tbuckley/cabot-search huggingface dataset:
Abstract 206: Development of a molecular imaging system based on the transcriptional activity of the DD3/PCA3 non-coding RNA for imaging specifically the prostate cancer cells
Authors: Pallavi Jain, Bertrand Neveu, Yves Fradet, Frederic Pouliot
Journal: Cancer Research (2015)

Abstract Development of a molecular imaging system based on the transcriptional activity of the DD3/PCA3 non-coding RNA for imaging specifically the prostate cancer cells OBJECTIVE: Molecular imaging plays an important role in oncology for staging of tumors. Unfortunately, the specificity and sensitivity of current techniques remains low. This study aims to improve the existing imaging system based on transcriptional activation, named as “Two -Step- Transcriptional Amplification (TSTA) system”, with the goal to precisely image in vivo prostate cancer cells (PCa) by Positron Emission Tomography (PET). We have studied the potential of DD3/PCA3 promoter, a gene specifically expressed in PCa, to achieve this goal. METHODS: Various adenovirus constructs incorporating the DD3 promoter, the TSTA system and the Firefly luciferase reporter gene were generated and their specificity for PCa cells was tested in transient infection. By molecular engineering, we have improved the TSTA system and generated the 3STA. The luciferase activities of DD3-TSTA, DD3-3STA and PSA-TSTA (Prostate Specific Antigen) were compared in vivo by bioluminescence in xenograft mouse models. Ex vivo prostate biopsy from RP (radical prostatectomy) specimen were exposed to DD3-3STA and luciferase expression was evaluated using bioluminescence and Immunohistochemistry. RESULTS: The DD3 promoter activity is both specific to prostate and cancer cells. When DD3 promoter is incorporated in the amplification systems TSTA and 3STA, it is specific to PCa cells and its activity is amplified 32 and 95 times, respectively, when compared to the activity of the DD3 promoter alone. Moreover, activity of DD3-TSTA and DD3-3STA is androgen-independent. In vivo, DD3-3STA activity is comparable to that obtained with the PSA-TSTA whose activity can be imaged by PET. DD3-3STA could detect primary prostate cancer cells ex vivo in prostate biopsy obtained from RP specimen (Figure 1). CONCLUSIONS: The new system DD3-3STA allows specific and sensitive imaging of PCa cells. The new amplification system 3STA allows the DD3 promoter to produce reporter signal high enough to be detected by PET, a technology available in the clinic. Citation Format: Pallavi Jain, Bertrand Neveu, Yves Fradet, Frederic Pouliot. Development of a molecular imaging system based on the transcriptional activity of the DD3/PCA3 non-coding RNA for imaging specifically the prostate 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 206. doi:10.1158/1538-7445.AM2015-206
A Novel DNM2 Mutation Displaying Embryonic Lethality and Impaired Transferrin Uptake Identified in a Mouse ENU Mutagenesis Screen for Genes Perturbing Erythropoiesis
Authors: Fiona C Brown, Michael Collett, Phillip J Robinson, James C Whisstock, Douglas J. Hilton, Benjamin T. Kile, Stephen M Jane, David J. Curtis
Journal: Blood (2012)
Prolonged circulation of tissue-type plasminogen activator in vivo by blocking mannose receptor and low-density-lipoprotein receptor-related protein-mediated liver uptake;
Authors: E.A.L. Biessen, J. Kuiper, M. van Teijlingen, H. Vietsch, M.K. Bijsterbosch, D.C. Rijken, T.J.C. van Berkel
Journal: Circulation (1995)
Synergistic Control of Acute GvHD: Effectively Down-Regulating T Cell Proliferation and Cytotoxicity with Combined mTOR Inhibition and CD28:CD80/86 Costimulation Blockade.
Authors: Natalia Kozyr, Swetha Ramakrishnan, Aneesah Polnett, Kelly Hamby, Divya Tiwari, Taylor Deane, Linda Stempora, Joe Jenkins, Elizabeth Strobert, Anapatricia Garcia, Prachi Sharma, Cynthia Courtney, Angela Panoskaltsis-Mortari, Cynthia R. Giver, Edmund K. Waller, Bruce R. Blazar, Leslie S. Kean
Journal: Blood (2012)
Abstract P048: The Role of p62 in Cardiac Protein Quality Control
Authors: Qingwen Zheng, Huabo Su, Xuejun (XJ) Wang
Journal: Circulation Research (2011)

Rationale: Two recent studies suggest an important role of autophagy in protection against αB-crystallin-based (CryAB R120G ) desmin-related cardiomyopathies (DRC) but this has not been demonstrated in a different model of cardiac proteinopathy. Moreover, mechanisms underlying the response of cardiomyocytes to increased expression of misfolded proteins remain incompletely understood. Objective: First,to determine whether and how the autophagic activity is changed in a mouse model of desminopathy; second, to investigate the role of p62 in the protein quality control of cardiomyocytes. Methods and Results: Using an autophagosome reporter and determining changes in LC3-II protein levels in response to lysosomal inhibition, we found significantly increased autophagic flux in mouse hearts with transgenic overexpression of a DRC-linked mutant desmin. Similarly, autophagic flux was increased in cultured neonatal rat ventricular myocytes (NRVMs) expressing a mutant desmin. Suppression of autophagy by 3-methyladenine increased, whereas enhancement of autophagy by rapamycin reduced, the ability of a comparable level of mutant desmin overexpression to accumulate ubiquitinated proteins in NRVMs. Furthermore, p62 mRNA and protein expression was significantly upregulated in cardiomyocytes by transgenic overexpression of the mutant desmin or CryAB R120G both in intact mice and in vitro. p62 depletion impaired aggresome and autophagosome formation, exacerbated cell injury, and decreased cell viability in cultured NRVMs expressing the misfolded proteins. Conclusions: Autophagic flux is increased in desminopathic hearts, serving as an adaptive response to overexpression of misfolded proteins. p62 is upregulated in mouse proteinopathic hearts. p62 protects cardiomyocytes against proteotoxic stress by promoting aggresome formation and autophagy activation.
Abstract 5417: The tumor suppressor klotho: A master regulator of metabolism in breast cancer
Authors: Tami Rubinek, Ido Wolf
Journal: Cancer Research (2017)

Abstract One of the hallmarks of cancer is reprogramming of energy metabolism, characterized by a shift to aerobic glycolysis (Warburg effect). A major regulator of this phenomenon is the IGF-1/Pi3K/AKT pathway. Klotho is a transmembrane protein, which can be cleaved, shed and act as a circulating hormone. Klotho-deficient mice manifest a syndrome resembling accelerated aging, while klotho overexpression extends life span. Klotho is a potent tumor suppressor in BC. As klotho is a potent inhibitor of the IGF-1/Pi3K/AKT pathway in BC, we hypothesized that it may revert the metabolic switch in BC cells. We first analyzed the effect of klotho on the energy sensor enzyme AMP-activated kinase (AMPK) and its down-stream effector acetyl CoA carboxylase (ACC). Overexpression of klotho, or treatment with the soluble protein, elevated AMPK and ACC phosphorylation in three BC cell lines. AMPK is activated by the tumor suppressor liver kinase B1 (LKB1) and elevated AMP/ATP ratio. Expression of a dominant negative LKB1 prevented activation of AMPK by klotho and decreased the ability of klotho to inhibit cell growth and migration, implying that klotho tumor suppressor activities are LKB1 dependent. We next analyzed the effects of klotho on critical components of glucose metabolism. Treatment with soluble klotho reduced expression of the glucose transporter GLUT1 and the key glycolytic enzymes hexokinase2 (HK2), phosphofructokinase1 (PFK1), pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase kinase 1(PDK1). Using the Seahorse analyzer we noted reduced oxidative mitochondrial metabolism and glycolysis following klotho treatment. Energy is obtained essentially in the mitochondria with the transfer of protons across the inner membrane that produces ATP. We, therefore, analyzed klotho effect on the mitochondria membrane potential and noted reduction in the mitochondria potential following treatment with klotho. Finally, we examined the effects of klotho on specific metabolites and also conducted an NMR-based metabolic profiling. In accordance with the alterations in signaling pathways and levels of glycolytic enzymes, klotho reduced glucose uptake and inhibited lactate, pyruvate and 3-hydroxy-butyrate production. Furthermore, klotho also inhibited ATP production. Taken together, our data indicate klotho as a regulator of metabolic activity in BC and suggest that reversal of the metabolic switch is a key mechanism of klotho-mediated tumor suppressor activities. Citation Format: Tami Rubinek, Ido Wolf. The tumor suppressor klotho: A master regulator of metabolism in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5417. doi:10.1158/1538-7445.AM2017-5417
Abstract 3861: Prognostic impact of KRAS copy number amplification in esophagogastric junction adenocarcinoma
Authors: Kenichi Nakamura, Yu Imamura, Ryuma Tokunaga, Mayuko Ohuchi, Yuki Kiyozumi, Keisuke Kosumi, Daisuke Izumi, Kazuto Harada, Junji Kurashige, Ryuichi Karashima, Yukiharu Hiyoshi, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hideo Baba
Journal: Cancer Research (2015)

Abstract Background: The incidence of esophageal adenocarcinoma (EAC) or esophagogastric junction adenocarcinoma (EGJA) has been dramatically increasing. KRAS oncogenic alterations activate multiple pathways in various types of cancer. A recent comprehensive genetic study has reported that around 20% of EAC harbor KRAS copy number gain (Dulak AM et al, 2012, Nat Genet). However, the prognostic role KRAS amplification has not been well examined in EAC/EGJA. Methods: DNA was extracted from formalin-fixed paraffin-embedded tissue of 145 EGJA (Siewert types I-III). KRAS copy number was detected by real-time quantitative PCR, and KRAS copy number gain was defined as KRAS/RNase P (as a reference) ratio ≥ 2.5. The impact of KRAS amplification was analyzed in relation to clinicopathological factors, and patient outcomes [disease free survival (DFS), and overall survival (OS)]. Multivariate cox proportional hazards model was performed adjusting clinicopathological factors. Results: KRAS amplification was observed in 40 (33.1%) cases. KRAS amplification was significantly associated with the lymph node metastasis (P = 0.0145), and was significantly associated with poorer patient outcome (P = 0.0355 in DFS, and P = 0.0067 in OS). In multivariate analysis, KRAS amplification was an independent prognostic factor for OS [multivatiate hazard ratio (HR) = 2.53; 95% confidence interval (CI), 1.22-5.25, P = 0.014] and DFS [multivatiate hazard ratio (HR) = 1.94; 95% confidence interval (CI), 1.04-3.56, P = 0.0382]. Conclusions: KRAS copy number gain may be a useful prognostic marker in EGJA. Citation Format: Kenichi Nakamura, Yu Imamura, Ryuma Tokunaga, Mayuko Ohuchi, Yuki Kiyozumi, Keisuke Kosumi, Daisuke Izumi, Kazuto Harada, Junji Kurashige, Ryuichi Karashima, Yukiharu Hiyoshi, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hideo Baba. Prognostic impact of KRAS copy number amplification in esophagogastric junction adenocarcinoma. [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 3861. doi:10.1158/1538-7445.AM2015-3861
Impact of 5-HT<sub>3 </sub>receptor antagonist (5HT3-RA) selection within triple antiemetic regimens on the risk of uncontrolled chemotherapy-induced nausea and vomiting with highly emetogenic chemotherapy (HEC) in breast cancer patients.
Authors: J. Jackson, G. Jain, S. Balu, D. Buchner, L. S. Schwartzberg
Journal: Journal of Clinical Oncology (2011)

e16519 Background: Palonosetron (a newer generation 5-HT3-RA) and dolasetron, granisetron, and ondansetron (older 5-HT3-RAs) are indicated to prevent chemotherapy induced nausea and vomiting (CINV). Despite guideline-recommended triple drug prophylaxis with 5HT3-RA, aprepitant and dexamethasone, patients receiving HEC may still have uncontrolled CINV. This study evaluates the likelihood of an uncontrolled CINV event following antiemetic prophylaxis with palonosetron + aprepitant + dexamethasone (group 1) versus any of the other 5-HT3-RAs + aprepitant + dexamethasone (group 2) among single-day HEC cycles in breast cancer patients. Methods: Single-day HEC cycles (a gap of at least 5 days between 2 administrations) among patients with a breast cancer diagnosis and initiating antiemetic prophylaxis with group 1 versus group 2 between 1/1/2006-6/30/2010 were identified from the IMS LifeLink claims database. Uncontrolled CINV events were defined as ICD-9-CM codes for nausea and vomiting, CPT codes for hydration, rescue medications, and/or use of antiemetic therapy from days 2-5 following HEC administration. Risk for an uncontrolled CINV event was analyzed at cycle level using a logistic multivariate regression model. Results: A total of 3,710 group 1 and 916 group 2 cycles (1,825 and 488 patients, respectively) were analyzed. Group 1 and group 2 were similar in age [mean (sd): 51.3 (10.0) vs. 50.5 (9.4) years; p=0.0949], Charlson comorbidity score [5.6 (2.7) vs. 5.6 (2.6); p=0.9456], and number of HEC cycles [mean (sd): 2.1 (1.3) vs. 2.0 (1.2); p=0.4605]. Versus group 2 cycles, group 1 cycles had a significantly lower unadjusted risk of an uncontrolled CINV event (16.2% vs. 19.0%; p=0.0404), while the multivariate regression analysis predicted a 17% lower risk for group 1 cycles [Odds Ratio: 0.83 (95% CI: 0.68 – 0.995); p=0.0439]. Conclusions: In this retrospective claims data analysis, patients with breast cancer receiving single-day HEC cycles and palonosetron based triple drug prophylaxis for CINV had a lower risk for an uncontrolled CINV event versus older generation 5-HT3RAs.
Abstract POSTER-TECH-1103: Aspirin, NSAIDS, and ovarian cancer survival from electronic medical records
Authors: Alicia Beeghly-Fadiel, Gwendolyn Holman, Samantha P. Stansel, Gretchen Edwards, Edward Baeg, Hannah Berke, Ryan J. Delahanty, Dineo Khabele
Journal: Clinical Cancer Research (2015)

Abstract Background: Extensive literature indicates that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are associated with reduced cancer incidence and mortality. For ovarian cancer, a pooled analysis of 12 case-control studies recently demonstrated a significantly reduced risk for regular aspirin use and a similar but non-significant reduced risk for non-aspirin NSAID use. However, studies specifically evaluating NSAIDs and ovarian cancer survival are absent from the published literature. Purpose: To determine if aspirin and other NSAIDs are associated with ovarian cancer survival. Methods: Ovarian cancer cases were identified from de-identified electronic medical records (EMR) from the Vanderbilt University Medical Center. Ever use of aspirin or any NSAID was determined by MedEx, a natural language processing system designed to capture medication use from EMR. Linked tumor registry data was used to generate hazard ratios (HR) and confidence intervals (CI) for overall survival using Cox proportional hazards regression; covariates included age, race, stage of disease, histologic subtype, treatments received, and year of diagnosis. Results: The majority of 1,147 confirmed ovarian cancer cases were Caucasian (87.0%), had serous histologic subtypes (53.6%), and late stage (III/IV, 50.0%) or stage unknown (29.3%) disease. Ovarian cancer cases with any aspirin use (207, 18.1%) had significantly longer overall survival in both unadjusted (HR: 0.56, 95% CI: 0.45-0.70) and adjusted analyses (HR: 0.59, 95% CI: 0.46-0.74). Similarly, ovarian cancer cases with any non-aspirin NSAID use (248, 21.6%) had significantly longer overall survival in both unadjusted (HR: 0.60, 95% CI: 0.48-0.74) and adjusted analyses (HR: 0.69, 95% CI: 0.54-0.88). Associations between any aspirin or other NSAID use (360, 31.4%) and longer ovarian cancer survival did not significantly differ by stage of disease (P-interaction=0.650), histologic subtype (P-interaction=0.076), or treatment with a platinum-based agent (P-interaction=0.069). Conclusions: Indication of aspirin or non-aspirin NSAID use ascertained retrospectively from EMR was associated with improved overall ovarian cancer survival. Further evaluation, including timing and duration of use, are underway; replication of this association in additional study populations is needed. Citation Format: Alicia Beeghly-Fadiel, Gwendolyn Holman, Samantha P. Stansel, Gretchen Edwards, Edward Baeg, Hannah Berke, Ryan J. Delahanty, Dineo Khabele. Aspirin, NSAIDS, and ovarian cancer survival from electronic medical records [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1103.
432. Aurora A Kinase Inhibition Enhances Oncolytic Herpes Simplex Virotherapy in Models of Neuroblastoma
Authors: Mark Currier, Tilat Rizvi, Brooke Nartker, Duo Chen, Pin-Yi Wang, Ami Patel, Katherine Chaney, Keri Streby, Balveen Kaur, Paola Grandi, Joseph Glorioso, E. Antonio Chiocca, Jeff Ecsedy, Joe Conner, Nancy Ratner, Timothy Cripe, Timothy Cripe
Journal: Molecular Therapy (2015)

Neuroblastoma, a heterogeneous tumor that arises from the neural crest, is the most common extracranial solid tumor in children. Fewer than half of patients with high-risk features survive long-term, despite multi-modal therapy with surgery, chemotherapy, antibody therapy, retinoic acid, high-dose chemotherapy, and autologous hematopoietic progenitor cell transplant. We previously reported neuroblastoma xenograft models were responsive to direct intratumoral injection of oncolytic Herpes Simplex Viruses (Parikh et al., Ped Blood Can 44:469, 2005; Mahller et al., Can Res 68:1170, 2008). We have confirmed these findings using an oncolytic HSV, Seprehvir (HSV1716), which is in clinical trials that include pediatric patients (NCT00931931, NCT02031965). The models showed wide variability, however, with CHP134 being highly responsive (4/8 complete responses (CR), 4/8 maintained complete responses (MCR)), CHLA-20 intermediately responsive (4/7 partial responses (PR), 3/7 MCR), SKNBE(2) somewhat responsive (6/7 PR, 1/7 MCR) and SK-N-AS minimally responsive (3/7 progressive disease (PD), 4/7 delayed progression (PD1), 0/7 PR). Because DNA viruses are highly dependent on normal nuclear machinery for DNA synthesis/replication and virus packaging/assembly, we postulated that increased transit time in mitosis may be beneficial to an oncolytic DNA virus. Aurora A Kinase is an enzyme critical for formation of centrioles and mitotic spindles during mitosis and is often dysregulated in cancer. The selective AAK inhibitor, Alisertib (MLN8237), arrests cells in G2/M and is highly effective in neuroblastoma models, making it an attractive candidate for combination studies with Seprehvir. We administered repeated 7-day cycles of combination therapy (10 mg/kg Alisertib once daily by gavage, days 1-5; 10e7 pfu Seprehvir day 5) to mice bearing SK-N-AS xenografts and found significant antitumor synergy (2/10 PD1, 4/10 SD, 2/10 PR, 2/10 CR). Our preliminary data assessing kinetics of virus infection suggest that Alisertib pretreatment enhances virus uptake and spread, accounting for the combinatorial effects. Overall, our findings support clinical testing of Alisertib combined with Seprehvir in patients with refractory neuroblastoma.
Frequency, Hematopathology and Detection of a New Isodicentric Variant of Deletion 20q.
Authors: Stephanie R. Fink, Stephanie A. Smoley, Sarah F. Paternoster, Kimberly J. Stockero, Lai P. Nguyen, Phuong L. Nguyen, Curtis A. Hanson, Gordon W. Dewald
Journal: Blood (2006)
Variants in<i>ANGPTL4</i>and the Risk of Coronary Artery Disease
Authors: Frederick E Dewey, Jesper Gromada, Alan R Shuldiner
Journal: New England Journal of Medicine (2016)

To the Editor: Genomic studies of cardiovascular disease that are based on samples obtained from patients have identified variants associated with the risk of disease that do not always predict the onset of disease shown in prospective studies. 1,2Dewey et al. (March 24 issue) 3 report lower levels of triglycerides and a lower risk of coronary artery disease among carriers of E40K and other inactivating mutations in ANGPTL4 than among noncarriers.Also, in the same issue of the Journal, Stitziel et al. report that in a cross-sectional study, low-frequency coding-sequence variants were associated with a reduced risk of coronary disease. 4e carried out an independent, large-scale study and confirmed the role of these genetic variants in incident coronary heart disease.Our study involved data that was collected prospectively from seven cohorts (the Age, Gene/Environment Susceptibility-Reykjavik Study; the Atherosclerosis Risk in Communities Study; the Cardiovascular Health Study; the Framingham Heart Study; the Genetic Studies of Atherosclerosis Risk; the Rotterdam Study; and the Women's Genome Health Study).A total of 5427 of 49,518 persons of European ancestry in these studies had incident coronary heart disease. 5e investigated 35,904 autosomal exome-array variants with a minor-allele frequency of greater than 1% for association, with adjustment for age, sex, and population substructure.Significant associations (Bonferroni-corrected P<1.39E-06) are summarized in Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org.We confirm previously reported 6 associations with noncoding common variants at 9p21 and PHACTR1, and we also found an association between a low-frequency variant in ANGPTL4 and a reduced risk of incident coronary heart disease.
Non-Functional ("haploinsufficient"), but Not Dominant Negative Clonal IKZF1 Deletions Confer an Adverse Prognosis in Adult BCR-ABL-Negative Acute Lymphoblastic Leukemia
Authors: Benjamin Kobitzsch, Nicola Gökbuget, Stefan Schwartz, Richard Reinhardt, Monika Brueggemann, Andreas Viardot, Ralph Wäsch, Michael Starck, Eckhard Thiel, Dieter Hoelzer, Thomas Burmeister
Journal: Blood (2015)
Molecular Characterization of PS-341 (bortezomib) Resistance: Implications for Overcoming Resistance Using Lysophosphatidic Acid Acyltransferase (LPAAT)-β Inhibitors.
Authors: Teru Hideshima, Dharminder Chauhan, Kenji Ishitsuka, Noopur Raje, Shaji Kumar, Klaus Podar, Constantine Mitsiades, Hiromasa Hideshima, Lynn Bonham, Nikhil C. Munshi, Paul G. Richardson, Jack W. Singer, Kenneth C. Anderson
Journal: Blood (2004)
Natural regulatory T cells from patients with end-stage renal disease can be used for large-scale generation of highly suppressive alloantigen-specific Tregs
Authors: Nicolle H.R. Litjens, Karin Boer, Joke M. Zuijderwijk, Mariska Klepper, Annemiek M.A. Peeters, Wenda Verschoor, Rens Kraaijeveld, Michiel G.H. Betjes
Journal: Kidney International (2016)