tbuckley/cabot-search huggingface dataset:
Abstract 2901: The role of basal and BRAF inhibitor-induced autophagy-driven secretion in remodeling the melanoma tumor secretome
Authors: Adam Kraya, David W. Speicher, Ravi Amaravadi
Journal: Cancer Research (2015)

Abstract Autophagy is a homeostatic process of cellular self-digestion and is an adaptive therapy resistance mechanism in cancer. Emerging studies indicate that autophagy is involved in secretion through non-classical mechanisms. It is not well understood, however, how this secretory function modifies the molecular composition of the tumor secretome, which plays an important role in tumor growth and tumor immune responses. In this work, we focused on the role of both basal and BRAF inhibitor (BRAFi)-induced autophagy in melanoma cells harboring BRAF V600E, a missense mutation observed in ∼60% of melanoma tumors. Using quantitative proteomics we previously showed that a small number of proteins were differentially secreted by low and high autophagy melanoma cells grown in three-dimensional culture. Secreted proteins associated with high autophagy included IL-1β, IL-8, LIF, FAM3C, and DKK3, which have known roles in tumorigenesis. Further, serum collected from untreated metastatic melanoma patients with high tumor autophagy levels exhibited higher levels of these proteins than serum from low autophagy patients. In the current study, melanoma cells with high autophagy and the BRAF V600E mutation (1205Lu) were treated with the BRAF inhibitor PLX4720, the autophagy inhibitor hydroxychloroquine (HCQ), PLX4720+HCQ, and the autophagy inducer rapamycin. The increase in autophagic flux upon the addition of PLX4720 or rapamycin was confirmed by western blotting and tandem fluorescently tagged LC3 (mCherry-eGFP-LC3). Secretomes were compared using quantitative proteomics, which resulted in identification of 1154 proteins with a false discovery rate of less than 1%. Hierarchical clustering and principal components analysis showed that secretomes from cells treated with the autophagy inducers rapamycin or PLX4720 correlated more closely with each other than those treated with HCQ either alone or in combination. A panel of proteins involved in extracellular matrix modification, cell-cell adhesion, and inflammation (including FAM3C and LIF) significantly increased in the supernatants of cells treated with PLX4720 or rapamycin and decreased in supernatants from cells treated with HCQ or HCQ+PLX4720. These results demonstrate that autophagy plays an active role in modifying the molecular composition of the tumor secretome. Proteins specifically shed in response to BRAF inhibitors and/or autophagy inhibition may have utility in the clinic for diagnostic and pharmacodynamic applications. Citation Format: Adam Kraya, David W. Speicher, Ravi Amaravadi. The role of basal and BRAF inhibitor-induced autophagy-driven secretion in remodeling the melanoma tumor secretome. [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 2901. doi:10.1158/1538-7445.AM2015-2901
Safety of Nonsteroidal Antiinflammatory Drugs
Authors: David T Felson
Journal: New England Journal of Medicine (2016)

Nonsteroidal antiinflammatory drugs (NSAIDs), one of the most widely used classes of drugs in the world, are effective antiinflammatory, analgesic, and antipyretic agents. Although they differ from one another in chemical class, all inhibit the synthesis of prostaglandins. Because prostaglandins serve a variety of physiological functions in organs throughout the body, NSAIDs frequently have side effects. For example, prostaglandins contribute to the protective barrier that prevents ulcerations in the mucosa of the stomach, and they are also critical in maintaining renal and gastromucosal perfusion when they are threatened. Thus, NSAIDs can increase the risk of gastric ulcers and of usually . . .
629. Intravenous Delivery of a MTMR2-Encoding AAV9 Vector Extends Lifespan and Improves Muscle Function in Mice with X-Linked Myotubular Myopathy
Authors: Nathalie Danièle, Laura Julien, Christelle Moal, Thibaut Jamet, Alban Vignaud, Ana Buj Bello
Journal: Molecular Therapy (2016)

X-linked myotubular myopathy is a rare genetic disease affecting the skeletal musculature. Male patients present profound neonatal muscle hypotonia and weakness, respiratory insufficiency, and in most cases have a very severe reduction in lifespan. At the pathological level, muscle fibers are hypotrophic and contain central nuclei with disorganized mitochondria and triads. The disease is caused by mutations in the MTM1 gene, which encodes myotubularin, the founder member of a family of 15 homologous proteins in mammals (including MTMR1 to 14). We recently demonstrated the therapeutic efficacy of intravenous delivery of rAAV vectors expressing MTM1 in murine and canine models of myotubular myopathy. In the present study, we tested whether Mtmr1 and Mtmr2 overexpression, Mtm1 closest homologs, could also rescue the XLMTM phenotype. Recombinant serotype-9 AAV vectors encoding either MTM1, MTMR1 or MTMR2 under the control of the desmin promoter were compared by injection into the tibialis anterior muscle of two-week-old Mtm1 deficient mice. Two weeks after vector delivery, a therapeutic effect was observed with Mtm1 and Mtmr2, but not Mtmr1, with Mtm1 being the most efficacious transgene. We further explored a systemic route of administration, intravenous injection of a single dose of rAAV9-Mtmr2 in XLMTM mice ameliorated muscle histology and strength, and extended lifespan throughout the 3-month period of the study. Even though Mtmr2-treated mutant mice remained smaller than their wild-type counterparts, with partial increase in body weight and myofiber size, most importantly, the contractile force of myotubularin-deficient muscles improved strongly. Altogether, these results establish the proof-of-concept that overexpression of MTMR2 in skeletal muscle represents a novel therapeutic approach for myotubular myopathy.
Graphic Medicine
Authors: Michael J. Green, MK Czerwiec
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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Abstract B45: Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids
Authors: Ling Huang, Audrey Holtzinger, Ishaan Jagan, Cristina Nostro, Rennian Wang, Lakshmi Muthuswamy, Cheryl Arrowsmith, Sean Cleary, David Schaeffer, Michael Roehrl, Tsao Ming-Sound, Steven Gallinger, Gordon Keller, Senthil Muthuswamy
Journal: Cancer Research (2016)

Abstract There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. Citation Format: Ling Huang, Audrey Holtzinger, Ishaan Jagan, Cristina Nostro, Rennian Wang, Lakshmi Muthuswamy, Cheryl Arrowsmith, Sean Cleary, David Schaeffer, Michael Roehrl, Tsao Ming-Sound, Steven Gallinger, Gordon Keller, Senthil Muthuswamy.{Authors}. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B45.
New Candidate Regulators of Hematopoietic Stem Cells Identified from Transcriptional Comparisons of Highly Purified Populations of Longterm Repopulating Cells with Markedly Different in Vivo Self-Renewal Activities
Authors: David G Kent, Michael R Copley, Claudia Benz, Brad J Dykstra, Elaine Ma, Jay Cheyne, Yongjun Zhao, Maura Gasparetto, Allen Delaney, Clayton Smith, Marco Marra, Connie J. Eaves
Journal: Blood (2008)
Early ICU Admission Of Newly Diagnosed Acute Myeloid Leukemia With No Organ Failure
Authors: Elodie Elkaim, Djamel Mokart, Norbert Vey, Aude Charbonnier, Evelyne D’Incan, Jerome Rey, Thomas Prebet, Jean-Paul Brun, Antoine Sannini, Muriel Picard, Christian Recher, Anne Etienne
Journal: Blood (2013)
Stro-1 Positive and Stro-1− Negtive Human Mesenchymal Stem Cells Express Different Levels of Immunosuppression.
Authors: Dominique Thierry 9, Y. Z. Zhang 1, A. Chapel 2, M. Benshidoum 3, C. Mazurier 4, S. Bouchet 5, A. Nashef 6, M. C. Lopez 7, N. C. Gorin 8, L. Fouillard 9
Journal: Blood (2004)
Abstract 5055: Role of insulin-like growth factor 1 receptor in pancreatic cancer pathogenesis
Authors: Ramadevi Subramani Reddy, Arunkumar Arumugam, Sushmita Bose Nandy, Elizabeth Gonzalez, Viviana Gonzalez, Sandrine Bonkoungou, Andrew Ortega, Rajkumar Lakshmanaswamy
Journal: Cancer Research (2015)

Abstract Pancreatic cancer incidence and the associated mortality are increasing worldwide. This indicates that there is a clear lack of understanding about pancreatic cancer pathogenesis. This can be attributed to the lack of specific symptoms to diagnose the disease at an early stage. Various growth factor receptors are known to play a vital role in the development of pancreatic cancer. In the present investigation, we have attempted to target insulin-like growth factor-1 receptor (IGF-1R) due to its well-established role in progression of pancreatic cancer. RNA interference (small interfering RNA [siRNAs]) approach targeted to IGF-IR was used to study the effect of IGF-1R silencing on pancreatic cancer growth and metastasis. For this we used HPAC and PANC-1 pancreatic cancer cell lines and primary pancreatic cancer tissue array. Our results demonstrated that silencing IGF-1R remarkably inhibited pancreatic cancer growth and metastasis. Silencing IGF-1R significantly altered key signaling molecules such as PI3K, AKT, MAPK, ERK1/2, mTOR, PTEN, p70S6K, JAK2 and STAT3. Further IGF-1R silencing also reduced epithelial to mesenchymal transition (N-Cad, Notch, Snail, Slug and Vimentin). In addition, silencing IGF-1R inhibited cell viability, invasive and migratory capabilities of PANC-1 and HPAC pancreatic cancer cell lines. Colony forming ability was also drastically reduced in IGF-1R silenced cells. Flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R decreased the expression of Kras, which is altered in almost 95% of pancreatic cancers. Overall, our data clearly demonstrates the significance of IGF-1R in pancreatic cancer pathogenesis and also identifies IGF-1R as a potential target for pancreatic cancer treatment and therapy. Citation Format: Ramadevi Subramani Reddy, Arunkumar Arumugam, Sushmita Bose Nandy, Elizabeth Gonzalez, Viviana Gonzalez, Sandrine Bonkoungou, Andrew Ortega, Rajkumar Lakshmanaswamy. Role of insulin-like growth factor 1 receptor in pancreatic cancer pathogenesis. [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 5055. doi:10.1158/1538-7445.AM2015-5055
The role of chemoradiotherapy in sub-optimally resectable locally advanced adenocarcinoma of the pancreas
Authors: R. Gillmore, V. Laurence, S. Paisey, S. Mukherjee, E. Hudson, S. Raouf, C. Collis, J. S. Tobias, K. Goodchild, J. Bridgewater
Journal: Journal of Clinical Oncology (2008)

15589 Background: The role of chemoradiotherapy (CRT) in locally advanced, sub-optimally resectable pancreatic tumours (LAPC) has not been evaluated. Methods: An analysis was conducted of 51 patients with LAPC treated between January 2002 and June 2007. Treatment consisted of CRT alone in 5 patients (radiotherapy dose 45–50.4Gy with gemcitabine (GEM) as a radiosensitiser) or chemotherapy (GEM alone, GEM/capecitabine (CAP) or GEM/cisplatin (CIS) followed by CRT (30–50.4Gy, GEM, CAP or GEM/CIS) in the remaining 46 patients. Patients were restaged following CRT and prior to being considered for surgery. Results: Median follow up was 14 months. Among 51 patients analysed, 9 did not complete the intended treatment for the following reasons: a decrease in performance status (PS) associated with toxicities from the initial chemotherapy (n=2), progression during/immediately after initial chemotherapy (n=3), a decrease in PS associated with toxicities from the CRT (n=3) and stent blockage (n=1). Among 42 patients who completed treatment there was 1 complete response, 13 partial responses, 20 stable disease and only 6 progressions, according to WHO criteria, with no assessment carried out for 2 patients. Median (range) survival among patients completing CRT was 16 months (5–54) compared to 8 months (4–14) among those who did not complete therapy (P <0.0001). Radiological regression justified surgical exploration in 9 patients of whom 4 underwent definitive surgery (R0 n=3, R1 n=1). All 4 operated patients were alive at censor with a median follow up of 34.5 months compared to a median survival of 16 months (5–54) among the 38 non-operated patients (P <0.05). Conclusions: Only 4 patients (9.5%) proceeded to definitive surgery, suggesting that CRT for this population is unlikely to be a successful strategy in converting patients with LAPC to curative surgery. Despite this, the median survival of 16 months compares well to the 10 months described in historical data suggesting local control does improve survival. We propose that this be investigated in a study of chemoradiation versus surveillance following optimum treatment for locally advanced pancreatic adenocarcinoma. No significant financial relationships to disclose.
530. Development of New Lentiviral Vectors With a Reduced Splicing Interference Potential and a Safer In Vivo Genotoxic Profile
Authors: Daniela Cesana, Andrea Calabria, Pierangela Gallina, Laura Rudilosso, Giulio Spinozzi, Eugenio Montini
Journal: Molecular Therapy (2015)

The excellent therapeutic potential of self-inactivating (SIN) lentiviral vectors (LV) has been demonstrated in pre-clinical studies and clinical trials. However, weaker mechanisms of insertional mutagenesis could endanger their clinical applications. Systemic vector injection into newborn tumor-prone Cdkn2a-/- and Cdkn2a+/-mice, conducted in our previous work, demonstrated that SINLVs harboring strong or moderate enhancer/promoters in internal position caused acceleration in hematopoietic tumor onset with respect to control mice. Integration sites analyses of vector-induced tumor showed that oncogene activations or tumor suppressor inactivation by LV integrations occur by combining mechanisms of transcript truncation, induction of aberrant splicing and/or enhancer-mediated overexpression of cellular transcription units. Although oncogene activation may be reduced by the use of self-inactivating design, moderate cellular promoters and insulator sequences how to reduce genotoxic splicing-capture events and aberrant transcript formation triggered by vector integration is still unclear. From this and a previous study, we identified the LV sequences most frequently involved in chimeric transcript formation. In our rationale, these LV sequences could be tagged by sequences complementary to microRNAs (mirT sequence) active in hematopoietic cells in order to allow selective degradation, through the miRNA pathway, of vector-mediated aberrantly spliced transcripts. Hence, we specifically designed SIN LVs harboring mirT sequences recognized by mir223 and mir142-3p (that are expressed in hematopoietic lineages) within the SIN LTR (mirsT-LTR LV) or in the vector backbone and outside the gene expression cassette (mirT LV). We then assessed the genotoxicity of the SIN LVs harboring mirT sequences by taking advantage of our in vivo models. Interestingly, injection of mirsT-LTR LV (N=73) and mirT LV (N=73) in Cdkn2a-/- mice did not caused any significant acceleration in hematopoietic tumor onset compared to control un-injected mice (N=40). Similar results have been obtained after injection in Cdkn2a+/- mice (N=28 for mirsT-LTR LV, N=26 for mirT LV and N=34 un-injected mice). We are currently performing integration site analyses in Cdkn2a-/- and Cdkn2a+/- treated mice to dissect if and how the integrated mirsT-LTR LV and mirT LV proviral genome interacts with the surrounding cellular genome. Overall, these studies show that this new advanced design lentiviral vectors completely abrogated residual vector genotoxicity in highly sensitive mouse models and could represent the vector design of choice in future gene therapy applications.
Expression of PIM-2 and NF-κB Is Increased in Patients with Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) and Correlates with Complete Remission Rate
Authors: Katarzyna Kapelko-Slowik, Donata Urbaniak-Kujda, Dariusz Wolowiec, Jaroslaw Dybko, Bozena Jazwiec, Miroslaw Slowik, Jacek Jakubaszko, Tomasz Owczarek, Krzysztof Grzymajlo, Kazimierz Kuliczkowski
Journal: Blood (2011)
The Functional Activity of the OCT-1 Protein Is Predictive of Molecular Response and Survival in CP-CML Patients Treated with Imatinib: A 5 Year Update of the TIDEL Trial.
Authors: Deborah L White, Verity A Saunders, Amity Frede, Phuong Dang, Stephanie Zrim, Michael Philip Osborn, Paul Manley, Timothy Hughes
Journal: Blood (2009)
Elipse, the first procedureless gastric balloon for weight loss: a prospective, observational, open-label, multicenter study
Authors: Evzen Machytka, Shantanu Gaur, Ram Chuttani, Martina Bojkova, Tomas Kupka, Marek Buzga, Andreas Giannakou, Kandiliotis Ioannis, Elisabeth Mathus-Vliegen, Samuel Levy, Ioannis Raftopoulos
Journal: Endoscopy (2016)

<b>Background and study aims</b> Conventional gastric balloons for weight loss require endoscopy for placement and removal. The Elipse device is swallowed, resides in the stomach for 4 months, and is then expelled. The objectives of this study were to assess the safety of Elipse and to measure its effects on weight loss, metabolic parameters, and quality of life. <b>Methods</b> Each participant swallowed one Elipse device, which was filled with 550 mL of filling fluid through a thin delivery catheter that was then removed. Weight was measured every 2 weeks, and metabolic parameters and quality of life were assessed at baseline and at trial exit. <b>Results</b> 34 patients, with a mean body mass index of 34.8 kg/m<sup>2</sup>, were enrolled. All 34 patients successfully swallowed the Elipse device. All adverse events were either self-limiting or resolved with medication. All balloons were safely excreted. At 4 months, the mean percent total body weight loss was 10 %. Mean waist circumference was reduced by 8.4 cm. Improvements were also seen in hemoglobin A1c, triglycerides, low density lipoprotein, and blood pressure. At trial exit, quality of life measures had improved across all domains. <b>Conclusion</b> These results demonstrate clinically significant weight loss with the Elipse, the first procedureless gastric balloon. The weight loss was similar to that seen in previous studies of endoscopically placed balloons. In addition, Elipse therapy led to improvements in waist circumference, several metabolic parameters, and overall quality of life. ClinicalTrials.gov identifier: NCT 02802007.
Abstract 4325: The role of FGFR fusion genes as novel oncogenic targets
Authors: Gabriela Martinez Cardona, Katherine Bell, Dana Gaffney, Joseph Portale, Suso Platero, Matthew Lorenzi, Jayaprakash Karkera
Journal: Cancer Research (2015)

Abstract Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Gene fusions can lead to the production of oncogenic fusion proteins or to enhanced expression of oncogenes. Advances in next-generation sequencing technologies have made possible to identify more efficiently novel fusion proteins in cancer. Recently, several FGFR fusion genes with intact kinase domains have been identified in bladder, lung, breast, thyroid, oral, and prostate cancers, as well as other tumor types. To date, several FGFR3 partner genes have been identified. In this study, we focused on the FGFR3-BAIAP2L1 and FGFR3-TACC3 gene fusions and investigated their tumorigenic activity, mechanism of activation, and sensitivity to the FGFR inhibitor JNJ-42756493. To determine the role and significance of FGFR fusion genes in cancer, FGFR fusion expression constructs were designed and individually transfected into normal rat kidney epithelial cells. FGFR fusion overexpressing cells not only showed increased cell proliferation, but also exhibited anchorage-independent cell growth. Cells harboring the FGFR fusions showed increased sensitivity to the FGFR inhibitor JNJ-42756493 in vitro, whereas the wild-type FGFR3 did not in the absence of FGF ligands. In addition, Western blotting analyses indicated that the overexpression of the FGFR fusions resulted in highly activated proteins that induce signaling via the MAPK pathway. These findings underline the oncogenic potential of the FGFR fusion genes and highlight their unique potential as predictive biomarkers in the selection of patients for FGFR-targeted therapy. Citation Format: Gabriela Martinez Cardona, Katherine Bell, Dana Gaffney, Joseph Portale, Suso Platero, Matthew Lorenzi, Jayaprakash Karkera. The role of FGFR fusion genes as novel oncogenic targets. [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 4325. doi:10.1158/1538-7445.AM2015-4325