteo Bassetti, Ricard Ferrer, Samir Jaber, Fanny Lanternier, Charles-Edouard Luyt, Flavia Machado, Malgorzata Mikulska, Laurent Papazian, Fréderic Pène, Garyphalia Poulakou, Claudio Viscoli, Michel Wolff, Lara Zafrani, Christian Van Delden
Journal: Intensive Care Medicine (2019)
Abstract 291: MANF, a Structurally Unique ER Stress-inducible Protein, Restores ER-protein Folding in ER Stressed Cardiac Myocytes and in the Ischemic Heart
Authors: Adrian Arrieta, Winston T Stauffer, Amber N Pentoney, Erik A Blackwood, Shirin Doroudgar, Christopher C Glembotski
Journal: Circulation Research (2016)

The sarco/endoplasmic reticulum (SR/ER) of cardiomyocytes is a critical site of protein synthesis and folding, as most secreted and membrane proteins including receptors, growth factors, ion channels, and calcium-handling proteins are made at this location. Myocardial ischemia induces ER stress, during which toxic, misfolded proteins accumulate in the SR/ER and contribute to cardiomyocyte death. The branch of the ER stress response mediated by the transcription factor, ATF6, induces ER chaperones that restore SR/ER protein folding. We found that ATF6 also induces mesencephalic astrocyte-derived neurotrophic factor (MANF), a novel, ubiquitously expressed, ER-luminal protein of unknown function. MANF is structurally unique, thus its function cannot be inferred by structural analogy to known proteins. Since it is ATF6-inducible, and resides in the ER lumen, we hypothesized that MANF is an ER chaperone required for optimal viability of cardiac myocytes during ER stresses, including ischemia. The characteristics of MANF gene induction by ER stress, and the effects of MANF knockdown on the ER stress response and cell viability were determined in cultured neonatal rat ventricular myocytes (NRVM). The ability of recombinant MANF to restore structure and function to model misfolded proteins was also examined. Finally, the effects of MANF loss-of-function in the ischemic heart, in vivo , were determined by generating a transgenic mouse model that expresses a cardiomyocyte-specific MANF-targeted microRNA. MANF induction and functional characteristics phenocopied those of a well-studied ER chaperone, glucose-regulated protein 78 (Grp78). Like Grp78, MANF was induced by ER stress in an ATF6-dependent manner. Like knockdown of Grp78, knockdown of MANF in NRVM increased myocyte death in response to ER stress. Like recombinant Grp78, recombinant MANF exhibited a robust ability to restore structure and function to model misfolded proteins, in vitro. Finally, MANF knockdown in the heart, in vivo , increased damage in a mouse model of myocardial infarction. These results suggest that MANF is an SR/ER-resident chaperone required for restoration of SR/ER protein folding during the adaptive ER stress response, and decreasing tissue damage in the ischemic heart.
Acupuncture May Reduce Menopausal Symptoms
Authors: Anita Slomski
Journal: JAMA (2019)

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DIPG-37. THE KETONE BODY β-HYDROXYBUTYRATE ACTS AS AN EPIGENETIC MODIFIER AND INCREASES RADIATION-INDUCED DNA DAMAGE IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Alex P Rossi, Nelofer Syed, Cynthia Wetmore, Adrienne C Scheck
Journal: Neuro-Oncology (2019)

Diffuse Intrinsic Pontine Glioma (DIPG) is a highly infiltrative pediatric tumor with a median survival of approximately 9 months. Due to its location, the tumor is generally considered inoperable and there are few therapeutic options. Radiation is the only primary treatment for these tumors; however, this provides only short-term benefits. New therapeutic modalities are critically needed, and recent publications have suggested that a more effective treatment regime may involve multiple concurrent therapies that also potentiate radiation. A variety of combination treatments are under investigation, particularly those including histone deacetylase inhibitors (HDACi). Unfortunately, the use of multiple pharmaceutical agents often leads to unacceptable toxicity and side effects. One potential non-toxic therapy is metabolic ketosis which can be achieved using a therapeutic ketogenic diet (KD). The KD causes an increase in blood ketones and a decrease in blood glucose and has been used to safely treat refractory pediatric epilepsy. We have previously used human and murine high-grade glioma cells and a mouse model of high grade glioma to demonstrate that therapeutic ketosis has pluripotent anti-tumor activity alone and in combination with radiation. BHB has been shown to act as an endogenous HDACi. As such, the potential therapeutic underpinnings of the KD may involve the epigenetic-modifying capabilities of BHB. We now report that BHB causes significant growth inhibition in a DIPG cell line (SU-DIPG33; a generous gift from M. Monje, Stanford U.). In addition, BHB increases radiation induced DNA damage as measured by γH2AX western blot analysis. These data suggest that therapeutic ketosis may be a non-toxic adjuvant therapy that both potentiates radiation and inhibits the growth of DIPG cells. (supported by Students Supporting Brain Tumor Research and the Jaydie Lynn King Program in Neuro-oncology).
Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial
Authors: Philipp Schuetz, Rebecca Fehr, Valerie Baechli, Martina Geiser, Manuela Deiss, Filomena Gomes, Alexander Kutz, Pascal Tribolet, Thomas Bregenzer, Nina Braun, Claus Hoess, Vojtech Pavlicek, Sarah Schmid, Stefan Bilz, Sarah Sigrist, Michael Brändle, Carmen Benz, Christoph Henzen, Silvia Mattmann, Robert Thomann, Claudia Brand, Jonas Rutishauser, Drahomir Aujesky, Nicolas Rodondi, Jacques Donzé, Zeno Stanga, Beat Mueller
Journal: The Lancet (2019)
Evaluation of the onset and progression of prostatic bone metastasis with Micro-CT imaging in a mouse model
Authors: Christopher T. Winkelmann, Wynn A. Volkert, Timothy J. Hoffman
Journal: Cancer Research (2004)

5124  Prostate cancer will be diagnosed in approximately 220,000 men in the US in 2003 (ACS Cancer Facts and Figures 2003). As many as 60%-90% of advanced cases of prostate cancer will develop bone metastases. In order to evaluate the efficacy of new therapies for prostate cancer bone metastatsis, mouse models of bone metastasis using human prostate cancer cell lines have been developed. In the literature, these bone metastasis models have been characterized by histopathology, planar radiographs, and, more recently, optical imaging. The purpose of this study is to determine if the development and progression of metastatic bone lesions can be followed in mice by Micro-CT imaging. Herein, we report the characterization of a mouse model of prostate cancer bone metastasis using non-invasive Micro-CT imaging correlated with histopathology. SCID mice were inoculated by intracardiac injection with 5x105 androgen-independent human prostate (PC-3) cancer cells. To determine successful intracardiac injection, planar nuclear scintigraphic images of mice were obtained immediately post-injection of PC-3 cells combined with 100 μCi of TcO4- to confirm intracardiac inoculation. The mice were then serially imaged under anesthesia by Micro-CT every week to follow metastatic lesion development. Mice were euthanized at the development of adverse clinical signs or at post-inoculation Day 56, and tissues were collected for histopathologic evaluation. Intracardiac inoculation was successful in 53% of mice by nuclear scintigraphy evaluation. Metastatic bone lesions were detected by Micro-CT imaging in 75% of the successfully injected mice as early as 21 days after cell inoculation. Bone metastasis lesion sites clearly identified by Micro-CT imaging included the tibia, fibula, mandible, humerus, and ulna. Bone lesions as small as 0.75 mm in diameter were clearly visualized. Multiple bone lesions occurred in 66% of the mice. Other metastatic tumor sites identified by histopathology following necropsy included adrenal gland, kidney, lung, and subcutaneous tissue. Soft tissue tumors including lung and subcutaneous tumors were identified following retrospective analysis of Micro-CT images. Tumors and calcifications were also noted in 30% of the mice on histopathology of the heart. Myocardial tumor involvement was located presumably along the injection tract. All metastatic lesions were confirmed by histopathology. These studies have shown that Micro-CT imaging can be used to follow the progression of bone lesions of an androgen independent prostate cancer bone metastasis model. These studies also demonstrate bone metastases of prostate cancer can be detected with lesions less than 1 mm in diameter and studied throughout disease progression using Micro-CT imaging techniques. This work was supported by NIH Grant DHHS-1P50-CA13013-01, NIH Grant T32 RR07004, and American Cancer Society Grant RSG-99-331-04-CDD.