tbuckley/cabot-search huggingface dataset:
Abstract LB-155: Epigenetic profiling of chemotherapy sensitivity
Authors: Zachary A. Gurard-Levin, Vera Pancaldi, Laurence OW Wilson, Elisabetta Marangoni, Sergio Roman-Roman, Alfonso Valencia, Paul Cottu, Genevieve Almouzni
Journal: Cancer Research (2015)

Abstract Many anti-cancer drugs act by directly binding or modifying DNA, or through indirect binding during processes that rely on the chromatin architecture. Mis-regulation of the expression of epigenetic factors may perturb chromatin organization and contribute to drug resistance mechanisms. Here, we aim to investigate the power of chromatin regulators and epigenetic factors as predictive markers for the efficacy of single chemotherapy drugs. We exploit transcriptome data from breast cancer cell lines and a validation set comprised of breast cancer patient derived xenograft (PDX) models that are either sensitive or resistant to individual chemotherapy agents, to correlate mRNA expression of chromatin regulators to drug efficacy. We then use Random Forests, a non-parametric machine learning method, to model the cell lines’ response to different compounds. The model is then used to predict the patients’ response to each drug, identifying which genes contribute the most to the prediction. We then compare our predictive gene signature to commercially available prognostic kits. Random Forest analysis revealed a 28-gene signature (termed EPOCH28) containing several histone chaperones, histone variants, histone modifying enzymes, among other chromatin regulators, which is highly predictive of drug efficacy. Indeed, our model accurately predicts 11 of 14 resistant PDX models and 15 out of 17 sensitive PDX models (∼ 84%), with an average confidence level of over 73%. Importantly, we find that the EPOCH28 gene signature is specific, and is thus not a general prognostic signature for patients who will benefit from any chemotherapy. In line with this, the EPOCH28 outperforms the breast cancer prognostic gene signatures of Mammaprint and Oncotype DX, suggesting that while these commercial tests may help guide clinical decisions, it will be critical to consider additional factors that can help identify which drug will be most beneficial to an individual patient. The integration of chromatin regulators as clinical biomarkers, in particular in the context of predictive markers for the response to a single drug, will help guide clinical decisions and treatment options for breast cancer. Importantly, our approach is general and thus can be applied to other chemotherapy drugs, including those in clinical trials to develop companion diagnostics, and for other cancer types. Citation Format: Zachary A. Gurard-Levin, Vera Pancaldi, Laurence OW Wilson, Elisabetta Marangoni, Sergio Roman-Roman, Alfonso Valencia, Paul Cottu, Genevieve Almouzni. Epigenetic profiling of chemotherapy sensitivity. [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 LB-155. doi:10.1158/1538-7445.AM2015-LB-155
177. Recapitulating the Triglyceride-Lowering Effect of Cold Exposure By Overexpression of Fibroblast Growth Factor-21 Gene
Authors: Mingming Gao, Yongjie Ma, Kexiu Song, Hao Sun, Dexi Liu
Journal: Molecular Therapy (2015)

Cold exposure reduces blood triglyceride level via repressing lipid synthesis and enhancing lipid oxidation, providing a potential option for hyperlipidemia therapy. However, cold exposure is not a practical therapeutic approach in humans due to its unacceptable requirements. As the effect of cold exposure is associated with elevated expression of fibroblast growth factor-21 (Fgf21) in the liver and brown adipose tissue (BAT), we assessed in this study whether the metabolic benefits of cold exposure in lowering blood triglyceride can be recapitulated by overexpressing Fgf21. Overexpression of Fgf21 was achieved by hydrodynamic delivery of plasmid driven by an albumin promoter for Fgf21 expression. Our results show that hydrodynamic transfer of the Fgf21 plasmid exclusively elevated Fgf21 expression in the liver in a dose-dependent manner. Fgf21 overexpression greatly improves triglyceride metabolism in regular as well as high-fat diet-induced obese mice, as evidenced by improved profiles of oral fat tolerance tests and reduced fasting triglyceride levels in blood. Mechanistically, improvements in triglyceride metabolism mediated by Fgf21 transfer were achieved by repressed lipid synthesis in the liver and enhanced lipid oxidation in BAT. At the molecular level, Fgf21 transfer repressed transcription of a variety of pivotal genes involved in lipid synthesis in liver, including Srebp1c, Fas, Scd1, Ppargamma2 and Mgat1, while increasing mRNA levels of Cpt1-alpha and Acadl, suggesting that the hepatic lipid synthesis was repressed while oxidation enhanced. In fact, transfer of the Fgf21 remained effective in attenuating hyperlipidemia in mice fed with 30% fructose and injected with lipase inhibitor, further verifying that this genetic approach markedly diminished hepatic lipid synthesis. In BAT, Fgf21 transfer induced a "super-brown" phenotypic change, which was accompanied by elevated expression of a panel of vital genes for adaptive thermogenesis, such as Ucp1, Pgc1-alpha, Cidea, Dio2 and Elovl3. Collectively, our findings unveil that the triglyceride-lowering effect of cold exposure can be fully recapitulated by liver-specific delivery of the Fgf21 using a hydrodynamics-based procedure, indicating that this new approach may provide an alternative and more acceptable option for hyperlipidemia therapy in humans.
A randomized phase II study of pemetrexed (PEM) with or without sorafenib (S) as second-line therapy in advanced non-small cell lung cancer (NSCLC) of nonsquamous histology: NCCTG N0626 study.
Authors: J. R. Molina, G. K. Dy, N. R. Foster, K. L. Allen Ziegler, A. Adjei, K. M. Rowland, M. Aubry, P. J. Flynn, S. J. Mandrekar, S. E. Schild, A. A. Adjei
Journal: Journal of Clinical Oncology (2011)

7513 Background: Based on preclinical data of additive cytotoxicity with sorafenib (S) and pemetrexed (PEM), this randomized phase II study was done to evaluate the safety and efficacy of the combination of S plus PEM vs PEM alone, as second line treatment of non-squamous NSCLC (determined by central pathology review). Methods: A lead-in phase to determine the tolerability of S plus PEM was followed by a 1:1 randomization of either PEM 500 mg/m2 q21 days plus S 400 mg p.o. BID for 21 days (arm A) or PEM 500 mg/m2 q21 days (arm B). The primary endpoint was progression-free survival (PFS). 47 patients (pts) per arm provided 82% power to detect an increase in the median PFS from 3.0 to 5.5 months (mos), with a 1-sided alpha of 0.05. Polymorphisms in VEGFA, VEGFR1-3, FPGS, GGH, SLC19A1 and TYMS were evaluated in germline DNA and correlated with outcomes. Results: One-hundred evaluable pts were randomized (49-A, 51-B). Baseline age, gender, and ECOG performance status were balanced between arms (p > 0.24). Prior exposure to bevacizumab (BEV) was 43% in A and 59% in B. Median number of cycles was 2 (1-31) on A and 4 (1-22) on B. A had a significantly increased rate of grade 3 non-hematologic (NH) adverse events (AE) (76% vs. 39%, p < 0.001). Grade 4/5 NH AE rates were similar for A and B (14% vs. 16%, p=1.00). No significant difference in grade 4 hematologic AE (20% vs 10.0%, p = 0.17). The overall median follow-up was 13.6 mos (1.6-27.8). PFS and OS was similar (PFS: A=3.4 mos vs B=4.1 mos, p = 0.22; OS: A=9.4 mos, B=9.7 mos, p=0.49). In arm A, the median PFS for patients with no prior BEV exposure was 2.8 mos compared to 5.0 mos in those with prior BEV exposure (p=0.06). In arm B, the median PFS was 3.5 vs 4.2 mos (p=0.91). The CT+TT genotypes of VEGFA rs3025039 was associated with worse PFS in A than in B (interaction p=0.03). Conclusions: Although the trial did not meet the protocol specified success criteria, post-hoc sub group analyses suggests a marginal improvement in PFS for patients on S plus PEM with prior exposure to BEV. Polymorphisms in VEGFA appear to predict for a worse outcome in patients receiving S. These preliminary findings warrant further investigation.
Gemtuzumab Ozogamicin (Mylotarg®) as Part of Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed Acute Myeloid Leukemia.
Authors: Martin Bornhaeuser, Thomas Illmer, Uwe Platzbecker, Johannes Schetelig, Markus Schaich, Alexander Kiani, Ulrich Schuler, Gerhard Ehninger
Journal: Blood (2004)
498. Optimization of rAAV Targets ON Bipolar Cells and Rescues the nobnyx Mouse Model of X-Linked Congenital Stationary Night Blindness
Authors: Miranda L. White, Sanford L. Boye, Frank M. Dyka, Kathryn M. Fransen, Charles N. de Leeuw, Elizabeth M. Simpson, Ronald G. Gregg, Maureen A. McCall, Neal S. Peachey, Shannon E. Boye
Journal: Molecular Therapy (2015)

Within the retina, Adeno associated virus (AAV) has been effectively used to target photoreceptors, retinal pigment epithelial cells, muller glia and retinal ganglion cells. However, transduction of cells in the middle of non-degenerate retina has proven more difficult. Transduction of bipolar cells is particularly attractive both for treating forms of Congenital Stationary Night Blindness (CSNB), in which the ON-type bipolar cells are unable to receive electrochemical input from photoreceptors, as well as for use in optogenetics. Even more attractive is the ability to target this cell type via a non-invasive intravitreal injection. The purpose of our study was to establish methodology to robustly and exclusively express transgene in ON bipolar cells utilizing AAV vectors, and to use these tools to restore retinal function to an animal model of the X-linked form of complete CSNB. Like patients, the nobnyx mouse carries a mutation in NYX, which encodes nyctalopin, a protein essential for proper localization of the TRPM1 cation channel in ON BCs. This disease is characterized by an absence of the electroretinogram (ERG) b-wave in addition to a high incidence of myopia, nystagmus, strabismus, and low visual acuity. A construct containing an ON BC specific promoter, Ple155, driving either hGFP or YFP_Nyx was packaged into rationally designed AAV2(quadY-F+T-V). nobnyx mice were intravitreally injected with 6.5×1012 VG/ml. GFP expression and localization were confirmed using immunohistochemistry before proceeding with Nyx replacement. ERG was performed 4 weeks post injection on mice injected with the YFP_Nyx vector, and then retinas were harvested for single cell recordings, and immunohistochemistry. Mice intravitreally injected with Ple155-hGFP had robust and exclusive GFP expression in their ON bipolar cells. Additionally, Ple155-YFP_Nyx- injected mice exhibited NYX (YFP) expression exclusively in ON BCs, as well as restoration of the glutamate cascade, as evidenced by wild-type responses to capsaicin, an agonist of the disrupted TRPM1 cation channel, in a YFP+ cell. Both scotopic and photopic ERG b-waves were restored to P2-treated mice. This is the first demonstration of therapy following gene replacement in a model of ONBC-mediated disease and provides proof of concept for an AAV-based strategy to treat Congenital Stationary Night Blindness and effectively target ON BCs. Efforts are currently underway to further modify the AAV capsid and genome in order to enhance transduction and increase window of therapy.
Aloe Vera in Dermatology—The Plant of Immortality
Authors: Valencia Long
Journal: JAMA Dermatology (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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors
Authors: Morgan S. A. Gilman, Carlos A. Castellanos, Man Chen, Joan O. Ngwuta, Eileen Goodwin, Syed M. Moin, Vicente Mas, José A. Melero, Peter F. Wright, Barney S. Graham, Jason S. McLellan, Laura M. Walker
Journal: Science Immunology (2016)

Anti–RSV F antibody repertoire profiling reveals new opportunities for vaccine design and passive therapy.
Prognostic Implications of PIM-2 Expression in Samples from Patients with Chronic Lymphocytic Leukemia and Impact in the Sensitivity to the Pan-PIM Kinase Inhibitor PIM447
Authors: Ana Alicia López-Iglesias, Irena Misiewicz-Krzeminska, Ignacio Criado, Miguel Alcoceba, Susana Hernández-García, Laura San-Segundo, Lorena González-Méndez, Montserrat Martín-Sánchez, Esperanza M Algarín, Teresa Paíno, Mercedes Garayoa, Norma C Gutierrez, Maria-Victoria Mateos, Marcos González-Díaz, Enrique M Ocio
Journal: Blood (2015)
Abstract 5007: A novel polyisoprenylated cysteinyl amide inhibitor, NSL-BA-055, selectively inhibits proliferation of hepatocellular carcinoma cells
Authors: Michelle K. Naidoo, Nazarius Lamango, Olorunseun O. Ogunwobi
Journal: Cancer Research (2015)

Abstract The monomeric GTP-ase, Ras, is mutated in over 30% of cancers where it promotes uncontrolled proliferation of cancer cells. Ras signaling is one of many pathophysiological pathways implicated in hepatocellular carcinoma that results in cell survival, differentiation, proliferation, and angiogenesis. Ras is bound to the cytoplasmic face of the plasma membrane where it relays intracellular signals. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) effectively disrupt the functions of polyisoprenylated proteins such as Ras. Many hepatocellular carcinomas (HCCs) have dysregulated Ras signaling. However, the effects of PCAIs on hepatocellular carcinoma (HCC) are unknown. The aim of this study was to investigate the effect of a novel PCAI, NSL-BA-055, on HCC. Concentrations of NSL-BA-055 ranging from 0 to 10 μM were used for experimentation. Effects on proliferation of BNL CL.2 (non-tumorigenic mouse hepatocytes) and BNL 1ME A.7R.1 (mouse HCC cells derived from BNL CL.2 hepatocytes) were analyzed. Next, the effects of NSL-BA-055 on Akt protein expression, a downstream component of Ras signaling, were examined by western blotting. NSL-BA-055 significantly inhibited the proliferation of BNL 1ME A. 7R.1 HCC cells, but not the non-tumorigenic BNL CL.2 hepatocytes. Also, concentrations of the NSL-BA-055 compound as low as 4 μM significantly inhibited the proliferation of BNL 1ME A.7R.1 HCC cells. Western blotting revealed that NSL-BA-055 inhibited Akt protein expression at 4μM. Therefore PCAIs such as NSL-BA-055 is a novel class of agents that selectively inhibit the proliferation of HCC cells, but not normal hepatocytes. This effect may be via inhibition of Akt, a downstream intermediate of Ras signaling. Consequently, NSL-BA-055 is a novel candidate agent for HCC therapy. Note: This abstract was not presented at the meeting. Citation Format: Michelle K. Naidoo, Nazarius Lamango, Olorunseun O. Ogunwobi. A novel polyisoprenylated cysteinyl amide inhibitor, NSL-BA-055, selectively inhibits proliferation of hepatocellular carcinoma cells. [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 5007. doi:10.1158/1538-7445.AM2015-5007
Evidence of Pre-Diagnostic Monoclonality in Blood Obtained up to 6.4 Years Preceding Diagnosis of Chronic Lymphocytic Leukemia (CLL).
Authors: Ola Landgren, Maher X. Albitar, Wanlong X. Ma, Fatima R. Abbasi, Richard B. Hayes, Gerald E. Marti, Neil E. Caporaso
Journal: Blood (2007)
Abstract 1983: Aryl hydrocarbon receptor activates NDRG1 transcription under hypoxia in breast cancer cells
Authors: En-Yu Li, Wei-Yung Huang, Mong-Hsun Tsai, Eric Y. Chuang, Liang-Chuan Lai
Journal: Cancer Research (2015)

Abstract Hypoxia has been intensively investigated over past decades based on the observations that hypoxic tumors were more resistant to therapy and had a worse prognosis. Previously, we reported that N-myc downstream-regulated gene 1 (NDRG1) was strongly up-regulated under hypoxia and may play an important role in tumor adaptation to fluctuation of oxygen concentrations. However, the regulatory mechanism of NDRG1 under hypoxia remains elusive. Therefore, the purpose of this study is to identify the novel transcription factors that regulate NDRG1 and to investigate the functional roles of NDRG1 in hypoxia. In silico analysis predicted binding sites of aryl hydrocarbon receptor (AHR) existing in the NDRG1 promoter. Western blotting showed that nuclear AHR was up-regulated in the presence of cobalt and hypoxia. Immunofluorescence staining and chromatin immunoprecipitation assays showed that AHR translocated to nuclei and bound to NDRG1 promoter in hypoxia. Luciferase reporter assays further showed that the binding site of AHR at -412 ∼ -388 bp played a crucial role in regulating NDRG1 under hypoxia-mimicking conditions. Moreover, hypoxia-mimetic induction of NDRG1 by was attenuated by knockdown of AHR expression using short interfering RNA. Also, overexpression of AHR facilitated cell proliferation and migration via up-regulation of NDRG1, whereas shRNA knockdown of NDRG1 reduced cell growth and motility. In summary, these results showed for the first time that AHR positively regulates NDRG1 transcription through a AHR binding site by hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regime to prevent tumor malignancy under hypoxia. Citation Format: En-Yu Li, Wei-Yung Huang, Mong-Hsun Tsai, Eric Y. Chuang, Liang-Chuan Lai. Aryl hydrocarbon receptor activates NDRG1 transcription under hypoxia in breast cancer cells. [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 1983. doi:10.1158/1538-7445.AM2015-1983
Decreased Activity of ADAMTS13 In Patients with Deep Vein Thrombosis Associated with Inflammatory Markers
Authors: Bruna M Mazetto, Fernanda Loureiro de Andrade Orsi, Aline Barnabé, Marinez Farana Matos, Erich de Paula, Vânia Maris Morelli, Joyce Maria Annichino-Bizzacchi
Journal: Blood (2010)
First Steps Into the Brave New Transdiscipline of Mobile Health
Authors: Bonnie Spring, Angela Pfammatter, Nabil Alshurafa
Journal: JAMA Cardiology (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 Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Comparison of the Efficacy and Safety of Early Rule-Out Pathways for Acute Myocardial Infarction
Authors: Andrew R. Chapman, Atul Anand, Jasper Boeddinghaus, Amy V. Ferry, Dennis Sandeman, Philip D. Adamson, Jack Andrews, Stephanie Tan, Sheun F. Cheng, Michelle D’Souza, Kate Orme, Fiona E. Strachan, Thomas Nestelberger, Raphael Twerenbold, Patrick Badertscher, Tobias Reichlin, Alasdair Gray, Anoop S.V. Shah, Christian Mueller, David E. Newby, Nicholas L. Mills
Journal: Circulation (2016)

Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the optimal approach is uncertain. We compared the European Society of Cardiology rule-out pathway with a pathway that incorporates lower cardiac troponin concentrations to risk stratify patients. Methods: Patients with suspected acute coronary syndrome (n=1218) underwent high-sensitivity cardiac troponin I measurement at presentation and 3 and 6 or 12 hours. We compared the European Society of Cardiology pathway (&lt;99th centile at presentation or at 3 hours if symptoms &lt;6 hours) with a pathway developed in the High-STEACS study (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary S yndrome) population (&lt;5 ng/L at presentation or change &lt;3 ng/L and &lt;99th centile at 3 hours). The primary outcome was a comparison of the negative predictive value of both pathways for index type 1 myocardial infarction or type 1 myocardial infarction or cardiac death at 30 days. We evaluated the primary outcome in prespecified subgroups stratified by age, sex, time of symptom onset, and known ischemic heart disease. Results: The primary outcome occurred in 15.7% (191 of 1218) patients. In those less than the 99th centile at presentation, the European Society of Cardiology pathway ruled out myocardial infarction in 28.1% (342 of 1218) and 78.9% (961 of 1218) at presentation and 3 hours, respectively, missing 18 index and two 30-day events (negative predictive value, 97.9%; 95% confidence interval, 96.9–98.7). The High-STEACS pathway ruled out 40.7% (496 of 1218) and 74.2% (904 of 1218) at presentation and 3 hours, missing 2 index and two 30-day events (negative predictive value, 99.5%; 95% confidence interval, 99.0–99.9; P &lt;0.001 for comparison). The negative predictive value of the High-STEACS pathway was greater than the European Society of Cardiology pathway overall ( P &lt;0.001) and in all subgroups, including those presenting early or known to have ischemic heart disease. Conclusions: Use of the High-STEACS pathway incorporating low high-sensitivity cardiac troponin concentrations rules out myocardial infarction in more patients at presentation and misses 5-fold fewer index myocardial infarctions than guideline-approved pathways based exclusively on the 99th centile. Clinical Trial Registration: URL: http://clinicaltrials.gov . Unique identifier: NCT01852123.