tbuckley/cabot-search huggingface dataset:
Abstract 1751: Preclinical development of a novel multi-targeted kinase inhibitor, MG516, for the treatment of sarcoma
Authors: Kathryn S. Ivy, Parag P. Patwardhan, Gary K. Schwartz
Journal: Cancer Research (2014)

Abstract Receptor tyrosine kinases (RTKs) are key regulators of tumor development as well as metastasis, aiding in the epithelial-mesenchymal transition, migration and angiogenesis. RTK signaling pathways such as VEGFR, PDGFR, and c-Met have been shown to be critical for cell survival, proliferation and metastasis in sarcomas. RTK inhibitors have been used with moderate success to block tumor cell survival and proliferation, however, internal compensatory signaling pathways give rise to drug resistance in a majority of cases. MG516, is a novel multi-targeted tyrosine kinase inhibitor that blocks RTK signaling pathways including c-Met, Ephrin receptors (Eph), and VEGFR with low nanomolar IC50 values. We evaluated the RTK inhibition profile and anti-proliferative effect of MG516 in a diverse panel of sarcoma cell lines including malignant peripheral nerve sheath tumor (MPNST), Ewing's sarcoma (A673) and leiomyosarcoma (SKLMS). MG516 inhibits tumor cell proliferation in vitro in a dose dependent manner with IC50s ranging from 500 to 2500 nM. We used a human phopho-RTK array kit, which allows the screening of 49 different phosphorylated human RTKs, in a panel of sarcoma cell lines. Our data indicates that MG516 provides robust blockade of a wide panel of RTKs including c-Met, EphB3, EphA10, PDGFR-β, Axl and IGF1-R at nanomolar to low micromolar concentrations. Western blot analysis showed a significant blockade of downstream effectors including p-AKT, p-FAK and p-STAT3. These results demonstrate the efficacy of MG516 in blocking RTKs and their downstream signaling pathways. Since PDGFR-β, c-Met and IGF1-R have been shown to be involved in tumor initiation, development and metastasis in a variety of sarcoma subtypes, our data would strongly support further development of MG516 as a novel agent in the treatment of sarcomas. Citation Format: Kathryn S. Ivy, Parag P. Patwardhan, Gary K. Schwartz. Preclinical development of a novel multi-targeted kinase inhibitor, MG516, for the treatment of sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1751. doi:10.1158/1538-7445.AM2014-1751
Abstract 9178: Cell-Based Prostacyclin Gene Therapy Prevents Pulmonary Arterial Hypertension
Authors: Lei Zhou, Zhiqiang Cheng, Peter Vanderslice, Shuiping So, Kehe Ruan, James T Willerson, Richard A Dixon
Journal: Circulation (2011)

Objectives: Intravenous prostacyclin is approved for the treatment of pulmonary arterial hypertension (PAH). However, it has limitations of a short half-life, the permanent placement of an intravenous catheter and substantial annual cost. We hypothesized that cell-based prostacyclin gene therapy may provide sustained therapeutic effects without the aforementioned limitations. Methods and Results: Since prostacyclin is produced from arachidonic acid by the enzymes cyclooxygenase (COX) and prostacyclin synthase (PGIS), we generated a vector expressing COX isoform 1 (COX1) and PGIS fusion protein that is capable of producing prostacyclin from arachidonic acid. Endothelium-like progenitor cells (ELPCs) from syngenetic Fisher 344 rats were transfected with COX1-PGIS expressing vector and lentivirus expressing nuclear localized red fluorescent protein (nuRFP). The engineered ELPCs expressing COX1-PGIS and nuRFP were tested in a monocrotaline (MCT) induced rat PAH model. Twenty-five days after cell transplantation, 48% of transplanted ELPCs resided in the lungs. MCT induced an increase in right ventricular systolic pressure (RVSP) compared to normal controls (51.9 ±2.2 mmHg vs. 26.3 ± 1.5 mmHg, p&lt;0.01). The increase in RVSP was significantly attenuated by treatment with ELPCs alone (40.9 ±1.6 mmHg, p&lt;0.01) or with ELPCs engineered to express the COX1-PGIS transgene (35.9 ±1.6 mmHg, p&lt;0.01). Engineered ELPCs were significantly more effective than ELPCs alone in preventing the increase in RVSP (p&lt;0.05). Right ventricle hypertrophy (right ventricle vs. left ventricle plus septum weight ratio) was reduced by treatment with ELPCs (28.8±0.8% vs. 36.5±3.1%, p &lt;0.01) or engineered ELPCs (30.5±0.9% vs. 36.5±3.1%, p &lt;0.01). Lung vessel thickness index increase (reflecting intima thickening and medial smooth muscle hypertrophy) was attenuated by treatment with engineered ELPCs (78.1±3.1% vs. 90.1±4.1%, p &lt;0.05). Conclusions: COX1-PGIS expressing ELPCs prevented MCT-induced PAH and showed enhanced efficacy over ELPCs alone. The one time cell delivery offered sustained therapeutic efficacy for at least 25 days, which may provide a promising option for patients with PAH.
STUMP un“stumped”: anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion
Authors: Vivek Subbiah, Caitlin McMahon, Shreyaskumar Patel, Ralph Zinner, Elvio G Silva, Julia A. Elvin, Ishwaria M. Subbiah, Chimela Ohaji, Dhakshina Moorthy Ganeshan, Deepa Anand, Charles F. Levenback, Jenny Berry, Tim Brennan, Juliann Chmielecki, Zachary R. Chalmers, John Mayfield, Vincent A. Miller, Philip J. Stephens, Jeffrey S. Ross, Siraj M. Ali
Journal: Journal of Hematology & Oncology (2015)

Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein.Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ).Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria.For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.
Abstract 3415: Cardiovascular Magnetic Resonance Accurately Detects Myocardial Hemorrhage in Reperfusion Injury
Authors: Andreas Kumar, Jordin D Green, Andrea J Mitchell, Jane M Sykes, Gerald Wisenberg, Matthias G Friedrich
Journal: Circulation (2007)

Introduction Hemorrhage can complicate reperfusion injury in myocardial infarction, but no in vivo imaging method exists. We hypothesized that a T2*-weighted cardiovascular magnetic resonance imaging (CMR) sequence accurately detects myocardial hemorrhage in vivo. Methods Reperfused myocardial infarcts were generated in 14 dogs by ligation of the LAD for 3– 6 hours. At day 3, a CMR study was performed using established sequences for quantification of function, microvascular obstruction and myocardial infarction in short axis slices covering the entire myocardium. For hemorrhage, a T2*-weighted multi-echo gradient-echo sequence was applied (TE=35msec, TR=1 RR, FOV 380x280mm, matrix 256 x 192). A segmental analysis was performed using 6 segments per slice: T2*-segments were considered hemorrhagic when signal intensity was &gt;2 standard deviations below the mean of remote myocardium. The contrast-to-noise ratio of hemorrhagic segments over normal segments was assessed. Post-mortem TTC staining was performed with infarcted and hemorrhagic areas analyzed with the same segmental approach. In vivo/ ex vivo correlation statistics were performed. Results In 14 dogs, 378 segments were assessed. Of the T2* CMR segments, 10.2% were excluded due to artifacts; 27 segments yielded a signal drop consistent with hemorrhage (see figure ). The correlation with ex vivo TTC staining was R=0.79 and contrast-to-noise ratio was 9.2±3.4. Sensitivity to detect a hemorrhagic segment was 77%, specificity 99%. Conclusion T2*-weighted CMR accurately detects reperfusion hemorrhage in vivo. The method may be applied in patients to study hemorrhage as a complication of reperfusion injury.
Posttranslational Modifications of the Master Transcriptional Regulator NPR1 Enable Dynamic but Tight Control of Plant Immune Responses
Authors: Abdelaty Saleh, John Withers, Rajinikanth Mohan, Jorge Marqués, Yangnan Gu, Shunping Yan, Raul Zavaliev, Mika Nomoto, Yasuomi Tada, Xinnian Dong
Journal: Cell Host & Microbe (2015)
Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa
Authors: Lori S. Sullivan, John R. Heckenlively, Sara J. Bowne, Jian Zuo, Winston A. Hide, Andreas Gal, Michael Denton, Chris F. Inglehearn, Susan H. Blanton, Stephen P. Daiger
Journal: Nature Genetics (1999)
35. Downregulation of Immune Responses Induced by Oral DNA Administration
Authors: Simon N. Waddington, Megha S. Nivsarkar, Ajay R. Mistry, Suzanne M. K. Buckley, Geoffrey Kemball-Cook, Karen L. Mosley, Kyriacos Mitrophanous, Pippa Radcliffe, Maxine V. Holder, Mairi Brittan, Tassos Georgiadis, Faisal Al-Allaf, Brian W. Bigger, Lisa G. Gregory, Terence H. Cook, Robin R. Ali, Adrian Thrasher, Edward G. D. Tuddenham, Mike Themis, Charles Coutelle
Journal: Molecular Therapy (2004)

Haemophilia B arises from mutations in the factor IX gene. Its treatment in humans, by recombinant protein substitution, is expensive thus limiting its application to intermittent treatment in bleeding episodes and prophylaxis during surgery; development of inhibitory antibodies is an associated hazard. This study demonstrates permanent therapeutic correction of this disease without development of immune reactions by introduction of HIV-based lentiviral vector encoding the human factor IX protein into the fetal circulation of immunocompetent haemophiliac and normal outbred mice. Plasma factor IX persists at therapeutic concentrations in all treated mice to date (ten months). Functional normalisation of the blood clotting has been achieved in two haemophiliac mice and significant correction in a third. In comparison, administration of an adenoviral vector encoding human factor IX resulted in transient and diminishing factor IX expression which was nearly undetectable by 8 months. Following lentiviral administration, no anti-factor IX antibodies were detected by ELISA and no cellular immunity was detected by immunohistochemical staining of macrophages, neutrophils, CD4-positive or CD8-positive cells. There was no elevation of serum liver enzymes or evidence of vector spread to the maternal circulation. No vector spread to sperm was detected by TaqMan analysis. This is the first demonstration of complete phenotypic correction of a severe genetic disease by in utero gene therapy with no evidence of toxicity.
Improving the outcome for children with cancer: Development of targeted new agents
Authors: Peter C. Adamson
Journal: CA A Cancer Journal for Clinicians (2015)

The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5‐year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short‐term and long‐term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosome‐positive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric‐specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra‐rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer. CA Cancer J Clin 2015;65: 212–220. © 2015 American Cancer Society.
MUC4 overexpression is associated with invasion and metastasis of pancreatic adenocarcinoma cells
Authors: Pallavi Chaturvedi, Nicholas Moniaux, Surinder K. Batra
Journal: Cancer Research (2006)

3522   MUC4 is a large, heavily glycosylated trans-membrane mucin, which is overexpressed in various cancers. Since MUC4 is overexpressed in pancreatic cancer and not expressed in the normal pancreas, it is critical to explore its role in this malignancy. MUC4 is synthesized as a single polypeptide chain, which may be cleaved to generate two subunits: a larger size mucin type-subunit, MUC4α (secreted) and a growth factor like-trans-membrane subunit, MUC4β. Due to its large size and the presence of various sialyl-lewis epitopes on the MUC4α subunit, MUC4 is hypothesized to confer anti-adhesive (by steric hindrance) and adhesive (by sialyl-selectin mediated mechanism) properties to the cancer cells. The MUC4β-subunit contains EGF-like domains and has been shown to interact and activate ErbB2/HER2, a receptor tyrosine kinase, which can promote the process of oncogenesis. In order to understand the function of MUC4 in pancreatic cancer progression, we first established a cell line model by repeated orthotopic implantations of SW1990, a human pancreatic cancer cell line, and generated new sub-cell lines (SW1990-Ln1 and SW1990-Ln2) by metastatic selection. These cell lines, derived from lymph node metastatic lesions, were more tumorigenic and displayed greater metastatic index in comparison to the parental cell line SW1990. Interestingly, in this model, MUC4 expression correlated with the tumorigenicity and metastatic potential of the cell lines. To further study the role of MUC4, its expression was inhibited in SW1990-Ln2, the highest generation metastatic cell line, by using the siRNA technology. The MUC4-downregulated clones were characterized by Western blot, real time-PCR and confocal microscopy, and used for  in vitro  and  in vivo  assays. MUC4 knockdown clones showed a five-fold decrease in cell motility and a three-fold decrease in invasiveness  in vitro . A significant decrease in tumor growth and metastatic potential was observed in MUC4 knockdown cells in comparison to the controls, when transplanted orthotopically into immunodeficient nude mice. The cDNA-microarray analysis showed differential expression of many metastasis and motility-associated genes. One of these genes, LI-cadherin, is known to be involved in lymph node metastasis. Since SW1990-Ln2 cells were derived from lymph nodes, a transient inhibition of LI-cadherin in these cells showed a noteworthy decrease in invasiveness of cells without significantly affecting the motility. These results provide evidence for the functional role of MUC4 in pancreatic adenocarcinoma and indicate that MUC4 can be a useful target in the development of therapeutic strategies for the treatment of pancreatic cancer.
Abstract 13048: Vardenafil Improves Clinical Symptoms and Digital Blood Flow in Patients With Primary and Secondary Raynaud Syndrome - Results From a Randomized Controlled Trial
Authors: Evren Caglayan, Sarah Axmann, Martin Hellmich, Pia Moinzadeh, Michael Huntgeburth, Nicolas Hunzelmann, Thomas Krieg, Erland Erdmann, Stephan Rosenkranz
Journal: Circulation (2011)

Raynaud's syndrome (RS) is a common, often disabling disorder with limited therapeutic options particularly in patients with connective tissue diseases. We have previously demonstrated in an open-l...
Under the Greenwood
Authors: M. Therese Southgate
Journal: JAMA (2002)

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 P335: The Number of Coronary Arteries with Calcified Plaque is Increased in Type 1 Diabetes
Authors: Lindsey M Duca, Gregory L Kinney, Amy C Alman, Janet K Snell-Bergeon
Journal: Circulation (2014)

Adults with type 1 diabetes (T1D) have a higher risk for cardiovascular disease than non-diabetic (non-DM) adults. Coronary artery calcification (CAC) is a marker for subclinical atherosclerosis and the Agatston CAC score is the standard used today. The aim of our study was to look at the number of coronary arteries with calcified plaques to determine if more diffuse disease is present in adults with T1D for a given level of CAC. In addition, we examined risk factors associated with the number of coronary arteries with CAC, as this could be a novel way to risk-stratify individuals. This study consisted of 1169 participants (T1D n=535 and non-DM n =634) with a mean ± SD age of 39±9 years. CAC was measured by electron beam CT (EBCT) using two scans performed five minutes apart and the maximum number of coronary arteries with CAC was used in the analysis. CAC lesions were determined in the left main, left anterior descending, circumflex, and right coronary arteries, with a maximum number of arteries with CAC ranging from zero to four. Chi square analysis was used to compare the number of coronary arteries with CAC by diabetes group. Subjects were then divided into categories based on their CAC score (&gt;0-10, 10-100, &gt;100-300, &gt;300) and poisson regression was used in multivariable analysis to examine associated risk factors. Adults with T1D had a significantly higher number of coronary arteries with CAC lesions than the non-DM adults (p &gt; 0.0001). Among subjects with CAC&gt;300 (n=58), adults with T1D had more coronary arteries with CAC than the controls (p = 0.03), but there were no differences in number of arteries with CAC among the other Agatston score categories. In multivariable analysis, HDL and LDL cholesterol, BMI, and hypertension were all independently associated with the number of coronary arteries with CAC lesions when adjusting for age, diabetes and CAC score (p&lt;0.0001). There were no significant associations of number of arteries with CAC with smoking status or hemoglobin A1c. People with T1D were still significantly more likely to have more coronary arteries with CAC lesions than non-DM individuals after adjusting for the above factors. In conclusion, T1D patients have more diffuse subclinical atherosclerosis, as indicated by a greater number of coronary arteries with CAC compared with non-DM adults. The number of coronary arteries with calcified plaque was independently associated with traditional CVD risk factors, even when accounting for CAC score. These findings are important because traditionally just the Agatston CAC score is used to determine CVD risk, but the number of coronary arteries affected could indicate how diffuse the subclinical artherosclerosis is prompt for aggressive treatment of traditional risk factors.
Redefining Rowell’s syndrome
Authors: N.C. Zeitouni, D. Funaro, R.A. Cloutier, E. Gagné, J. Claveau
Journal: British Journal of Dermatology (2000)

Rowell's syndrome is believed to be a distinct and rare clinical entity originally described as lupus erythematosus associated with erythema multiforme-like lesions with immunological findings of speckled antinuclear antibodies, anti-La antibodies and a positive test for rheumatoid factor. We report two additional patients with Rowell's syndrome and review all the diagnostic criteria found in the literature. In view of the inconsistent findings of some of the diagnostic features, we propose that major and minor criteria be used to diagnose Rowell's syndrome.