tbuckley/cabot-search huggingface dataset:
Abstract 3821: Understanding the functional role of retinoic acid receptor beta2 in the development of oral cancer
Authors: Raghu Radhakrishnan, Keith Hunter
Journal: Cancer Research (2015)

Abstract Background: Retinoids are the best studied chemopreventive agents in oral cancer patients, whose effects are mediated by retinoic acid receptors (RAR). The loss of RARβ2 expression early in the development of oral cancer is attributed to acquisition of cellular immortalization or abrogated senescence. Aim: To determine the functional effects of RARβ2 dysfunction (constitutive expression or loss) in precancerous oral keratinocytes. Methods: Characterization of a panel or mortal (D6, D30) and immortal precancerous oral keratinocytes (D19, D20, D34 and D38), and tert immortalized normal cells (FNB-6) for baseline RARβ2 expression and their role in senescence, differentiation, apoptosis, and methylation. Re-express RARβ2 in immortal cells by treatment with all trans retinoic acid, 5-aza-2′- deoxycytidine, administered alone and in combination and asses their effect on senescence and promoter methylation. Results: Mortal cells showed constitutive expression of RARβ2 in senescing cultures and loss of expression in immortal cells. This was reflected in tissue engineered 3D composites as well as in the corresponding biopsies, when stained with RARβ antibody. Concomitant expression of CDKN2A and CDKN1A in senescing cultures and their absence in immortals suggest that the loss of RARβ2 strongly correlate with transition from senescence to immortalization. Re-expression of RARβ2 in immortal cells by treatment with retinoic acid (RA), 5-aza-2′-deoxycytidine (Aza-C) and combination of RA + Aza-C with simultaneous upregulation of CDKN2A and CDKN1A confirm RARβ2 as tumor suppressor gene, which is silenced due to hypermethylation. Increase in the Histone Repressor A (HIRA) foci and Senescence associated β- galactosidase (SA-β gal) activity in treated cell confirmed the restoration of senescence program in an immortal cell. Promoter methylation analysis confirmed that the silencing of RARβ2 in immortal cell was due to hypermethylation. Conclusion: The role of demethylating agent in growth inhibition and apoptosis highlights the importance of RAR beta serving as an intermediate biomarker in chemoprevention. Identification of methylation status may prove useful as a selective biomarker prior to combined demethylation and retinoid treatment in oral precancerous lesions. Citation Format: Raghu Radhakrishnan, Keith Hunter. Understanding the functional role of retinoic acid receptor beta2 in the development of oral cancer. [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 3821. doi:10.1158/1538-7445.AM2015-3821
Association of Cardiovascular Risk Factors and Myocardial Fibrosis With Early Cardiac Dysfunction in Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study
Authors: Anderson C. Armstrong, Bharath Ambale-Venkatesh, Evrim Turkbey, Sirisha Donekal, Elzbieta Chamera, Jye-Yu Backlund, Patricia Cleary, John Lachin, David A. Bluemke, João A.C. Lima
Journal: Diabetes Care (2016)

OBJECTIVE We investigated the association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 diabetes. RESEARCH DESIGN AND METHODS Participants with type 1 diabetes aged 13–39 years without a known history of cardiovascular disease (CVD) (n = 1,441) were recruited into the Diabetes Control and Complications Trial (1983–1993) and subsequently followed in the Epidemiology of Diabetes Interventions and Complications study (1994 to present). Seven hundred fourteen participants underwent cardiac magnetic resonance (CMR) imaging (2007–2009) with late gadolinium enhancement sequences to assess ischemic and nonischemic scars and tagging sequences to evaluate circumferential strain. CMR-derived T1 mapping also was used to assess interstitial fibrosis. The influence of cardiovascular risk factors and myocardial scar on circumferential strain was assessed using linear regression. RESULTS Circumferential dysfunction was consistently associated with older age, male sex, smoking history, obesity, higher blood pressure, lower HDL cholesterol, and higher mean HbA1c. Participants with nonischemic scars (n = 16) had the worst circumferential function compared with those without scars (β ± SE 1.32 ± 0.60; P = 0.03). In sex-adjusted models, the correlation between T1 times and circumferential strain was not significant. In the fully adjusted models, a trend toward circumferential dysfunction in participants with nonischemic scars was found. Left ventricular ejection fraction was not associated with risk factors but was significantly lower if a myocardial scar was present. CONCLUSIONS Traditional CVD risk factors and elevated HbA1c levels are major factors related to early cardiac dysfunction in type 1 diabetes. Nonischemic myocardial scar, possibly as a marker of chronic exposure to known risk factors, may predict early cardiac dysfunction mediated by diffuse myocardial fibrosis as seen in diabetic cardiomyopathy.
Outcome of systemic treatments after first line platinum and cetuximab treatment in patients with recurrent/metastatic (RM) head and neck squamous cell cancer (HNSCC): a retrospective analysis
Authors: C. Resteghini, M. Siano, M.C. Cau, S. Alfieri, C. Bergamini, R. Granata, R. Miceli, G. Infante, M. Imbimbo, L. Locati, L. Licitra, P. Bossi
Journal: Annals of Oncology (2015)
Clinical Benefit of Ruxolitinib Treatment after Crossover from Best Available Therapy in Patients with Polycythemia Vera: Analysis of the RESPONSE Trial
Authors: Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Martin Griesshammer, Tamas Masszi, Simon Durrant, Francesco Passamonti, Claire N Harrison, Fabrizio Pane, Pierre Zachee, Ruben Mesa, Mark M Jones, Shui He, Jingjin Li, Dany Habr, Srdan Verstovsek
Journal: Blood (2014)
Tandem Autologous-Nonmyeloablative (NMA) Allogeneic(Allo) Transplant (Tx) in Newly Diagnosed Multiple Myeloma (MM) Leads to Improved Survival When Compared to Conventional Allogeneic Transplant
Authors: Waleed Sabry, Amelie Fontaine, Richard Le Blanc, Guy Sauvageau, Denis-Claude Roy, Lambert Busque, Sandra Cohen, Thomas Kiss, Silvy Lachance, Jean Roy
Journal: Blood (2008)
The Impact of Age and Body Fat on Graft-Versus-Host Disease (GVHD) in Mice
Authors: Chien-Chun Steven Pai, Mingyi Chen, Lam Khuat, Annie Mirsoian, Anthony E Zamora, Steven Grossenbacher, Christine Mall, Arta Monjazeb, Julian Perks, Shuaib Juma, Mehrdad Abedi, William J Murphy
Journal: Blood (2014)
Single Cell Level Genome-Wide Gene Expression Analysis of Bone Marrow-Derived Oct-4+ very Small Embryonic-Like Stem Cells (VSELs) Revealed That a Polycomb Group Protein Ezh2 Regulates VSELs Pluripotency by Maintaining Bivalent Domains At Promoters of Important Homeodomain-Containing Developmental Transcription Factors
Authors: Magda Kucia, Rui Liu, Kasia Mierzejewska, Wan Wu, Janina Ratajczak, Dong-Myung Shin, Mariusz Z Ratajczak
Journal: Blood (2011)
576. A Novel Gene Editing-Based Strategy for Myotonic Dystrophy Type 1
Authors: Mirella Lo Scrudato, Samia Martin, Geneviève Gourdon, Denis Furling, Ana Buj-Bello
Journal: Molecular Therapy (2015)

Myotonic dystrophy type 1 (DM1) is an autosomal dominant muscular disease caused by an expansion of the CTG trinucleotide repeat located in the 3' untranslated region (3' -UTR) of the DMPK gene. The size of the expansion correlates with disease severity and to date there is no effective treatment for patients. Mutated DMPK transcripts aberrantly interact with proteins in the nucleus and form stable complexes where splicing factors are sequestered. As a consequence, the alternative splicing of numerous transcripts is pathogenically misregulated. We aim at developing a strategy to delete the CTG expansion from the human DMPK locus by using the CRISPR/Cas9 system. We have generated several constructs which express a small size Cas9 nuclease and guide-RNAs (gRNAs), and show their ability to excise the targeted DNA region in various cell lines. We are currently producing adeno-associated vectors for in vivo delivery of these constructs in a DM1 mouse model.
High Dose Celecoxib and Metronomic ‘Low-Dose’ Cyclophosphamide Is Effective Therapy in Patients with Relapsed and Refractory Aggressive Histology NHL.
Authors: Rena Buckstein, M. Crump, Y. Shaked, D. Spaner, E. Piliotis, K. Imrie, R. Nayar, C. Foden, R. Turner, D. Taylor, S. Man, S. Baruchel, D. Stempak, I. Quirt, J. Sturgeon, F. Bertolini, R.S. Kerbel
Journal: Blood (2004)
PTH-070 The impact oral bowel cleansing agents on patients undergoing colonoscopy and the potential service implications of the draft BSG guidelines for NPSA alert (RRR012)
Authors: P Flanagan, S Mahmood, M Nasser, S Sarkar
Journal: Gut (2010)

<h3>Introduction</h3> Bowel preparation is essential for successful lower GI endoscopy but can be unpleasant for patients. Responding to the NPSA alert (NPSA/2009/RRR012) the BSG issued draft guidelines, stipulating assessment and eGFR for all patients and product depending on patient risk (risks; CCF, low eGFR, cirrhosis, diuretics/ACEi/ARB/NSAIDs). Compliance will have service implications for most units. We aimed to determine the effect of oral bowel cleaning agents on patient experience and quantify the service implications of the draft guidelines. <h3>Methods</h3> All colonoscopies performed in Oct 2009 were included. Data were obtained from patient interview, hospital IT systems and Unisoft. A structured patient telephone interview evaluating side-effects, assessment process and their experience was determined using a satisfaction scale (1=much worse than expected 2=slightly worse 3=as expected 4=slightly better 5=much better) or a severity scale (between 1=none and 5=worst imaginable). <h3>Results</h3> General: 265 colonoscopies (M/F 1:1) were performed, 186 patients were contacted with 115 responding (sample rate 43% uptake rate 61.8%). Mean age was 62.2 years (SD 14.5, 58% male). 96.5% took all the bowel preparation, with unpleasant side effects (incontinence, pain, nausea/vomiting, faint, dizzy, collapse) in 23.5%. Median responses for; experience of the bowel prep and overall experience, were 3 (as expected). For; pain caused by prep, prep affecting decision to have a repeat test and severity of side effects, the medians were 1 (none). However prep had a moderate (score 3) impact on their lives. <h3>BSG Guidelines</h3> 97.4% were reviewed before colonoscopy and 98.3% received written instructions. 20% had no traceable eGFR. Interestingly 22% of patients with no comorbidities and no medications had GFR&lt;60. 38.2% were “at risk” (neprotoxic drugs, low eGFR, significant comorbidities). Overall 6.9% has adverse side effects (collapse, dizzy, fainting). Incidence of adverse side effects was higher in those with eGFR &lt;60 (17.9%) than those with eGFR &gt;60 (4.7%). Significant comorbidity identified 50% of patients with adverse side-effects, comorbidity and medication identified 62.5%, while eGFR &lt;60 and comorbidity combined (± medication) increased the sensitivity to 87.5%. <h3>Conclusion</h3> The majority manage the full bowel preparation but almost a quarter experienced side-effects. Service provision for eGFR would be required in 20%. The “at-risk” classification identifies some patients with adverse side effects but a combination of eGFR &lt;60 and significant comorbidities (cirrhosis, CCF) was more sensitive. A service stratification using PEG based preparations for patients with eGFR&lt;60, Cirrhosis or CCF or changing to just using PEG preparations is being reviewed locally as a solution to the guidance.
Abstract 4138: Integrating SNPs, epigenetics and transcriptomics to better understand the inherited predisposition to breast cancer metastasis
Authors: Anjali Shukla, Ling Bai, Howard Yang, Anthony Doran, Ying Hu, Thomas Geiger, Maxwell Lee, Thomas Keane, Kent W. Hunter
Journal: Cancer Research (2015)

Abstract Breast cancer is the most frequent cancer and the second leading cause of cancer mortality in women. The vast majority of breast cancer mortality is due to metastatic disease since the primary tumor can be relatively easily surgically resected. More comprehensive understanding of biology of metastasis is therefore clearly warranted to unveil novel metastasis-associated molecules and cellular processes that might be targeted for clinical intervention. Previously we demonstrated that like cancer incidence, metastatic progression has a significant inherited component. Using mouse complex trait mapping strategies we have been isolating metastasis susceptibility genes from backcross analysis. However, studies suggest that many of these QTL peaks are the result of the contribution of multiple genes, suggesting that causal genes are not being identified. To increase our ability to detect causal genes we have implemented a new integrated strategy. Whole genome sequencing of appropriate high or low metastatic mouse strains is performed to identify variants, which are then filtered for those within DNAse hypersensitive sites (DHS), based on the hypothesis that most inherited phenotypes are due to expression differences rather than missense variants. The genes associated with polymorphic DHS are then screened through mouse and human tumor expression databases to identify those genes associated with development of metastatic disease. This strategy was able to identify genes previously associated with metastatic breast cancer in both mouse and humans and new genes have also been validated. The results further suggest that inherited variation in cellular mediated immune response may be an important contributor to metastatic disease. Citation Format: Anjali Shukla, Ling Bai, Howard Yang, Anthony Doran, Ying Hu, Thomas Geiger, Maxwell Lee, Thomas Keane, Kent W. Hunter. Integrating SNPs, epigenetics and transcriptomics to better understand the inherited predisposition to breast cancer metastasis. [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 4138. doi:10.1158/1538-7445.AM2015-4138
Abstract 730: The role of ZEB1/ZEB2 and βIII-tubulin in mediating docetaxel-resistant prostate cancer
Authors: Karen Hanrahan, Maria Prencipe, Jane Bugler, Lisa Murphy, Amanda O'Neill, R. William Watson
Journal: Cancer Research (2015)

Abstract Docetaxel therapy is the gold standard treatment for advanced castrate-resistant prostate cancer (CRPC). However, patients either do not respond or develop resistance over time. Transcriptomic and proteomic analysis of docetaxel-resistant prostate cancer sub-lines developed by our group revealed multiple mechanisms of resistance in line with advanced disease, including over-expression of anti-apoptotic proteins and alterations of NF-KB activation. The sub-lines also demonstrated a coordinated loss and gain of epithelial and mesenchymal markers respectively; a process characteristic of Epithelial-Mesenchymal Transition (EMT). Studies have highlighted a role of EMT in prostate cancer progression, metastasis and docetaxel resistance. However, the role of EMT drivers in mediating resistance is not defined. We hypothesise EMT to be a central mechanism of apoptotic resistance in advanced docetaxel-resistant prostate cancer, representing a target for therapeutic manipulation. EMT was characterised in the PC-3 D12 and DU145 R docetaxel-resistant sub-lines through an increased invasive capacity, MMP-1 secretion and protein expression of E-cadherin transcriptional repressors ZEB1 and ZEB2, in comparison to parental cell lines. This was associated with an increased expression of βIII-tubulin; a tubulin isotype linked to taxane resistance and tumour aggressiveness. Upon treatment with the apoptotic trigger docetaxel (20nM), the PC-3 D12 and DU145 R sub-lines demonstrated significant resistance compared to parental controls. Simultaneous siRNA knockdown of ZEB1 and ZEB2 resulted in both a partial reversal in apoptotic resistance and a decrease in cell viability; this was also associated with a down-regulation of βIII-tubulin and a re-expression of E-cadherin. Our results provide evidence of the process of EMT in in vitro models of docetaxel-resistant prostate cancer, which is associated with differential susceptibility to docetaxel and is partially reversed through siRNA knockdown of the EMT drivers, ZEB1 and ZEB2. In addition, we have identified a link between EMT and βIII-tubulin in our models of docetaxel resistance. Current experiments are investigating the tissue expression of ZEB1 and βIII-tubulin in prostate cancer metastases following docetaxel therapy, which will determine the clinical relevance of EMT and βIII-tubulin as mediators of docetaxel resistance in CRPC. Citation Format: Karen Hanrahan, Maria Prencipe, Jane Bugler, Lisa Murphy, Amanda O'Neill, R. William Watson. The role of ZEB1/ZEB2 and βIII-tubulin in mediating docetaxel-resistant prostate cancer. [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 730. doi:10.1158/1538-7445.AM2015-730
Cytomegalovirus Reduces the Relapse Risk for Acute Leukemia After Transplant: There Is a Virus-Versus-Leukemia Effect.
Authors: Ahmet H Elmaagacli, Monika Lindemann, Bertram Opalka, Michael Koldehoff, Tania Gromke, Hellmut Ottinger, Rudolf S. Ross, Sebastian Bauer, Inken Hilgendorf, Dietrich W. Beelen
Journal: Blood (2009)
Abstract 2845: Co-acquisition of T790M and EMT in resistant EGFR mutant non-small cell lung cancer can be overcome by combined irreversible EGFR and BCL-XL inhibition
Authors: Aaron N. Hata, Matthew J. Niederst, Hannah L. Archibald, Hillary Mulvey, Jungoh Ham, Maria Gomez-Caraballo, Anuj Kalsy, Anthony C. Faber, Jeffrey Engelman
Journal: Cancer Research (2015)

Abstract The development of acquired drug resistance limits the effectiveness of targeted therapies for lung cancer. In 50% of patients with EGFR mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR inhibitors can be attributed to the development of a secondary T790M mutation that prevents drug binding. Third generation irreversible EGFR inhibitors that effectively inhibit EGFR with T790M are currently under clinical development. Using patient-derived EGFR mutant NSCLC models of T790M+ acquired resistance, we observed that the presence of a mesenchymal phenotype was associated with a decreased response to subsequent irreversible EGFR inhibitor therapy. Epithelial-to-mesenchymal transformation (EMT) led to suppression of pro-apoptotic signaling and a blunted apoptotic response to EGFR inhibition. Combination BCL-XL and irreversible EGFR inhibitor therapy restored the apoptotic response and resulted in regressions of T790M+ resistant tumors that exhibited poor response to single agent irreversible EGFR inhibitors. This suggests that combining BCL-XL and irreversible EGFR inhibitors may be an effective treatment strategy for T790M+ resistant EGFR mutant lung cancers with suppressed apoptotic signaling due co-acquisition of a mesenchymal phenotype. Citation Format: Aaron N. Hata, Matthew J. Niederst, Hannah L. Archibald, Hillary Mulvey, Jungoh Ham, Maria Gomez-Caraballo, Anuj Kalsy, Anthony C. Faber, Jeffrey Engelman. Co-acquisition of T790M and EMT in resistant EGFR mutant non-small cell lung cancer can be overcome by combined irreversible EGFR and BCL-XL inhibition. [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 2845. doi:10.1158/1538-7445.AM2015-2845
616. Tailored Expression of a Transgene to Specific Cell Types in the Central Nervous System After Peripheral Injection of AAV9
Authors: Eloise Hudry, Jonathan Dashkoff, Paul Lerner, Shuko Takeda, Nhi Truong, Casey Maguire, Bradley T. Hyman
Journal: Molecular Therapy (2016)

Because of their efficient tropism for the neural tissue and their well-established safety and tolerability profile, adeno-associated vectors (AAV) hold great potential to express therapeutic genes in the context of various neurodegenerative disorders. Importantly, the characterization of novel AAV serotypes (AAV9; rhAAV10, etc …) that can cross the blood brain barrier after intravenous delivery now offer an opportunity for non-invasive delivery to the brain. However, in absence of a well-tailored system, the use of a peripheral route injection may lead to undesirable transgene expression in various cell types of the nervous system as well as in other organs. In order to refine this approach, the present study characterizes the transduction profiles of newly engineered self-complement AAV9 (scAAV9) expressing the Green Fluorescent Protein (GFP) either under an astrocyte (GFA') or neuronal (Synapsin, Syn) promoter, after a single injection in the lateral tail vein of adult mice (5×10e11vg/animal). We report that our scAAV9-GFA'-GFP and scAAV9-Syn-GFP respectively led to robust and long-lasting transduction of astrocytes (10%) and neurons (8%) throughout the entire cerebral tissue, in the absence of aberrant expression leakage in other cell types of the brain or in the liver. GFP positive excitatory as well as inhibitory neurons could be observed in the CNS, while motor neurons were also efficiently transduced in the PNS. In addition, both activated (GFAP positive) and resting astrocytes expressed the reporter gene. Quantitative stereological assessment demonstrated an increase in reactive astrocytes after transduction with scAAV9 but did not lead to any obvious detrimental phenotype in any animals. These data suggest the potential interest of tailoring AAV to drive expression of therapeutic genes specifically in astrocytes or neurons of the CNS after intravenous delivery, thus preventing adverse side-effects associated with peripheral expression.
20. Carboxylesterase-Secreting Neural Stem Cells Increase Efficacy of Irinotecan in Orthotopic Glioma Models: Translation Toward the Clinic
Authors: Lucy Y. Ghoda, Revathiswari Tirughana, Megan Gilchrist, Marianne Metz, Margarita Gutova, Vazgen Khankaldyyan, Timothy Synold, Suzette Blanchard, Massimo D'Apuzzo, Rex Moats, Michael Barish, Karen S. Aboody
Journal: Molecular Therapy (2015)

Human neural stem cells (NSCs) are serving as vehicles for targeted delivery of cytosine deaminase/5-flucytosine enzyme/prodrug therapy to recurrent glioma patients in first in human Phase 1 clinical trials (IND 14041). The initial safety/feasibility clinical study demonstrated safety, non-tumorigenicity, non-immunogenicity with 1 round of treatment, and proof of concept for localized conversion of 5-Flucytosine to the active chemotherapeutic agent, 5-Fluorouracil. We have now developed a second generation NSC brain tumor therapy, engineering NSCs to secrete a modified human carboxylesterase (hCE1m6) that converts irinotecan (IRN) to the potent topoisomerase inhibitor SN-38. Biodistribution, efficacy, and safety/toxicity studies have been completed and an Investigational New Drug application has been filed with the Food and Drug Administration (IND 16265). Early studies on the CE-expressing human NSCs was described in Metz, et al., Stem Cells Transl Med. 2013 Dec;2(12):983), demonstrating tumor tropism in orthotopic human glioma models and tumor localized conversion of IRN to SN-38 in a time-dependent manner. The current preclinical studies show in vivo biodistribution of varying doses of intracranially delivered CE-NSCs and optimization of a clinically relevant adult IRN treatment regimen based on pharmacokinetic and long term survival studies. These studies demonstrated a statistically significant increase in long-term survival distributions with the addition of CE-NSCs + IRN as compared to IRN alone (see figure). These data, together with our preclinical safety/toxicity data, support clinical translation of this schema to phase I clinical trials for patients with recurrent glioma.