tbuckley/cabot-search huggingface dataset:
221. A New Retroviral Gene Therapy Approach for Cystinuria Research
Authors: Sreedhar Sagi, Marcus Picard-Maureau, Rudiger Dorries, Peter Alken, Maurice S. Michel, Thomas Knoll
Journal: Molecular Therapy (2006)

Objectives: For cystinuria, gene therapy might provide a correction of the cellular dysfunction by expressing the deficient gene. Currently there is no stable cellular model which mimics the cystinuria phenotype and genotype to study the potential benefits of gene therapy in vitro. We initially developed an antisense expressing vector for the SLC3A1 gene using a non viral vector. To optimize the system we decided to create stable cell lines with retroviral vectors. Retroviral vectors are efficient vehicles to deliver genes into the cell and for stable integration into the genome. We used Murine leukemia virus (MLV) vector to generate a stable cell line which represents the cystinuria type 1 disease in vitro to serve as a tool for the development of gene therapy. Materials and methods: HK-2 is a proximal tubular cell (PTC) line derived from normal human kidney. The presence of the SLC3A1 (rBAT) gene was determined using the c-DNA of HK-2 cells by PCR with the SLC3A1 primers. The SLC3A1 gene was cloned into a Murine leukemia virus (MLV) transfer vector. This vector additionally contains a puromycin resistance marker. We also cloned the SLC3A1 gene in an antisense orientation to obtain a knockout of the rBAT protein by antisense RNA. Two controls were generated with mutations in the start codons of the both the sense and antisense constructs. Phoenix A is a second-generation MLV packaging cell line for the generation of helper free amphotropic retroviral vectors. Calcium phosphate was used to transfect the individual vector into the phoenix cells to generate the virus with the respective SLC3A1 constructs. The viral particles are obtained from the supernatant and filtered through a 0,45 μM filter to obtain cell-free supernatant. The four different viral supernatants are then used to transduce the target HK-2 cells in the presence of polybrene. 48 hrs post infection the HK-2 cells were subjected to puromycin selection (1 microgram/ml). After 3 days the selection pressure was removed and the cells were cultured normally. Results: The SLC3A1 gene amplified by RT-PCR from HK-2 cells in sense and anti sense orientation was analyzed by automated sequencing. The HK-2 cells after transduction with the different viral vectors and after puromycin selection were checked by PCR and Western blot for the expression of the constructs. Discussion: The stable knock down cell line representing the cystinuria type 1 can be used to validate the efficiency of gene therapy in vitro. We would transduce the stable knock down cell line of the SLC3A1 gene with a feline immunodeficiency viral (FIV) vector expressing the SLC3A1 gene to determine the efficiency of gene therapy and to compare it to the FIV based gene therapy of the cystinuria animal model in vivo.
Carbimazole and autoantibody synthesis in Hashimoto's thyroiditis.
Authors: A M McGregor, H K Ibbertson, B R Smith, R Hall
Journal: BMJ (1980)

Serum thyroxine, thyrotrophin, and thyroid microsomal antibody levels were measured in 20 patients with Hashimoto9s thyroiditis and hypothyroidism before, during, and after treatment with carbimazole or placebo. Thyroid microsomal antibody levels fell during treatment in the 10 patients who received carbimazole, while serum thyroxine and thyrotrophin levels did not change. There were no changes in the placebo group. The study proves support for the concept that carbimazole may act directly on autoantibody synthesising lymphocytes localised in the thyroid. Such an effect might be valuable in influencing the autoimmune process in autoimmune thyroid disease.
Pott's Abscesses in the Lumbar Region
Authors: John J. Lowrey
Journal: New England Journal of Medicine (1955)

THIS report deals with the treatment of 5 patients with Pott's abscesses in the lumbar region. They were treated by retroperitoneal exposure of the abscess, evacuation of the contents and thorough curettage of the abscess wall and the insertion of a strut of iliac bone to prevent collapse of the adjacent vertebral bodies. Three patients were operated on, and all 5 were cared for postoperatively, at Leahi Hospital, Honolulu.This subject should be of interest to all practicing physicians and surgeons who see patients with low-back pain, because backache is the invariable complaint. The signs and symptoms and even myelographic . . .
Impact of Management Change and an Intervention Program on Health Care Personnel
Authors: C.T. Johan Lökk, Bengt B. Arnetz
Journal: Psychotherapy and Psychosomatics (2000)

&lt;i&gt;Background:&lt;/i&gt; There has been a major shift in the organization and responsibility for the provision of geriatric care in Sweden. This was believed to be stressful. We therefore decided to launch a controlled intervention program on health care personnel aimed at enhancing their adaptation and ability to cope. The purpose of this study was to assess the impact of management change on psychosocial parameters of health care personnel and the effects, if any, of a structured intervention program. &lt;i&gt;Methods:&lt;/i&gt; Two separate wards were randomly allocated to be either intervention (I) or control (C) ward. The I-ward personnel were subjected to a psychologist’s structured 10-session intervention program for 20 weeks. The program consisted of an initial educational part followed by a practical problem-solving discussion part. A structured questionnaire on psychosocial issues was answered by the participants before (0 weeks), immediately after (20 weeks), and 10 weeks after the intervention (30 weeks). &lt;i&gt;Results:&lt;/i&gt; There were no significant changes in the psychosocial parameters of the C-ward personnel. In the I-ward, however, there was a significant increase in work demand as well as in positive feelings about work, as compared to the C-ward at the 30-week follow-up. There was also significantly better work comfort in the I-ward. &lt;i&gt;Conclusions:&lt;/i&gt; We did not find any anticipated negative psychosocial effects on health care personnel undergoing an organizational change. However, by offering a structured intervention program to one group of health care personnel, we found some positive psychosocial effects. Future research is needed to pinpoint which factor or factors in the intervention program were the most crucial for the effects to occur.
Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction
Authors: Katsuyuki Nagatoya, Toshiki Moriyama, Noritaka Kawada, Masanobu Takeji, Susumu Oseto, Takahiro Murozono, Akio Ando, Enyu Imai, Masatsugu Hori
Journal: Kidney International (2002)
P134Increased beta-adrenergic inotropy in ventricular myocardium from Trpm4 knockout mice
Authors: M Kecskes, I Mathar, J Griet, G Van Der Mieren, T Voets, P Herijgers, R Vennekens
Journal: Cardiovascular Research (2014)

TRPM4 have an extensive role in regulating intracellular calcium dependent cell functions in many cells including mast cells, chromaffin cells and recently in neurons. TRPM4 proteins constitute calcium activated, but calcium impermeable, non-selective cation channels and are expressed both in atrial and ventricular cardiomyocytes. The Trpm4 gene has recently been associated with several disorders, including cardiac conduction diseases such as Progressive Familial Heart Block Type 1, Right Bundle Branch Block and Brugada Syndrome. The physiological function of TRPM4 in the heart remains however incompletely understood. The objective of this study was to establish the role of TRPM4 in left ventricular muscle function. We used TRPM4 knockout mice and performed patch-clamp experiments, membrane potential measurements, microfluorometry, contractility measurements and in vivo pressure-volume loop analysis. We demonstrate that TRPM4 proteins are functionally present in mouse ventricular myocytes and are activated upon calcium induced calcium release. Measurements of action potential duration show that TRPM4 is active during the repolarization of the ventricular action potential. We show a significantly decreased time for 50 % and 90 % repolarization in Trpm4 knockout ventricular myocytes. We also provide evidence that this change in action potential shape leads to an increased driving force for the L-type calcium current during the action potential. Moreover, in vivo pressure-volume analysis and in vitro contraction strength measurement on isolated papillary muscles displays an increased β-adrenergic inotropic response in TRPM4 knockout mice. Taking together these data, our results show that functional TRPM4 proteins are novel determinants of the inotropic effect of β-adrenergic stimulation on the ventricular heart muscle.
The effect of level of skill and instruction of internal and external focus of attention on the performance of skate crossover
Authors: Zahra Chharbaghi, Fateme Kashefolhagh, Mohammad Sadegh Dadashi, Maryam Karimian
Journal: British Journal of Sports Medicine (2010)

The purpose of this study was to investigate the effect of level of skill and instruction of internal and external focus of attention on the performance of skate crossover. Sixty students (30 novice and 30 expert; age: 20–24) participated voluntarily, according to their records in 10 pretest trials assigned into for groups involving, namely novice with internal focus instruction, expert with internal focus instruction, novice with external focus instruction, expert with external focus instruction. Each participant performed 300 practice trials (10 sessions and each session 30 trails). The results indicated that there is significant interaction between level of skill and attention focus. In addition internal focus of attention was meaningfully better for novice performers and external focus of attention was meaningfully better for expert performers. These results provide evidence in support of deautomatisation hypothesis.
Abstract 5058: Phosphatase Nuclear Targeting Subunit (PNUTS) is phosphorylated by AKT kinase
Authors: Nancy A. Krucher, Brittany Perry, Brandon Lentine, Violeta Dzaferovic, Filipa Cardoso
Journal: Cancer Research (2010)

Abstract Phosphorylation of the tumor suppressor protein, Retinoblastoma (Rb) is associated with a highly proliferative state of the cell and cancer. Rb phosphorylation state is partly controlled by the activity of Protein Phosphatase 1 (PP1) which is regulated by Phosphatase Nuclear Targeting Subunit (PNUTS). It is likely that PNUTS plays a role in cell survival and/or apoptosis because siRNA mediated knockdown of PNUTS causes apoptosis in breast and colon cancer cells. This occurs through activation of PP1 phosphatase activity toward Rb which leads to Rb dephosphorylation which can trigger apoptosis. Here we show that PNUTS may be regulated by the PI3K-AKT pathway which has been shown to be involved in many cellular functions including proliferation, growth and survival. In addition, signaling in this pathway has been shown to be disrupted in several cancers. In response to a sub-lethal dose of UV radiation of HCT116 colon cancer cells, activation of the AKT kinase occurs, with phosphorylation of known AKT substrates GSK-3 and mdm2 observed. Phosphorylation of Ser473 of AKT further verifies AKT activation. Under these conditions PNUTS is phosphorylated by the AKT kinase. Inhibition of PNUTS phosphorylation occurs when cells are treated with the LY294002 PI3K-AKT pathway inhibitor. Thus PNUTS is a putative substrate of AKT, and may play an important role in the survival of cells in response to stress. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5058.
Abstract 3331: MicroRNAs regulate breast cancer stem cells and spontaneous metastases in orthotopic xenograft models
Authors: Huiping Liu, Jessica Bockhorn, Rachel Dalton, Chika Nwachukwu, Aleix Prat, Kathy Yee, Simo Huang, Kaitlin Swanson, Charles M. Perou, Olufunmilayo I. Olopade, Michael F. Clarke, Geoffrey L. Greene
Journal: Cancer Research (2012)

Abstract To examine the role of microRNAs (miRNAs) in breast cancer progression, we profiled miRNA and gene expression in both clinical breast tumors and human-in-mouse breast tumor models, where breast cancer stem cells (BCSCs) contribute to spontaneous metastasis. CD44+ cells from both primary tumors and lung metastases were highly enriched for tumor initiating cells. Based on the miRNA profile analyses, we identified a limited number of miRNAs that are differentially expressed in metastatic triple-negative breast tumors and regulate BCSCs and tumor invasion in vitro. To facilitate miRNA functional studies in vivo, we also developed tumor imaging approaches by transducing BCSCs with optical reporter fusion genes (Luc2-eGFP or -tdTomato), which enabled both bioluminescence imaging (BLI) and FACS-based analysis and sorting. With non-invasive BLI approaches, as few as 10 cells of stably labeled BCSCs can be tracked in vivo. When optical reporters are expressed along with miRNA precursors or inhibitors, the effects of introduced miRNA candidates can be evaluated by selective imaging of labeled tumor cells, thereby eliminating the noise of unlabeled cells. Using this model system and imaging technology, we have screened and identified miRNAs that regulate BCSCs and metastatic CSCs (MCSCs) by targeting polycomb repressors (BMI1 and the PC2 components) and cytoskeleton genes (TWF1 and VIM). Clinical studies demonstrated that the expression of candidate miRNAs was associated with and regulated by GATA3, suggesting a transcriptional regulation of aberrantly expressed miRNAs in breast tumors. The GATA3-miRNA-target genes signaling pathway was also strongly associated with relapse-free survival of breast cancer patients, indicating the clinical importance of the miRNA-gene network in breast cancer. Supported in part by the University of Chicago Women's Board Fellowship (J.B.), NIH T90 Fellowship DK070103-05, DOD Postdoctoral Fellowship W81XWH-09-1-0331, and Chicago Fellows Program and CTSA UL1 RR024999 at The University of Chicago (H.L.), University of Chicago Cancer Research Center Pilot Research Fund, UCMC/Northshore Collaborative Research Award and the Virginia and D.K. Ludwig Fund (G.L.G and H.L). NIH R01 and Breast Cancer Research Foundation (M.F.C. and H.L.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3331. doi:1538-7445.AM2012-3331
A phase transition between localist and distributed representation
Authors: Peter C. M. Molenaar, Maartje E. J. Raijmakers
Journal: Behavioral and Brain Sciences (2000)

Bifurcation analysis of a real-time implementation of an ART network, which is functionally similar to the generalized localist model discussed in Page's manifesto shows that it yields a phase transition from local to distributed representation owing to continuous variation of the range of inhibitory connections. Hence there appears to be a qualitative dichotomy between local and distributed representations at the level of connectionistic networks conceived of as instances of nonlinear dynamical systems.
On Federal Regulation of Methadone Treatment
Authors: Vincent P. Dole
Journal: JAMA (1995)

A RECENT report from the Institute of Medicine (an affiliate of the National Academy of Sciences) provides an authoritative review of the history and consequences of federal regulation of methadone treatment.<sup>1</sup>It examines the assumptions that justified imposition of special restrictions on prescription of methadone and the effects of enforced guidelines on the function of treatment programs. Since the Narcotic Addict Treatment Act (1974) authorized an unprecedented restriction of the right of physicians to prescribe an approved drug, the experience of the past 20 years can be seen as a major experiment in governmental regulation of medical practice. Given the controversial nature of the subject, both the government and the medical profession in general are fortunate to have had the results of this experiment evaluated at the highest scientific level. Quite properly, I was not included in the deliberations for the Institute of Medicine report. My views on the
Abstract 3610: Potent preclinical anti-tumor activity of MGCD265, an oral Met/VEGFR multitargeted kinase inhibitor in clinical development, in combination with taxanes
Authors: Christiane R. Maroun, Helene Ste-Croix, Normand Beaulieu, Claire Bonfils, Marielle Fournel, Isabelle Dupont, Christian Lemoyne, James Wand, Jeffrey M. Besterman
Journal: Cancer Research (2011)

Abstract MGCD265, a multitargeted receptor tyrosine kinase inhibitor in clinical development, inhibits the activation of Met, VEGFR1, 2, 3, Tie-2 and Ron. Met is a promising molecular target for the development of cancer therapeutics and is found overexpressed and phosphorylated in a large proportion of NSCLC patients. Several agents targeting Met are currently under clinical investigation in NSCLC including MGCD265, and early clinical results are encouraging. Interestingly, to our knowledge, no Met inhibitor has been explored in NSCLC in combination with a taxane. In support of the clinical development of MGCD265, we have investigated preclinically the anti-tumor activity of MGCD265 in combination with taxanes. The combination of MGCD265 with docetaxel or paclitaxel resulted in enhanced anti-tumor activities compared to treatment with either agent alone in multiple xenograft models, including human NSCLC, glioblastoma, breast, prostate and gastric carcinomas. Enhanced efficacy occurred in the absence of overt toxicity. Moreover, PK analyses demonstrated lack of drug-drug interactions. Interestingly, in a gastric Met-driven carcinoma model in which MET is amplified (MKN45), treatment with MGCD265 in combination with docetaxel resulted in tumor regression at suboptimal doses of the taxane. Immunohistochemistry analyses in this model showed that this combination altered tumor vascularization as detected by endothelial cells labeling (CD31). While it has been suggested that changes in tumor vascularization may increase tumor exposure to docetaxel, the exposure of either MGCD265 or docetaxel was not altered in tumors treated with the combination. To gain insights into the molecular mechanism through which improved anti-tumor activities were achieved by the combination, we performed gene expression analyses on xenograft tumors. Genes differentially regulated by either agent alone were simultaneously regulated and sometimes enhanced, when the two agents were combined. Confirmations are currently ongoing. Together, these studies provide support for the development of MGCD265 in combination with taxanes for the treatment of cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3610. doi:10.1158/1538-7445.AM2011-3610
Hepatitis B Vaccine in Health Care Personnel: Safety, lmmunogenicity, and Indicators of Efficacy
Authors: JULES L. DIENSTAG
Journal: Annals of Internal Medicine (1984)

In a double-blind trial, we randomly assigned 1330 high-risk health care personnel to receive three 20-µg doses of hepatitis B vaccine or placebo. Among vaccine recipients 58% responded within 1 month and 97% within 9 months; there was no difference in immune response to the vaccine between men and women. Efficacy was evaluated after a mean follow-up of only 13.2 months, just before the vaccine was released commercially. Five hepatitis B infections were identified in placebo recipients and one in a vaccine recipient. Although the number of infections was too small to allow confident conclusions about protective efficacy of the vaccine, we saw a 67% reduction in the need for hepatitis B immune globulin after accidental hepatitis B inoculation in the vaccine group (relative risk, 5.08; 95% confidence intervals, 1.3 to 19.9). Minor side effects occurred with equal frequency after vaccine (28.7%) and placebo (27.2%) injections; no participant had a severe adverse reaction. Vaccination with the 20-µg hepatitis B vaccine was highly immunogenic and safe in health care workers.
Useful Advice to Patient Whose Spouse Has Died: 'Establish a Routine, Mingle With Other People'
Authors: Chris Raymond
Journal: JAMA (1989)

A STUDY of persons recently widowed finds that it may be possible to identify, as early as 3 weeks after the spouse's death, those most likely to remain severely depressed a year later. For the physician, it offers data to back up common-sense advice to patients who have lost a spouse. "They should force themselves to get into a routine and get out [with other people]," says principal investigator Joseph Flaherty, MD, professor of psychiatry and community health at the University of Illinois, Chicago. <h3>Timekeeper Theory</h3> The Chicago study is one of three under way across the country to begin testing out facets of a new theory of the etiology of depression—one that weaves together the insights of biologic and psychosocial research into the disorder. Known as the "social zeitgeber" [timekeeper] theory, it posits that, in susceptible individuals, abrupt changes in the schedule of daily events and tasks may set
Dendritic Cell-Derived Exosomes for Cancer Immunotherapy: What's Next?
Authors: Sophie Viaud, Clotilde Théry, Stéphanie Ploix, Thomas Tursz, Valérie Lapierre, Olivier Lantz, Laurence Zitvogel, Nathalie Chaput
Journal: Cancer Research (2010)

Exosomes are nanovesicles originating from late endosomal compartments and secreted by most living cells in ex vivo cell culture conditions. The interest in exosomes was rekindled when B-cell and dendritic cell-derived exosomes were shown to mediate MHC-dependent immune responses. Despite limited understanding of exosome biogenesis and physiological relevance, accumulating evidence points to their bioactivity culminating in clinical applications in cancer. This review focuses on the preclinical studies exploiting the immunogenicity of dendritic cell-derived exosomes (Dex) and will elaborate on the past and future vaccination trials conducted using Dex strategy in melanoma and non-small cell lung cancer patients.
Elevated lipoprotein(a) and premature coronary heart disease
Authors: V. M. Maher
Journal: JAMA (1997)

To the Editor.  —The article by Dr Bostom and colleagues 1 reaffirms the importance of an elevated lipoprotein(a) [Lp(a)] level as a cardiac risk factor. We have postulated previously, based on our analysis of published works, 2 that a pathological interaction exists between increased Lp(a) levels and elevated low-density lipoprotein (LDL) cholesterol levels, which is confirmed by our own experience. 3 Furthermore, by lowering LDL cholesterol levels alone, the adverse effects of the interaction of these 2 particles is greatly diminished. 3   Bostom and colleagues did not observe such an interaction. The most likely explanation is that LDL cholesterol levels in their study were low (mean, 3.5 mmol/L [135 mg/dL]) relative to the mean LDL cholesterol levels in most studies previously published. 2 We observed that, in the presence of such low LDL cholesterol levels, increased Lp(a) levels had only a small or negligible impact on disease outcome. 2 In