tbuckley/cabot-search huggingface dataset:
335. Long-Term Genetic Modification of the Ocular Outflow Tract Coupled with Non-Invasive Real-Time Imaging of Gene Expression
Authors: Nils A. Loewen, Michael P. Fautsch, Wu-Lin Teo, Cindy K. Bahler, Douglas H. Johnson, Eric M. Poeschla
Journal: Molecular Therapy (2004)

Top of pageAbstract
The anterior chamber of the human eye is the site of dysregulated outflow of aqueous humor that underlies the intraocular hypertensive pathophysiology of glaucoma, a chronic disease that remains one of the leading causes of irreversible blindness worldwide. We hypothesized that the distinctive properties of this circulation could enable a unique approach to problems of accessibility and scale that have hindered the realization of gene therapy and monitoring of its efficacy. Permanent, properly targeted transgene expression within the anterior chamber would facilitate glaucoma research and development of glaucoma gene therapy, but this has not been achieved. In this study with 19 domestic cats, a model chosen for a larger, available animal with similarity to the human eye, we show reproducible high grade, stable transgenesis of the entire critical target tissue, the trabecular meshwork, with lentiviral vectors. The virtually complete transduction is targeted to this tissue within the anterior chamber, occurs after a single trans-corneal injection and persists stably for more than 10 months. It can be monitored serially and non-invasively in living animals. These studies provide a basis for administering glaucoma gene therapy to the anterior chamber of the eye and development of new glaucoma disease models.
686. CAR-Expression Is Essential for Tumor Inititation in Lung Cancer Xenografts
Authors: Min Qin, Brian Escuadro, Ling Zhang, Sherven Sharma, Raj K. Batra
Journal: Molecular Therapy (2004)

Top of pageAbstract
Rationale: CAR, the Coxsackievirus Adenovirus Receptor, has primarily been studied in its role as the initial cell surface attachment receptor for Coxsackie and group C-Adenoviruses (Ad). Recent studies indicate that CAR serves to mediate homotypic cell-cell adhesion as a component of the tight junction and/or adherens junction. CAR's role in tumorigenesis has been considered, but no mechanistic studies probing this role have been reported.

Experimental Design: Non-small cell lung cancer (NSCLC) cells with exuberant CAR expression (FACS: 99.9% positive w/ MCF 55.2) were stably transfected with control and AS-CAR vectors, and CAR(−)clones isolated (FACS: 1.9% positive w/ MCF 9.6). Cells were phenotypically characterized and tumorigenesis was compared in xenograft models. In separate experiments, CAR was functionally blocked using a monoclonal antibody and a specific ligand (Ad fiber knob), and the impact on tumor formation assessed.

Results: Expectedly, CAR (−) cells were refractory to Ad-transduction and demonstrated marked reductions in CAR-mRNA by RT-PCR. Silencing CAR expression in cells that exhibited relatively “high” surface expression of this molecule profoundly inhibited their ability to develop xenografts in host mice (Day 40 tumor volume: CAR (+) cells 574 + 304 mm3, CAR (−) cells 0 mm3; n = 10 scid/scid mice, p<0.001). In survival studies, whereas 5/5 mice sufficed to tumor by day 53 post implantation by CAR (+) cells, all 5/5 mice injected with CAR (−) cells survived (p<0.001). Indeed, 4/5 mice injected with CAR(−)cells were euthanized without tumor on day 120. However, one of 5 mice injected with CAR (−) cells displayed delayed tumor growth beginning at 3 months post-injection, and when this tumor was extirpated and analyzed, CAR-expression had re-emerged. In the second series of experiments, co-injection of NSCLC-cells with high and intermediate surface expression of CAR with a blocking antibody inhibited tumorigenesis in nude mice by these cells (p<0.05). The impact of Ad-fiber knob and siRNA-inhibition of CAR-expression in situ is currently underway.

Conclusion: Results to date indicate that CAR subserves a novel biological function in tumor-initiation by lung cancer xenografts. The molecular and cellular mechanisms for this function are being explored.
Abstract 2497: Extracellular vesicle-mediated reversal of the prostate cancer phenotype
Authors: Kiriaki Panagopoulos, Sam Cross-Knorr, Joseph F. Renzulli, Peter J. Quesenberry, Devasis Chatterjee
Journal: Cancer Research (2014)

Abstract Extracellular vesicle (EV) trafficking is a fundamental cellular process that occurs in cells and is required for different aspects of pathophysiology. EV trafficking leads to changes in cellular function including apoptosis, angiogenesis and proliferation required for increased tumor formation. In our current study we report several phenotypic changes mediated by EVs isolated from non-malignant and malignant prostate cells as well as patient biopsied prostate tumor samples. EVs can reverse the resistance of prostate cancer cells to camptothecin EVs isolated from non-malignant PrECs (Prostate Epithelial Cells) can reverse soft agar colony formation of malignant DU145 cells, with the reciprocal effect observed. Isolation of EVs from 2 Gleason grade 8 prostate cancer patients significantly induced soft agar colony formation of non-malignant PrECs. We have identified proteins via antibody and Mass spectrometry analysis that may be responsible for the phenotypic changes. Mass spectrometry analysis of protein lysates using ProteoIQ revealed protein candidates associated with gene ontology annotations that may be responsible for this phenotypic change. Ingenuity Pathway Analysis was used to identify statistically relevant canonical pathways and functions associated the protein IDs and expression values obtained using ProteoIQ. Western blot analysis confirmed the increase of 14-3-3 zeta, pRKIP and prohibitin protein levels in PrEC cells co-cultured with patient EVs. 14-3-3 proteins were also found as common proteins of 3 other Gleason grade 8 patients. Our results provides a rational basis to further investigate putative proteins, such as 14-3-3 and prohibitin and genetic factors that may be responsible for phenotypic changes that are associated with prostate cancer progression. Citation Format: Kiriaki Panagopoulos, Sam Cross-Knorr, Joseph F. Renzulli, Peter J. Quesenberry, Devasis Chatterjee. Extracellular vesicle-mediated reversal of the prostate cancer phenotype. [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 2497. doi:10.1158/1538-7445.AM2014-2497
Antioxidant supplementation attenuates changes in innate immunity associated with diesel exhaust (DE) in the lung: A controlled crossover exposure study
Authors: Chris Carlsten, Mandy Pui, Meaghan MacNutt, John Lay, Neil Alexis
Journal: European Respiratory Journal (2011)

Rationale:  Oxidative stress is thought to induce negative health effects associated with exposure to DE and may result from altered innate immunity. Therefore, anti-oxidant supplementation may modify DE-related changes in phagocytosis in airways.   Methods:  12 participants (4 mild asthmatics and 8 healthy controls) completed a double-blinded, randomized, crossover, counter-balanced study of 3 exposure conditions, each separated by a 2-wk washout period: (1) DE (300ug PM 2.5 /m 3  for 2 hours) with anti-oxidant (N-acetylcysteine 600mg 3x/day for 5 days preceding, and on the day of the exposure) [“DEN”], (2) DE with placebo [“DEP”], or (3) filtered air with placebo [“FAP”]. Induced sputum was collected 6 hours after each exposure. Sputum neutrophils and macrophages were analyzed by flow cytometry for changes in innate immune response (phagocytosis). Those with PC20≤8 were defined as “reactive” and those with PC20>8 as “non-reactive”.   Results:  Phagocytosis in sputum macrophages was greater after DEP than after FAP (mean phagocytosis units = 22.8 and 15.8, respectively) and this difference was attenuated by DEN (mean phagocytosis units = 17.8 units). 6 subjects were methacholine-reactive at baseline; reactivity status did not modify phagocytosis.   Conclusions:  DE-associated increase in phagocytosis in human airways appears mitigated by anti-oxidant supplementation (N-acetylcysteine). The suggestion that DE upregulates the innate immune response in sputum macrophages, and that this is mediated by oxidative stress, parallels novel data from our lab regarding changes in airway reactivity to methacholine in response to FAP, DEP, and DEN.
Exploiting the success and failure of cancer therapies: Investing now in accurate biomarker data to improve outcomes later
Authors: Peter Nelson
Journal: Clinical Cancer Research (2008)

ED01-01   Most therapeutic clinical trials of anti-neoplastic agents are not designed to anticipate or exploit the most likely outcome: failure to meet the primary endpoint. In the vast majority of these trials, the reason for failure is poorly understood. Unfortunately, clinical studies are rarely structured for iterative analyses of cause-and-effect, a core principle of scientific investigation. However, several recent studies demonstrate the power and importance of recognizing tumor and host subtypes, and measuring drug effects at the target level. The advent of new tools for assessing biomarkers of tumor and host heterogeneity and drug response have provided unprecedented opportunities for refining concepts of success and failure in clinical trials. This presentation will highlight key advances and discuss issues in the accurate assessment of biomarkers in the context of the complexities of normal human variation and disease phenotypes.
Abstract 17652: Application of Pediatric and Adult Lipid Treatment Guidelines to U.S. Adolescents Transitioning to Young Adulthood
Authors: Holly C Gooding, Angie M Rodday, John B Wong, Donald Lloyd-Jones, Matthew W Gillman, Laurel K Leslie, Sarah D de Ferranti
Journal: Circulation (2014)

Introduction: Current pediatric and adult lipid treatment guidelines differ in their approach to pharmacologic treatment of cholesterol in adolescents and young adults. We hypothesized that a greater proportion of young people ages 17-21 would meet criteria for statin treatment under the pediatric guidelines compared to adult guidelines, but that overall eligibility for statin treatment would be low in this age group. Methods: We applied treatment algorithms from the 2011 NHLBI Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents and the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults to participants in the 1999-2011 National Health and Nutrition Examination Surveys who were 17-21 years of age and had an LDL level measured (n=2,652). We extrapolated the results to a population of 11.2 million individuals ages 17-21 years living in the US. Results: Almost 2% of participants (n=50, 1.9%) qualified for statin treatment under the pediatric guidelines, but only 0.7% (n=18) met treatment criteria under the adult guidelines. Participants who met pediatric criteria had lower mean LDL levels but were more likely to have other cardiovascular risk factors, including hypertension, smoking, and obesity (Table 1). Despite the relatively low percentage of participants reaching LDL treatment thresholds under either guideline, 258,816 U.S. young people would be eligible for statin treatment under the pediatric guidelines and 84,651 would be eligible for treatment under the adult guidelines. Conclusions: Providers who care for adolescents transitioning to adulthood are faced with incongruent lipid guidelines. Application of pediatric guidelines, which use a life course approach and consider additional cardiovascular risk factors beyond age, may result in statin treatment for more young people.
Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects
Authors: John S. Millar, Gissette Reyes-Soffer, Patricia Jumes, Richard L. Dunbar, Emil M. deGoma, Amanda L. Baer, Wahida Karmally, Daniel S. Donovan, Hashmi Rafeek, Laura Pollan, Junichiro Tohyama, Amy O. Johnson-Levonas, John A. Wagner, Stephen Holleran, Joseph Obunike, Yang Liu, Rajasekhar Ramakrishnan, Michael E. Lassman, David E. Gutstein, Henry N. Ginsberg, Daniel J. Rader
Journal: Journal of Clinical Investigation (2015)

Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.ClinicalTrials.gov NCT00990808.Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).
The Binding and Cleavage Characteristics of Human Hageman Factor during Contact Activation
Authors: Susan D. Revak, Charles G. Cochrane, John H. Griffin
Journal: Journal of Clinical Investigation (1977)

The ability of human Hageman factor (coagulation factor XII) to bind to a glass surface and its susceptibility to limited proteolytic cleavage during the contact activation of plasma have been studied using normal human plasma and plasmas genetically deficient in factor XI, prekallikrein, or high molecular weight kininogen (HMWK). When diluted normal plasma containing 125I-Hageman factor was exposed to a glass surface for varying times, the Hageman factor was found to bind to the surface, and within 5 min became maximally cleaved from its native 80,000 mol wt to yield fragments of 52,000 and 28,000 mol wt. Hageman factor in factor XI-deficient plasma behaved similarly. In prekallikrein-deficient plasma, the binding of Hageman factor to the glass surface occurred at the same rate as in normal plasma but the cleavage was significantly slower, and did not reach maximum until 60 min of incubation. Cleavage of Hageman factor in HMWK-deficient plasma occurred at an even slower rate, with greater than 110 min of incubation required for maximal cleavage, although the rate of binding to the glass was again the same as in normal plasma. Normal rates of cleavage of Hageman factor were observed for the deficient plasmas after reconstitution with purified human prekallikrein or HMWK, respectively. These observations suggest that normal contact activation in plasma is associated with proteolytic activation of surfacebound Hageman factor.
Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia
Authors: Eyal Banin, Elisha Gootwine, Alexey Obolensky, Raaya Ezra-Elia, Ayala Ejzenberg, Lina Zelinger, Hen Honig, Alexander Rosov, Esther Yamin, Dror Sharon, Edward Averbukh, William W Hauswirth, Ron Ofri
Journal: Molecular Therapy (2015)

Achromatopsia is a hereditary form of day blindness caused by cone photoreceptor dysfunction. Affected patients suffer from congenital color blindness, photosensitivity, and low visual acuity. Mutations in the CNGA3 gene are a major cause of achromatopsia, and a sheep model of this disease was recently characterized by our group. Here, we report that unilateral subretinal delivery of an adeno-associated virus serotype 5 (AAV5) vector carrying either the mouse or the human intact CNGA3 gene under the control of the red/green opsin promoter results in long-term recovery of visual function in CNGA3-mutant sheep. Treated animals demonstrated shorter maze passage times and a reduced number of collisions with obstacles compared with their pretreatment status, with values close to those of unaffected sheep. This effect was abolished when the treated eye was patched. Electroretinography (ERG) showed marked improvement in cone function. Retinal expression of the transfected human and mouse CNGA3 genes at the mRNA level was shown by polymerase chain reaction (PCR), and cone-specific expression of CNGA3 protein was demonstrated by immunohistochemisrty. The rescue effect has so far been maintained for over 3 years in the first-treated animals, with no obvious ocular or systemic side effects. The results support future application of subretinal AAV5-mediated gene-augmentation therapy in CNGA3 achromatopsia patients.
Abstract 15251: Dual Role of Inducible Nitric Oxide Synthase in Left Ventricular Injury and Protection after Myocardial Infarction in Mice
Authors: Takayuki Shimazu, Hajime Otani, Kei Yoshioka, Toru Okazaki, Masanori Fujita, Toshiji Iwasaka
Journal: Circulation (2010)

Background: Uncoupling of nitric oxide synthase (NOS) plays a crucial role in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). Although previous studies have indic...
The Obesity Paradox in Type 2 Diabetes Mellitus: Relationship of Body Mass Index to Prognosis
Authors: Pierluigi Costanzo, John G.F. Cleland, Pierpaolo Pellicori, Andrew L. Clark, David Hepburn, Eric S. Kilpatrick, Pasquale Perrone-Filardi, Jufen Zhang, Stephen L. Atkin
Journal: Annals of Internal Medicine (2015)

Whether obesity is associated with a better prognosis in patients with type 2 diabetes mellitus is controversial.To investigate the association between body weight and prognosis in a large cohort of patients with type 2 diabetes followed for a prolonged period.Prospective cohort.National Health Service, England.Patients with diabetes.The relationship between body mass index (BMI) and prognosis in patients with type 2 diabetes without known cardiovascular disease at baseline was investigated. Information on all-cause mortality and cardiovascular morbidity (such as the acute coronary syndrome, cerebrovascular accidents, and heart failure) was collected. Cox regression survival analysis, corrected for potential modifiers, including cardiovascular risk factors and comorbid conditions (such as cancer, chronic kidney disease, and lung disease), was done.10,568 patients were followed for a median of 10.6 years (interquartile range, 7.8 to 13.4). Median age was 63 years (interquartile range, 55 to 71), and 54% of patients were men. Overweight or obese patients (BMI >25 kg/m²) had a higher rate of cardiac events (such as the acute coronary syndrome and heart failure) than those of normal weight (BMI, 18.5 to 24.9 kg/m²). However, being overweight (BMI, 25 to 29.9 kg/m²) was associated with a lower mortality risk, whereas obese patients (BMI >30 kg/m²) had a mortality risk similar to that of normal-weight persons. Patients with low body weight had the worst prognosis.Data about cause of death were not available.In this cohort, patients with type 2 diabetes who were overweight or obese were more likely to be hospitalized for cardiovascular reasons. Being overweight was associated with a lower mortality risk, but being obese was not.National Institute for Health Research and University of Hull.
Abstract 300: Expression profiling of miRNA in asbestos-related lung adenocarcinoma
Authors: Yasen Mahmut, Hironori Ninomiya, Noriko Motoi, Satoru Itoh, Mutsunori Fujiwara, Yuichi Ishikawa
Journal: Cancer Research (2014)

Abstract Lung cancer has the highest mortality rate of all of the cancers in the world and asbestos-related lung cancer is one of the leading occupational cancers. The identification of asbestos-related molecular changes has long been a topic of increasing research interest. Microarray technology is a powerful high-throughput tool capable of monitoring the expression of thousands of small noncoding RNAs at once within tens of samples processed in parallel in a single experiment. The aim of this study was to construct a genome-wide expression profile of miRNA of asbestos-related lung cancers, and was to identify novel asbestos-related molecular biomarkers. The miRNA profiling was performed on 31 patients (13 patients with asbestos-exposed and 18 patients with non- asbestos-exposed) undergoing lung resection for primary adenocarcinoma, both fresh and FFPE materials of whom were available. Data analyses on miRNA expression revealed four novel asbestos-related miRNAs (three over-expressed miR-210, miR-200a, miR-429, and one under-expressed miR-140-3p). Also, 16 target genes, expression of which were inversely correlated, were identified. Among them we obtained a set of miRNAs that were involved in hypoxia-regulated and oxidative stress responders, seemingly related to asbestos burden. For example, miR-210 is involved in a wide-range of processes, including cell proliferation, migration, apoptosis, differentiation, DNA repair and cell metabolism, and more recently in the regulation of antitumor immune responses, suggesting roles of this miRNA as a central master regulator of the hypoxic response. According to gene ontology analyses of the target genes were mostly transcription factors, cyclins and cyclin-dependent kinases. For validation, we compared the expression levels of miRNA between fresh and FFPE materials, resulting in good correlations (R=0.76-0.90). The miRNAs/genes presented here may be interesting targets for further investigation and could eventually have potential diagnostic implications. Citation Format: Yasen Mahmut, Hironori Ninomiya, Noriko Motoi, Satoru Itoh, Mutsunori Fujiwara, Yuichi Ishikawa. Expression profiling of miRNA in asbestos-related lung adenocarcinoma. [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 300. doi:10.1158/1538-7445.AM2014-300
The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm–specific protein with an extracellular cysteine-rich domain
Authors: Sundeep Kalantry, Sharon Manning, Olivia Haub, Carol Tomihara-Newberger, Hong-Gee Lee, Jennifer Fangman, Christine M. Disteche, Katia Manova, Elizabeth Lacy
Journal: Nature Genetics (2001)