tbuckley/cabot-search huggingface dataset:
915. Insertional Analyses in Rhesus Monkey Blood Cells after Non-Myeloablative Hematopoietic Stem Cell Marking with a Therapeutic Onco-Retroviral Vector for X-Linked Chronic Granulomatous Disease
Authors: Martin F. Ryser, Sebastian Brenner, Narda Whiting-Theobald, Romy Lehmann, Uimook Choi, Gilda F. Linton, Elizabeth Kang, Andrew G. Rudikoff, Ann M. Farese, Thomas J. MacVittie, Mitchell E. Horwitz, Harry L. Malech
Journal: Molecular Therapy (2004)

Wild-type murine onco-retroviruses cause cancer in part by insertional mutagenesis, but until recently, cancers had not been observed in humans or animals subjected to marking or treatment with the highly modified murine retrovirus vectors in current use. Recently, mutagenesis activation of the LMO-2 gene was observed to be associated with the development of lymphoid leukemia several years after two infants with X-SCID had their immune systems restored by gene therapy with a therapeutic onco-retrovirus vector. Insertional mutagenesis activation of other oncogenes associated with development of cancers has been reported in vector-marked mice. These observations highlight the importance of encouraging many investigators to conduct large animal marking studies which follow the insertional pattern of vectors planned for human treatments. We have recently reported that a very high titer RD114 pseudotyped MFGS-gp91phox vector achieves unprecedented levels of correction of the oxidase defect in CD34+ cells from patients with X-linked chronic granulomatous disease in the NOD/SCID mouse model. In anticipation of considering clinical use of this vector, we transduced mobilized peripheral blood CD34+ cells (PBSC CD34+) of two healthy rhesus macaques with the RD114-MFGS-gp91phox. Transduced PBSC CD34+ with an average two vector copies per cell were transplanted on culture day 4 into two non-myeloablative (2× 300 Rads) irradiated animals. The moderately high levels of in vivo marking (>6%) seen in the first months following gene marking decreased and stabilized at about 8 months post transplant. Marking for animal J976 and D406 at 15 and 19 months, respectively is 1.3% and 0.3% in B lymphocytes, 0.3% and 0.3% in neutrophils and 0.7% and 0.4% in T lymphocytes at which time the animals remained healthy. Vector insertion analysis was performed by LAM-PCR, using gel electrophoresis and GeneScan analysis to demonstrate that despite the relative low marking at 10 months and later animal D406 had more than 25 and animal J976 had more than 40 separate insertional events. 34% of integration sites are located in coding regions. No predominant clone was seen to emerge over time and no patterns of insertion site preferences were detected up to this point.
Characterization of the Human Platelet α-Adrenergic Receptor
Authors: R. Wayne Alexander, Barry Cooper, Robert I. Handin
Journal: Journal of Clinical Investigation (1978)

Human platelets aggregate and undergo a release reaction when incubated with catecholamines. Indirect evidence indicates that these events are mediated through α-adrenergic receptors. We used [3H]dihydroergocryptine, an α-adrenergic antagonist, to identify binding sites on platelets that have the characteristics of α-adrenergic receptors. Catecholamines compete for the binding sites in a stereo-specific manner with the potency series of (−) epinephrine > (−) norepinephrine > (±) phenylephrine > (−) isoproterenol. The dissociation constant (Kd) of (−) epinephrine is 0.34 μM. Binding is saturable using a platelet particulate fraction but not with intact platelets. There are 0.130 pmol binding sites per milligram protein in fresh platelet membranes. This number represents approximately 100 binding sites per platelet. The Kd for [3H]-dihydroergocryptine was 0.003−0.01 μM. The α-adrenergic antagonist phentolamine (Kd = 0.0069 μM) was much more potent than the β-adrenergic antagonist (±) propranolol (Kd = 27 μM) in competing for the binding sites. The binding data were correlated with catecholamine-induced platelet aggregation and inhibition of basal and prostaglandin E1-stimulated adenylate cyclase. (−) Epinephrine was more potent than (−) norepinephrine in producing aggregation whereas (−) isoproterenol was ineffective. The threshold dose for inducing aggregation by (−) epinephrine was 0.46 μM. Phentolamine and dihydroergocyrptine blocked this response, whereas (±) propranolol had no effect. (−) Epinephrine and (−) norepinephrine inhibited basal and prostaglandin E1-stimulated adenylate cyclase in a dose-related manner. The concentration of (−) epinephrine inhibiting adenylate cyclase 50% was 0.7 μM. This inhibition was also blocked by phentolamine and dihydroergocryptine but not by (±) propranolol. The specificity of binding and the close correlation with α-adrenergic receptor-mediated biochemical and physiological responses suggest that the [3H]dihydroergocryptine binding site represents, or is closely related to, the human platelet α-adrenergic receptor. The ability to assay this receptor directly and to correlate these data with independently measured sequelae of receptor activation should facilitate increased understanding of the physiology and pathophysiology of the human platelet α-adrenergic receptor.
Is there a geographical variation in eczema prevalence in the U.K.? Evidence from the 1958 British birth cohort study
Authors: N.J. McNally, H.C. Williams, D.R. Phillips, D.P. Strachan
Journal: British Journal of Dermatology (2000)

Some studies have suggested that the prevalence of atopic eczema may vary between geographical regions. This descriptive study investigates the regional and subregional geography of reported and examined eczema prevalence at the age of 7, 11 and 16 years in Britain using data from the 1958 birth cohort study (n = 828). Estimates of the relative risk of reported eczema associated with residence in each region of the country were calculated and the regional distribution of reported and examined eczema prevalence was compared. The reported prevalence of eczema was mapped at the smaller county level. Comparisons were made with the county-level distribution of asthma and hay fever prevalence. The study showed a marked and statistically significant variation in eczema prevalence across the regions in Britain which was present for examined as well as reported eczema. The highest risk was associated with four regions: North Midlands; Eastern; London and the South-East; and Southern. This regional pattern was not altered significantly after adjustment for social class and family size. The geographical distribution of eczema prevalence was largely maintained when analysed at the county level. Few similarities were found between the county-level distribution of eczema prevalence and that for asthma and hay fever. Explanations for this strong regional variation now need to be sought in terms of environmental and life-style associations.
Steroid Production &lt;italic&gt;In Vitro&lt;/italic&gt; by Normal and Adrenal Tumor-Bearing Male Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: E Bloch, A I Cohen
Journal: JNCI Journal of the National Cancer Institute (1960)

Journal Article Steroid Production In Vitro by Normal and Adrenal Tumor-Bearing Male Mice Get access Eric Bloch, Eric Bloch Departments of Obstretics and Gynecology and Biochemistry, Albert Einstein College of Medicine, Yeshiva University, New York, New York, The Children's Cancer Research Foundation, and Departments of Pathology, The Children's Hospital and Harvard Medical School, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar Arthur I. Cohen, Arthur I. Cohen Departments of Obstretics and Gynecology and Biochemistry, Albert Einstein College of Medicine, Yeshiva University, New York, New York, The Children's Cancer Research Foundation, and Departments of Pathology, The Children's Hospital and Harvard Medical School, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar Jacob Furth Jacob Furth Departments of Obstretics and Gynecology and Biochemistry, Albert Einstein College of Medicine, Yeshiva University, New York, New York, The Children's Cancer Research Foundation, and Departments of Pathology, The Children's Hospital and Harvard Medical School, Boston, Massachusetts Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 24, Issue 1, January 1960, Pages 97–107, https://doi.org/10.1093/jnci/24.1.97 Published: 01 January 1960 Article history Received: 22 January 1959 Published: 01 January 1960
Modulation of survivin expression: A potential therapeutic drug action mechanism for drug resistance and drug sensitivity
Authors: Xiang Ling, Ali Ghadersohi, Youcef M. Rustum, Fengzhi Li
Journal: Cancer Research (2005)

5944  T138067 is a recently identified novel antitumor compound that can disrupt microtubule polymerization in cancer cells by covalently modifying beta-tubulin. It has been shown that T138067 is a better drug against multiple drug resistance (MDR) tumor cells than taxol (Shan et al., PNAS 96:5686-91, 1999). CPT-11/irinotecan, the pro-drug of SN-38, is a hopeful drug in cancer treatment, although the relative high toxicity to patients at high doses is a concern in the clinic. Here, we studied the role of survivin in drug resistance and drug sensitivity. We found that treatment of lung or breast cancer cells with T138067 induced the expression of survivin, a known drug resistant factor, while T138067 has no effect on the modulation of Bcl-2 expression in these cells. Upregulation of survivin by T138067 was associated with an increased phosphorylation of Akt and Erk1/2 MAPK but a decreased phosphorylation of p38 MAPK, and an increased drug resistance. Therefore, inhibition of T138067-induced survivin expression by alternatively targeting survivin will make T138067 be an even better drug to kill cancer cells. To this end, our data indicated that treatment of lung and breast cancer cells with SN-38, an active metabolite of CPT-11, downregulates survivin expression, although SN-38 is known to target/inhibit topoisomerase I as its drug action mechanism. Intriguingly, inhibition of survivin expression by SN-38 was more effective at a low concentration than at the high concentration in the cell-based in vitro experiments, making SN-38 be an ideal survivin modulator. Furthermore, in contrast with the decreased phosphorylation of p38 MAPK after T138067 treatment, inhibition of survivin expression by SN-38 was associated with an increased phosphorylation of the p38 MAPK. Based on these findings, we hypothesized that combination of T138067 with a low concentration of SN-38 as a survivin modulator will synergistically increase T138067 effectiveness to kill breast and lung cancer cells. Consistent with this hypothesis, our in vitro experiments indicated that T138067 in combination with SN-38 synergistically induces cell death in comparison with each drug alone. Together, these results highlight a new concept that unique signaling cross-talk converged to survivin may represent a novel criterion for drug combination in the clinic, which may possibly be developed into new and effective therapeutic approaches.
Inhibition of the epidermal growth factor receptor prevents immortalization of cervical epithelial cells by human papillomavirus type 16 E6 and E7 proteins
Authors: Abdulmajid Mohammed, David Jette, Michael Moses, Craig Woodworth
Journal: Cancer Research (2008)

3291   Infection with a subset of high risk human papillomaviruses (HPV) is the major risk factor for cervical cancer. The HPV E6 and E7 viral oncogenes are selectively retained and expressed in most cervical carcinomas, and expression of E6 and E7 is sufficient to immortalize normal human epithelial cells. However, most HPV infections do not progress to malignancy, indicating that additional cofactors are important. Cervical epithelial cells express multiple epidermal growth factor-related mitogens, and the epidermal growth factor receptor (EGF-R) is often over expressed in cervical carcinoma. EGF-R function can be selectively inactivated by small molecule kinase inhibitors that block ATP binding and autophosphorylation of the receptor on tyrosine. We investigated whether one EGF-R inhibitor, Erlotinib, could prevent immortalization of human cervical epithelial cells by the HPV-16 E6/E7 oncoproteins. Cells were cultured from normal cervix and infected  in vitro  with HPV-16 E6 and E7 genes using recombinant retrovirus vectors. Cultures were treated with Erlotinib (0.001 to 3.0 micro molar) for 6 weeks and the number of cultures that became immortal was determined. Erlotinib inhibited immortalization of human cervical cells by HPV E6/E7 in a dose-dependent manner. The drug stimulated apoptosis selectively in cells that expressed the HPV-16 E6/E7 oncoproteins. Cells expressing only E7 were more susceptible than those expressing E6 or E6/E7. Erlotinib induced senescence in a subpopulation of E6/E7-expressing cells that did not undergo apoptosis. These results suggest that inhibition of the EGF-R prevents immortalization by stimulating apoptosis or senescence in cells that express HPV-16 E6 and E7. Since immortalization by HPV-16 E6/E7 is an important early event in cervical carcinogenesis, the EGF-R may be a potential target for therapy.
Abstract 16788: Delivery of Pluripotent Stem Cell Specific Microrna-294 Induces Cardiomyocyte Proliferation Augmenting Cardiac Function After Myocardial Infarction
Authors: Mohsin Khan, Suresh K Verma, Venkata N Garikipati, Jibin Zhou, Cynthia Benedict, Emily Nickoloff, Jennifer Johnson, Walter J Koch, Raj Kishore
Journal: Circulation (2014)

Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to sufficient numbers required to build a working myocardium. In contrast, cardiomyocytes retain some proliferative capacity in the neonates but lose most of it in adulthood. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs regulating the unique cell cycle of ESCs and their characteristic pluripotency. Nevertheless, expression of miR-294, a member of the ESCC miRs is lost during developmental transitions from the ESCs to mature cells. Effect of miR-294 to induce cardiac proliferation and heart function has not been previously studied. Objective: To determine whether miR-294 drives cardiomyocyte cell cycle reentry leading to augmentation of cardiac function after myocardial infarction. Methods and Results: miR expression analysis was carried out in the heart during development to determine levels of miR-294. Elevated level of miR-294 was observed in the prenatal heart confirmed by qRT-PCR. In contrast, miR-294 expression is lost in the neonates and adult mice. To further assess the effect of miR-294, neonatal ventricular cardiomyocytes (NRVMs) were treated with miR-294 mimic to determine the effect on proliferation and cell cycle. Elevated mRNA levels of cyclins A2 and E1 together with CDK2 was observed in NRVMs treated with 25nM mimic for miR-294. Increased expression of p-histone 3, PCNA (S-phase), Aurora B kinase (G2/M) and Ki67 was confirmed by immunocytochemistry in NRVMs after miR-294 treatment compared to control cells. Intramyocardial administration of miR-294 was carried out in mice at the time of myocardial infarction to determine whether miR-294 delivery increases cardiomyocyte proliferation and survival in response to injury. Enhance cardiac function was observed in mice receiving miR-294 3 weeks after myocardial infarction. Concurrently, increase myocyte proliferation was observed in the heart after miR-294 treatment as analyzed by BrdU uptake, PCNA and Aurora B expression by immunostaining. Conclusion: Ectopic expression of miR-294 recapitulates embryonic signaling and enhances cardiomyocyte ability to proliferate and reenter the cell cycle leading to augmented cardiac function in mice after myocardial infarction.
Insertion Site for Central Venous Catheters
Authors: Leonard A. Mermel, Jean-Jacques Parienti
Journal: JAMA Internal Medicine (2015)

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487. Influence Surface Modification of Lipoplexes on the Pharmacokinetics of Non-Viral Vectors for Gene Delivery
Authors: Eric Perouzel, Annabelle Caussin, Kristina Ulrich, Andrew D. Miller, Charles Coutelle, Michael Keller, Michael Jorgensen
Journal: Molecular Therapy (2004)

Top of pageAbstract
Background Systemic administration of cationic lipoplexes is known to result mainly in lung expression probably due to charge-induced aggregations in this first-pass organ. To exploit the potential of non-viral vectors, delivery vehicles should ideally have extended circulation in the blood stream in order to gain access to the target organ or tumor.

Objective The objective of this study was to investigate the influence of the nature of the surface of lipid/plasmid complexes on in vivo gene transfer and biodistribution characteristics. We explored whether polysaccharides-modified lipoplexes could allow for different biodistribution and gene expression patern.

Methods New lipid/DNA/polysaccharide formulations were assessed for stability in serum, gene expression and biodistribution in vivo.

Results Polysaccharide coated lipoplexes have increased serum stability resulting in low accumulation in the first pass organ (lung). The structural characterstics of the polysaccharides dramatically influence the biodistribution of the resulting particles.

Conclusion Polysaccharides-lipoplexes have superior circulation characteristics compared to their non-modified controls. However, further work is required to exploit their potential as in vivo gene transfer agent particularly in a cancer context.
Abstract 18449: Genetic Variants for Katp Channels as Protective Factors in Ischemic Heart Disease Susceptibility: Gender Differences
Authors: Paolo Severino, Alessandra Cinque, Giorgio Calabrese, Nicolò Salvi, Pasqualina Bruno, Maria Teresa Pucci, Maria Laura De Marchis, Raffaele Palmirotta, Massimo Mancone, Francesco Fedele
Journal: Circulation (2014)

Background: Coronary artery disease has been widely considered a “man’s disease” and not a major concern for women. However, scientists have been trying to unlock the female physiology of ischemic heart disease (IHD). In fact, women are more prone than men to microvascular coronary dysfunction. Recently, we proposed that genetic polymorphisms (SNP) of coronary ion channels may be involved in IHD susceptibility. Our published data showed that the genotype distribution of SNP rs5215 for Kir6.2 subunit of ATP-dependent potassium (KATP) channels moderately deviated from the HW equilibrium and that rs5215_GG is correlated with IHD susceptibility. In particular, we described that rs5215_GG genotype of Kir6.2 might have a ‘‘protective’’ role in IHD genesis. Aim and methods: In order to better describe the role of SNP rs5215_GG in IHD susceptibility in woman, we conducted a gender difference in term of prevalence of rs5215_GG on our previous population, i.e. 242 patients with acute coronary syndrome or stable angina, of which 155 with CAD, 46 with microvascular dysfunction and 41 with anatomically and functionally normal coronary arteries. Results: Among 242 patients, rs5215_GG was found to be more frequent in women (16/82; 19.51%; p=0.0450) compared to men. In particular, rs5215_GG was more frequent in female patients with anatomically and functionally normal coronary arteries (8/24; 33.3%; p=0.0428) compared with women with CAD, whereas there was no difference between men in normal and CAD groups. Discussion and conclusion: The polymorphism rs5215_GG is a missense SNP (ATC-GTC) that results in the substitution of isoleucine (I) residue with valine (V) in the Kir6.2 subunit of KATP channels. Our data validate the hypothesis that rs5215_GG could reduce susceptibility to IHD. In fact, rs5215_GG was confirmed to be present more frequently in woman presenting anatomically and functionally normal coronary arteries. Our results suggest that coronary KATP channels expressing rs5215_GG play a protective key role against IHD. Our data endorse the prospect of associations between SNP encoding coronary ion channels and IHD, validating the idea that ion channels play in coronary homeostasis and that their polymorphisms act in IHD genesis.
Abstract 14735: Carotid Artery Stenting and Carotid Endarterectomy are Comparable Among Medicare Beneficiaries Treated in Routine Clinical Practice
Authors: Jessica J Jalbert, Louis L Nguyen, Marie D Gerhard-Herman, Lauren A Williams, Chih-Ying Chen, Jun Liu, Hiraku Kumamaru, Andrew T Rothman, Michael R Jaff, John D Seeger, James F Benenati, Peter A Schneider, Herbert D Aronow, Joseph A Johnston, Thomas G Brott, Thomas T Tsai, Christopher J White, Soko Setoguchi
Journal: Circulation (2014)

Introduction: The relative performance of carotid artery stenting (CAS) and carotid endarterectomy (CEA) among Medicare beneficiaries in routine clinical practice has not been established. Objective: To compare the performance of CAS relative to CEA among Medicare beneficiaries. Methods: We linked Medicare data (2000-2009) to the Society for Vascular Surgery’s Vascular Registry (SVS-VR; 2005-2008) and to the NCDR® Carotid Artery Revascularization and Endarterectomy Registry (CARE; 2006-2008/9). Medicare patients aged ≥66 years undergoing CAS or CEA were followed from the procedure date for the outcomes of death, stroke/transient ischemic attack (TIA), peri-procedural myocardial infarction (MI) or a composite endpoint for these outcomes. We derived high-dimensional propensity scores using registry and Medicare data to control for patient-level factors and adjusted for provider-level factors including past-year CAS/CEA physician and hospital volume, hospital ownership, teaching affiliation, and hospital size in a Cox regression model comparing CAS to CEA. Results: Among 5,254 SVS-VR (1,999 CAS and 3,255 CEA) and 4,055 CARE (2,824 CAS and 1,231 CEA) patients, CAS patients were more often at higher surgical risk (SVS-VR: 96.7% vs. 44.5%; CARE: 71.3% vs. 44.7%) and had a higher comorbidity burden. Crude outcome risks for death and stroke/TIA were lower for CEA. Adjusting for patient-level factors drove estimates downwards for CAS relative to CEA but only after further adjustment for provider-level factors did the performance of CAS and CEA become comparable on all outcomes (figure 1). Conclusion: Performance of CAS and CEA among Medicare beneficiaries was comparable after accounting for patient- and provider-level factors, which is consistent with landmark trials. Further studies are needed to understand the role of heterogeneity in provider-level characteristics.