tbuckley/cabot-search huggingface dataset:
Abstract 18834: Genetic Ablation of S-nitrosoglutathione Reductase (GSNOR) in Mice Enhances Proliferative Expansion of Adult Heart Progenitors and Myocytes Post Myocardial Infarction
Authors: Konstantinos E Hatzistergos, Ellena C Paulino, Raul A Dulce, Lauro M Takeuchi, Shathiyah Kulandavelu, Wayne Balkan, Rosemeire M Kanashiro-Takeuchi, Joshua M Hare
Journal: Circulation (2014)

Introduction: The molecular pathways underlying the proliferative activity of adult cardiac myocytes and stem/progenitors in response to heart damage remain elusive. Since perturbing nitroso-redox balance in mice by genetic deletion of GSNOR (GSNOR-/-) confers resilience to experimental myocardial infarction (MI), we investigated whether GSNOR knockout influences the proliferative activity of the post-MI heart. Hypothesis: Knockout of GSNOR in mice enhances the proliferative expansion of CMs and cKit+ cardiac stem cells (CSCs) in response to MI. Methods: Wild-type (WT) and GSNOR-/-mice (n=5/ group) underwent experimental MI. To assess proliferative activity, animals received intraperitoneal injections of 5-bromodeoxyuridine (BrdU) at selected time-points during the first 2 weeks post-MI. Immunnohistochemical evaluation was performed 1 month post-MI. Results: Confocal immunofluorescence revealed that GSNOR-/- hearts exhibited higher rates of BrdU incorporation in CSCs after MI (10.9%±4.99 of WT CSCs compar...
Weight-loss changes PPAR expression, reduces atherosclerosis and improves cardiovascular function in obese insulin-resistant mice
Authors: Wim Verreth, Peter Verhamme, Michael Pelat, Javier Ganame, John K. Bielicki, Ann Mertens, Rozenn Quarck, Nora Benhabiles, Gerard Marguerie, Bharti Mackness, Mike Mackness, Ewa Ninio, Marie-Christine Herregods, Jean-Luc Balligand, Paul Holvoet
Journal: Circulation (2003)

Weight-loss in obese insulin-resistant, but not in insulin-sensitive, persons reduces CHD risk. It is not known to what extent changes in the adipose gene expression profile are important for reducing CHD risk. We studied the effect of diet restriction-induced weight-loss on gene expression in adipose tissue, atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia and insulin-resistance are associated with hypertension, impaired left ventricle function and accelerated atherosclerosis in those mice. Diet restriction during 12 weeks caused a 45% weight-loss and changes in the gene expression in adipose tissue of PPARa and PPAR? and of key genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. These changes were associated with increased insulin-sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. Thus, induction of PPARa and PPAR? in adipose tissue is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight-loss. Our observations point to the critical role of PPARs in the pathogenesis of cardiovascular features of the metabolic syndrome.
Abstract 429: Rosiglitazone Reduces Development and Rupture of Experimental Aortic Aneurysms
Authors: Rajdeep Deb, Evelyn Torsney, Matthew M Thompson, Alun Jones, Franklyn Howe, Gillian W Cockerill
Journal: Circulation (2008)

Several case-control studies have shown a negative correlation between diabetes and aortic aneurysm. Using an animal model of aneurysm, and cell cultures, we investigated the effects of Rosiglitazone (RGZ), a drug used in the treatment of type II diabetes. Twenty-eight 12 month old ApoE-deficient mice were randomised to three groups. All animals had an osmotic pump inserted subcutaneously on the flank, the positive control group and treatment group released Angiotensin-II (Ang-II) (1μg/min/kg), the sham operated group released saline. The treatment group received RGZ (10mg/kg/day) in their drinking water one week before inserting the pumps and continuously during the following 28 day release of Ang-II. Plasma was collected to measure the lipid profile and determine concentration of IL-6 and active MMP-2 and MMP-9. Gross pathology was evaluated using video micrometry. Expression of proteins and RNAs were analysed using immunohistochemistry, ELISA and quantitative real time RT-PCR. The effect of RGZ on Ang-II induced DNA-binding of transcription factor Egr-1 was determined using electrophoretic mobility shift assays of human aortic smooth muscle cell cultures. In comparison to the positive control group of animals, treatment with Rosiglitazone inhibited the occurrence of fatal rupture (5/10 vs 0/10) and reduced maximal dilatation of the aorta (5.6 ± 0.26 vs 2.6 ± 0.4 mm 2 ). RGZ reduced the concentration of total cholesterol but no significant difference in the atherosclerotic burden was found between groups. RGZ inhibited the angiotensin II-induced tissue expression of AT1a receptor, but had no affect on increased mRNA expression of AT2 receptor, MMP-2 or MMP-9. Plasma protein concentrations of IL6, and MMP-9 were increased by Ang-II and decreased by RGZ. The amount of collagen deposited in the supra-renal region of the abdominal aortae was increased in animals treated with RGZ. RGZ inhibited Ang-II induced DNA binding of the transcription factor, early growth response-1 (Egr-1) in human smooth muscle cells. These data suggest that RGZ reduces the incidence of development and rupture in this murine model of aneurysm through AT1a mediated effects on transcriptional regulation of genes which determine phenotypic status of the vessel wall.
Research pointers: Lifestyle, hormones, and risk of breast cancer
Authors: G. Jasienska
Journal: BMJ (2001)

Lifestyle, hormones, and risk of breast cancerThe incidence of breast cancer is much higher among women in industrialised countries than among women in countries with more traditional lifestyles.Energy intake, energy expenditure, and energy balance may influence ovarian physiology and the concentrations of ovarian oestrogen and progesterone produced during the menstrual cycle.Oestrogen and progesterone are hypothesised to play a crucial part in the development of breast cancer in women. 1 Women from populations with a high risk of breast cancer are expected to have comparatively high concentrations of ovarian steroid hormones.
Abstract 647: CD20-specific Engineered Toxin Body demonstrates direct cell kill of multiple B-cell Non-Hodgkin's lymphoma types
Authors: Sangeetha Rajagopalan, Rachel Wirth, Jennifer Erdman, Kari Grant, Brigitte Brieschke, Rodney Flores, William Null, Jen-Sing Liu, Erin K. Willert, Jack P. Higgins
Journal: Cancer Research (2014)

Abstract The B-cell membrane protein CD20 is expressed by both benign and neoplastic lymphocytes. It has been a superb target for immunotherapies targeting B-cell derived diseases. There are several anti-CD20 antibodies which have been developed for B-cell lymphoma therapy. The most successful example of this targeted approach is rituximab, which is approved for front and second line therapy of Non-Hodgkin lymphoma (NHL). However, rituximab has limited direct cell-kill effects, acting primarily through indirect immune responses induced by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). While CD20-targeted radiotherapeutics have shown promise, their administrative challenges have curtailed their clinical utility. Thus, a therapeutic approach with direct cell-kill activity against CD20-expressing cells would be clinically useful. We have developed an engineered toxin body (ETB) comprising a CD20 scFv and a modified Shiga-like Toxin A (MT-3724) capable of specifically recognizing and killing CD20 expressing cells. MT-3724 is selectively cytotoxic against B-cell NHL cell lines and against NHL cells obtained from patients. It demonstrated potent cytotoxicity against Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma with IC (50) values ranging from 1.4 nM to 12 nM. Through immunofluorescent tracking, MT-3724 internalizes within one hour after binding to CD20 (+) B cells. To our knowledge, this is the first example of efficient internalization of an immunotoxin via CD20. Consistent with the in vitro activity, MT-3724 demonstrated anti-tumor efficacy in mice-bearing NHL cell line xenografts. These results show that MT-3724 is a promising targeted therapeutic agent against CD20 positive B-cell lymphomas and is currently under further development. Citation Format: Sangeetha Rajagopalan, Rachel Wirth, Jennifer Erdman, Kari Grant, Brigitte Brieschke, Rodney Flores, William Null, Jen-Sing Liu, Erin K. Willert, Jack P. Higgins. CD20-specific Engineered Toxin Body demonstrates direct cell kill of multiple B-cell Non-Hodgkin's lymphoma types. [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 647. doi:10.1158/1538-7445.AM2014-647
Phase II study of oxaliplatin (OXA) and docetaxel (DTX) in recurrent ovarian cancer
Authors: G. Ferrandina, M. Ludovisi, G. D’Agostino, A. Naldini, D. Lorusso, A. C. Testa, F. Legge, V. Salutari, G. Scambia
Journal: Journal of Clinical Oncology (2006)

5086 Background: We conducted a phase II study to evaluate the efficacy and safety of OXA and DTX in recurrent platinum-sensitive ovarian cancer patients. Methods: Patients received DTX 75 mg/m 2 (60-min i.v.) on day 1, followed by OXA 100 mg/ m 2 (120-min i.v.) on day 1 every 21 days. Results: Between October 2002 and November 2005, 30 Caucasian patients (median age: 53.5 yrs; range, 31–73) were enrolled; 7 (23.3%) patients had FIGO stage I-II disease, 22 (73.3%) had FIGO stage III, and 1 (3.3%) had FIGO stage IV disease. Sites of relapse were as follows: abdominal 3 (10.0%), pelvis 5 (16.7%), lymph nodes 10 (33.3%), peritoneal 7 (23.3%), lung 1 (3.3%), and mixed 4 (13.3%). The median PFI was 28.5 months (range 13–91). The median CA125 was 182 U/ml (range 21–5,596 U/ml). Of the 30 patients evaluable, 13 (43.3%) had complete responses and 7 (23.3%) had partial responses, for an overall response rate of 66.6%. The median time to response was 9.5 wks (range 5–32) and the median duration of response was 43 wks (range 5–124). 8 (26.7%) patients had stable disease (median duration of stabilization: 26.5 wks, range 12–43). 2 (6.7%) patients progressed while on treatment. An overall clinical benefit was observed in 93.3% of patients. All patients were evaluable for toxicity. A total of 186 courses were given, with a median of 6 cycles per patient (range 2–11). Severe toxicities (Grade 3–4 NCI-CTC) included: neutropenia in 29.4% of cycles; severe anemia and thrombocytopenia were not observed. Grade 3–4 neurotoxicity and alopecia were detected in 2.8% and 22.8% of cycles respectively. Allergic reaction was observed only in one case. Doses were reduced by 20% in 14.0% of cycles. Conclusions: In recurrent platinum-sensitive ovarian cancer patients the OXA/DTX combination is highly active with acceptable toxicity, thus making it an attractive regimen. No significant financial relationships to disclose.
Covalent Incorporation of Trehalose within Hydrogels for Enhanced Long‐Term Functional Stability and Controlled Release of Biomacromolecules
Authors: Timothy M. O'Shea, Matthew J. Webber, Alex A. Aimetti, Robert Langer
Journal: Advanced Healthcare Materials (2015)

Hydrogels with covalently incorporated trehalose are synthesized using thiol-ene Michael addition. Trehalose hydrogels afford prolonged stabilization and ­controlled release of model enzymes in vitro and in vivo as well as preservation of protein stability under heat and ­lyophilization stressors. Strong and ­ordered hydrogen bonding interactions within covalently incorporated trehalose hydrogels represent a possible mechanism for protein stabilization. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
869. Unique Potential of Gene Therapy for GSD-II Using Fully Deleted Adenovirus Based Vectors Expressing hGAA
Authors: Shobha M. Ramsubir, Claudine Tardy, Stephane Carpentier, Thierry Levade, Jeffrey A. Medin
Journal: Molecular Therapy (2004)

Farber disease is a rare, lysosomal storage disorder that is caused by the deficient activity of the enzyme acid ceramidase. As a result, the sphingolipid ceramide accumulates in the lysosomal compartment. Patients typically present with subcutaneous granulomas, painful swollen joints and progressive neurological deterioration. Affected tissues show massive infiltrations of granulomatous cells and lipid-laden macrophages. Current treatment is only palliative and patients usually succumb to the disease as infants. While bone marrow transplantation has been shown to relieve some symptoms of the disease, it is does not provide a lasting cure since it is unsuccessful in resolving the neurological effects. Previously, our lab demonstrated the feasibility of gene therapy to correct Farber disease using an early recombinant onco-retroviral vector. Here we have developed novel recombinant onco-retroviral and lentiviral vectors to improve correction. A bi-cistronic onco-retroviral vector has been constructed that encodes human acid ceramidase and huCD25, a cell surface marker that allows for enrichment of transduced cells. This vector uses the MoMLV backbone and has been pseudotyped with the RD114 envelope. The lentiviral vector construct is a second generation, self-inactivating HIV-1-derived vector pseudotyped with the VSV-g envelope. Immortalized Farber patient fibroblasts and B cells have been transduced with both recombinant therapeutic viruses and subsequent quantitation of ceramide levels by thin layer chromatography showed that Farber patient cells were enzymatically corrected – while Farber fibroblasts contain 84% ceramide (as a percentage of sphingomyelin metabolites), normal fibroblasts, and Farber fibroblasts transduced with onco-retrovirus and with lentivirus show ceramide levels of 26%, 11% and 16%, respectively. Normal B cells, Farber B cells and Farber B cells transduced with the onco-retrovirus show ceramide levels of 11%, 76% and 16%, respectively. In addition, transduced fibroblasts show the ability to cross-correct non-transduced Farber fibroblasts, i.e. culture media from Farber fibroblasts transduced with onco-retrovirus and lentivirus were able to reduce ceramide levels in non-transduced Farber fibroblasts from 80% to 19% and 21%, respectively. Subsequently, the outcome of transplantation of transduced cord blood-derived hematopoietic stem/progenitor cells will be tested in vivo in a NOD/SCID mouse model. Late experiments using these novel vectors will also begin to address some of the central nervous system manifestations of the disease. These studies represent significant advances towards the development and clinical implementation of gene therapy for Farber disease as well as adding support to the concept that this class of disorders (lysosomal storage disorders) may be especially amenable to gene therapy.
Abstract 3350: Impact of Genetic Screening on the Development to End-Stage Phase in Hypertrophic Cardiomyopathy: From the Comparison of Clinical Course in Carriers With Thick Filament Mutations and Thin Filament Mutations
Authors: Noboru Fujino, Hidekazu Ino, Kenshi Hayashi, Katsuharu Uchiyama, Eiichi Masuta, Yuicihro Sakamoto, Toshinari Tsubokawa, Akira Funada, Akihiko Muramoto, Junichiro Yokawa, Masakazu Yamagishi
Journal: Circulation (2009)
A faded memory: My old school
Authors: O. P Sharma
Journal: BMJ (2000)

important repercussions for treatment.Doctors may need to put more effort into explaining the potential consequences of concealment to the patient.At a broader policy and legislative level, this study suggests that the government might need to consider reducing the period that epileptic patients are required to remain seizure free in order to hold a driving licence.For example, in Wisconsin, United States, which has one of the lowest accident rates measured, 23 24 the current restriction on driving is three months.This study was originally carried out for a dissertation for an MSc in health sciences at the University of East Anglia (School of Health Policy and Practice) by JD.We thank the general practitioners and patients who took part in the study and Miranda Mugford and Malcolm Adams for useful comments and statistical advice.
Botulism in injecting drug users, Dublin, Ireland, November-December 2008
Authors: J Barry, M Ward, S Cotter, J MacDiarmada, M Hannan, B Sweeney, K A Grant, P McKeown
Journal: Eurosurveillance (2009)

In November and December 2008, six cases of suspect wound botulism were reported in heroin injecting drug users, all residents in Dublin, Ireland. Patients were aged between 23-42 years of age; four cases were male; one patient died shortly after admission. The patients presented to four different hospitals across the city. Botulism in injecting drug users in Ireland was last reported in 2002.
533. In Vitro and In Vivo Expression of Modified Mouse Galactosylceramidase in the Twitcher Mouse Model of Krabbe Disease
Authors: James Cronin, Xian-Yang Zhang, Jacob Reiser
Journal: Molecular Therapy (2004)

The neurodegenerative disease globoid cell leukodystrophy (GDL), commonly known as Krabbe disease, is caused by an autosomal recessive disruption of the lysosomal enzyme galactosylceramidas (galactocerebroside β-galactosidase, GALC). Enzyme disruption causes an accumulation of undegraded psychosine, resulting in demylination due to loss of oligodendrocytes. With advancing pathology, there is a progressive loss of nervous system function, invariably leading to death. As currently there is no effective treatment, we have worked on developing gene therapy strategies using the HIV-1 based lentivector system. In initial in vitro experiments, monkey COS-7, human 293T, and human bone marrow derived mesenchymal stem cells were transduced with lentiviral vectors encoding mouse GALC. After 4 days, GALC expression increased from 15 to 190 fold over baseline activity, depending on the cell type, with elevated GALC expression persisting for at least 2 weeks. Transduction of skin derived fibroblast cells taken from the Twitcher mouse (a murine GDL model) with the GALC lentivector produced an in vitro correction of the enzyme deficiency. To facilitate monitoring transgenic GALC, and to distinguish transgenic from endogenous GALC, a myc epitope and 6 HIS residues were added to the C terminus of GALC (GALC-MH). A Tat protein transduction domain (PTD) was also added to improve in vivo distribution (GALC-TMH). In vitro comparisons showed that the addition of myc-HIS did not impair GALC specific activity, while that of GALC-TMH was only slightly impaired. These tags allowed detection of GALC protein in cell extracts and culture medium. GALC was found to be secreted by transduced cells, and taken up by neighboring cells via mannose-6-phosphate receptor (M6PR) mediated endocytosis. The addition of Tat significantly stimulated M6PR-independent uptake of GALC. Ongoing studies are assessing the biodistribution of both GALC expressing cells and secreted extracellular GALC after direct CNS injection of GALC lentiviral vectors. Additionally, therapeutic effects of transgenic GALC are being evaluated in the Twitcher mouse.
INDUCTION AND RECALL IN CONTACT SENSITIVITY
Authors: Maria A. B. de Sousa, Delphine M. V. Parrott
Journal: The Journal of Experimental Medicine (1969)

The cellular events in the ear skin and draining lymph node during the induction of contact sensitivity to 2-ethoxy methylene-5-oxazolone (oxazolone) have been studied in three strains of mice. The principal findings in the skin during the first 24 hr were invasion of polymorphs and destruction of pilosebaceous units, in both intact and thymectomized mice. Subsequently, the dermal cellular infiltrate increased and there was acanthosis of the epidermis. No lymphocytes were seen in the dermis or penetrating the epidermal basal cell layer in thymectomized mice. During the first 24 hr in the draining node, polymorphs and macrophages bearing a pigment with staining properties similar to melanin were seen in the marginal and medullary sinuses, in intact and thymectomized mice. Major differences, however, were revealed during 2-4 days when massive proliferation of large pyroninophilic blast cells occurred in the thymus-dependent area of the nodes from intact mice only. On testing, there was a prompt, measurable increase in ear thickness only in intact mice. This increase reached a peak at 24 hr - typical of a delayed type reaction. At testing, the ears from intact mice showed epidermal vesiculation and a considerable dermal cellular infiltrate with a substantial number of lymphocytes. This was in contrast with the completely quiescent appearance of the ear skin of thymectomized mice. Finally, we have discussed the use of the mouse as an experimental tool for studying contact sensitivity and have analyzed the role of the thymus-derived lymphocyte and the site where it becomes sensitized, in the light of current theory on the origin of cells and site where sensitization takes place in cell-mediated reactions.
Abstract 2966: Detection of Viral Genome in the Myocardium: Lack of Prognostic and Functional Relevance in Patients with Dilated Cardiomyopathy
Authors: Friedhelm Kuethe, Holger H Sigusch, Kristina Hilbig, Christiane Tresselt, Brigitte Glueck, Renate Egerer, Andreas Krack, Hans R Figulla
Journal: Circulation (2006)

Background: The presence of viral genome in the myocardium of patients with dilated cardiomyopathy has been suggested as causative for the underlying cardiac disease. Nevertheless the results of present studies are conflicting regarding the natural course of heart diseases associated with detection of viral genome. Methods and Results: In 216 patients admitted to the hospital with clinical signs of heart failure, left ventricular endomyocardial biopsies (EMB) were performed after exclusion of coronary artery disease. Analysis for viral genome, enteroviral replication and immunohistology was performed from EMBs. Patients with specific cardiomyopathies were excluded from the study, thus only patients with a diagnosis of dilated cardiomyopathy (DCM) were included into the study (n = 197). Adenovirus (ADV) genome was detected in 1.5%, enterovirus (EV) genome in 15.3%, parvovirus B19 (PVB19) genome in 31.8%, and a double infection of EV and PVB19 was detected in 12.9%. The increase of ejection fraction (EF) wa...