tbuckley/cabot-search huggingface dataset:
324. The Degron Motif: A Protein Destruction Module with Potent Transcriptional Activation Properties for ZFP-Targeted Gene Regulation
Authors: Siyuan Tan, Dmitry Guschin, Carolyn Dent, Andreas Reik, Pei-Qi Liu, Philip D. Gregory
Journal: Molecular Therapy (2004)

Engineered zinc finger protein transcription factors (ZFP TFs) can be designed to regulate any intended gene target, with single gene specificity within the genome. This  mode of gene up-regulation outperforms that of the cDNA since (i) very low levels of expression of the ZFP TF activator are required for a dramatic effect on the gene target; and (ii) the ZFP TF also upregulates all of the splice variants, a fact which may, in many instances, be critical to therapeutic efficacy. To fully exploit the remarkably low steady-state levels of engineered ZFP TFs necessary for in vivo function we describe here a ZFP TF construct that has been modified to induce proteasome mediated self-destruction following transcriptional activation of the target gene. To do this, we have made use of the  motif, a protein degradation module present in the most potent of natural transcription factors, including VP16. We show that incorporation of the degron motif into an engineered ZFP TF resulted in the proteasome-dependent degradation of ZFP TF, leading to an almost undetectable level of ZFP TF protein at steady state. Importantly, the low protein levels observed for these degron-containing ZFP TFs did not impair their ability to activate gene expression. Indeed, for the genes tested, equivalent or even increased activation of the target gene was obtained by the degron-constructs. Furthermore, we show that a degron containing ZFP TF may be combined with a regulatable switch such as the progesterone receptor ligand-binding domain, resulting in mifpristone-dependent up-regulation of the target gene. The degron motif thus represents a potent, self-limiting activation domain that permits maximal efficacy of the ZFP TF while simultaneously restricting ZFP TF protein levels. The specificity and potency of ZFP TFs can thus be controlled even within the context of gene therapy.
Antiangiogenic Therapy a Two-Trick Pony?
Authors: Tracy Hampton
Journal: JAMA (2005)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A memorable patient: Treves's young patient
Authors: M. Lavelle
Journal: BMJ (2000)

cord blood banks should alleviate this problem, especially if the banks can store donations from ethnic minorities in satisfactory numbers.The expansion of stem cell numbers from these small donations by their culture in the laboratory will, if successful, increase the numbers of allogeneic transplants being performed and potentially increase the numbers of patients being cured.In addition, we see closer collaboration with other medical specialists being necessary to assess the place of autologous transplantation in the treatment of more solid tumours and currently intractable autoimmune conditions.For further reading we recommend the guide to internet resources for cancer at www.ncl.ac.uk/child-health/guides.
Abstract 17048: Exosomes From Induced Pluripotent Stem Cells Deliver Cardioprotective Mirnas and Prevent Cardiomyocyte Apoptosis in the Ischemic Myocardium
Authors: Yingjie Wang, Lan Zhang, Neal L Weintraub, Yaoliang Tang
Journal: Circulation (2014)

Induced pluripotent stem (iPS) cells exhibit enhanced survival and proliferation in ischemic myocardium and thus represent a promising source of cell-based therapy for myocardial ischemia-reperfusion (MIR) injury. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes, nanovesicles that contain proteins, mRNAs and microRNAs (miRNAs) that can regulate cell function. Exosomes secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph and protein expression of the exosome markers CD63 and Tsg101. We observed that iPS-exo are taken up by cultured H9C2 cardiomyocytes with high efficiency in time-dependent fashion. Uptake of iPS-exo protects H9C2 cells against H2O2-induced oxidative stress by inhibiting caspase 3/7 activation (P&lt;0.05, n=6). To investigate whether iPS-exo treatment can protect against MIR injury, we injected exosomes secreted by CF (CF-exo), iPS-exo, or PBS (control) intramyocardially into mouse ischemic myocardium before reperfusion. After 24hs, TUNEL analysis showed that iPS-exo reduced cardiomyocyte apoptosis by about 66% in comparison with PBS control (p&lt;0.05, n=6), and by about 50% in comparison with CF-iPS (P&lt;0.05, n=6). Western blotting demonstrated that iPS-exo treatment significantly decreased the active caspase3 compared with PBS and CF-exo treatment (P&lt;0.05, n=3). Furthermore, iPS-exo deliver cardioprotective miRNAs, including Nanog-regulated miR-21 and HIF-1α-regulated miR-210, to H9C2 cardiomyocytes in vitro. In conclusion, iPS-exo are biological nanoparticles carrying survival messages that can be efficiently transmitted to cardiomyocytes to protect against MIR.
Effectiveness of seasonal 2010/11 and pandemic influenza A(H1N1)2009 vaccines in preventing influenza infection in the United Kingdom: mid-season analysis 2010/11
Authors: R Pebody, P Hardelid, D M Fleming, J McMenamin, N Andrews, C Robertson, D R Thomas, P Sebastianpillai, J Ellis, W Carman, T Wreghitt, M Zambon, J  M Watson
Journal: Eurosurveillance (2011)

This study provides mid-season estimates of the effectiveness of 2010/11 trivalent influenza vaccine and previous vaccination with monovalent influenza A(H1N1)2009 vaccine in preventing confirmed influenza A(H1N1)2009 infection in the United Kingdom in the 2010/11 season. The adjusted vaccine effectiveness was 34% (95% CI: -10 - 60%) if vaccinated only with monovalent vaccine in the 2009/10 season; 46% (95% CI: 7 - 69%) if vaccinated only with trivalent influenza vaccine in the 2010/11 season and 63% (95% CI: 37 - 78%) if vaccinated in both seasons.
Abstract P4-11-02: Worse breast cancer prognosis in insulin treated diabetic patients - A population based registry study in Sweden
Authors: Håkan Olsson, Rickard Einefors, Per Broberg, Mona Landin Olsson
Journal: Cancer Research (2015)

Abstract Background. Diabetes may be linked to incidence of different tumor diseases and prognosis through various mechanisms such as the disease itself, hyperglycemia, obesity and anti-diabetes therapy. Material and methods. The study includes all women with BC diagnosed in Sweden between 2000 through 2008 (n=54406). The women had no previous cancer diagnosis during the period of 1958-1999. Dates of birth, BC diagnosis and TNM-stage where directly extracted from the cancer registry. The women’s anti-diabetes therapy was gathered from the Swedish Prescribed Drug Registry. Information regarding the cause of death and date of death was obtained from the Cause of Death Registry and tbe Swedish Population Register up until the 31st of December 2012 and 31st of December 2013 respectively. Analyses have been restricted to patients receiving insulin therapy (n=2463) and their breast cancer prognosis has been calculated in comparison with breast cancer patients without diabetes. All analyses were adjusted for TNM-stage and age at diagnosis. Results. Patients with insulin treated diabetes had a worse prognosis compared with other women with breast cancer (HR 1.7, 95%CI 1.5-2.0). The worse prognosis could be seen both for patients with ER+ and ER- tumors. The worst prognosis was seen for patients treated with NPH insulins (HR 2.8, 95% CI 2.4-3.3) while patients treated with long-acting insulin analogs had an intermediate prognosis (HR 1.6, 95% CI 1.2-2.2). Those women treated with NPH insulins and metformin had a slightly worse prognosis (HR 1.4, 95% CI 1.0-1.8). The results for breast cancer specific survival and total survival were similar. Conclusion. Our results imply that insulin treated breast cancer patients have a worse survival compared with other women with breast cancer regardless of tumor stage. Metformin therapy may partially counteract the association. Citation Format: Håkan Olsson, Rickard Einefors, Per Broberg, Mona Landin Olsson. Worse breast cancer prognosis in insulin treated diabetic patients - A population based registry study in Sweden [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-02.
Quality of Care in Medicaid Managed Care vs Commercial Managed Care Plans
Authors: Margaret E O'Kane
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cognitive Therapy and Preventing Suicide Attempts
Authors: Martin Tepper, Jeff Whitehead
Journal: JAMA (2005)

In their study of suicide prevention, Dr Brown and colleagues conclude that cognitive therapy reduces the risk for subsequent suicide attempts. We have some methodological concerns that we believe affect this conclusion. First, 15 (25%) of the participants in the cognitive therapy group and 20 (33%) of the participants in the control group were lost to follow-up. With these relatively large numbers of unknown outcomes, it is difficult to assess whether the study results are accurate estimates of the true effect. As the authors suggest in the Comment section of their article, given a small number of patients in each group and a small number of outcome events, a few misclassified or unknown outcomes could have substantial impact on the comparison between the 2 groups. It would be helpful for the authors to provide the results of their sensitivity analysis.
Synbiotics reduce allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics
Authors: M. A. Van De Pol, R. Lutter, B. S. Smids, E. J. M. Weersink, J. S. Van Der Zee
Journal: Allergy (2010)

To cite this article: van de Pol MA, Lutter R, Smids BS, Weersink EJM, van der Zee JS. Synbiotics reduce allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics. Allergy 2011; 66: 39–47. Background: Previous studies suggest that pre/probiotics can be used in the prevention and treatment of early allergic disease in newborns and young children. Objective: To determine the effect of treatment with synbiotics (90% short-chain galacto-oligosaccharides, 10% long-chain fructo-oligosaccharides: Immunofortis® and Bifidobacterium breve M-16V) on allergic responses in adults with established allergic asthma. Primary outcome was allergen-induced bronchial inflammation as represented by eosinophil counts. Methods: Twenty-nine patients with asthma and house dust mite (HDM) allergy were randomized in a double-blind, parallel design to receive placebo or synbiotics for 4 weeks. At study entry and after treatment, a bronchial allergen challenge with HDM was performed, followed by lung function tests, collection of blood (in/ex vivo IL-5) and induced sputum (inflammatory parameters). During treatment, a diary was kept with peak expiratory flow (PEF) and asthma scores. Results: Treatment did not affect the allergen-induced increase in sputum eosinophils at 6 and 24 h after challenge. Likewise, other parameters for bronchial inflammation and early and late changes in lung function did not differ upon treatment. Both the morning and evening PEF, however, significantly increased during synbiotics treatment (morning P = 0.003, evening P = 0.011). Also, the increase in serum IL-5 after allergen challenge was significantly inhibited by synbiotics (P = 0.034), as was ex vivo allergen-induced Th2-cytokine (IL-5 and IL-4+ IL-13) production by PBMCs (P = 0.046). In vivo (24 h) and ex vivo IL-5 production were associated. Conclusion: Four-week treatment with synbiotics had no effect on bronchial inflammation and LAR, but did significantly reduce systemic production of Th2-cytokines after allergen challenge and improved PEF.
Synergistic Cell Inactivation of Human NHIK 3025 Cells by Cinnamaldehyde in Combination with cis-Diamminedichloroplatinum(II)
Authors: John M. Dornish, Erik O. Pettersen, Reidar Oftebro
Journal: Cancer Research (1988)

The cell-inactivating effect induced by cinnamaldehyde in combination with cis -diamminedichloroplatinum(II) ( cis -DDP) on human NHIK 3025 cells in culture was investigated. Cell inactivation was measured as a loss in the ability of single cells to give rise to macroscopic colonies following drug treatment. Although 2 h treatment of asynchronous cells with 0.3 mm cinnamaldehyde alone induced little cell inactivation, the drug combination of 0.3 mm cinnamaldehyde and 10 µm cis -DDP resulted in synergistic cell inactivation. Cinnamaldehyde potentiated the cell-inactivating effect of cis -DDP by a dose-modifying factor of 1.8. Drug synergism was found to occur only when cinnamaldehyde and cis -DDP were given in simultaneous combination. Treatment of synchronized cells demonstrated that cinnamaldehyde potentiated the inactivating effect of cis -DDP in all phases of the cell cycle. Dinnamic acid and cinnamyl alcohol were found to have no synergistic or potentiating effect on cell survival following treatment of cells with cis-DDP, thus indicating the importance of an aldehyde moiety for drug synergism.
Randomized Trial of Low Molecular Weight Heparin (Dalteparin) in Prevention of Left Ventricular Thrombus Formation and Arterial Embolism After Acute Anterior Myocardial Infarction: The Fragmin in Acute Myocardial Infarction (FRAMI) Study 11This study was supported by grants from the Norwegian Council on Cardiovascular Diseases, Oslo, Norway and Pharmacia AB, Stockholm, Sweden.
Authors: Frederic Kontny, Jon Dale, Ulrich Abildgaard, Terje R. Pedersen
Journal: Journal of the American College of Cardiology (1997)
736. Evaluation of an EIAV Gene Therapy Vector for Delivery of Therapeutic Antibodies
Authors: Geoffrey C. Owens, Craig T. Fredrickson, Edward W. Keefer
Journal: Molecular Therapy (2004)

Gene therapies for progressive degenerative disorders of the nervous system will require the long-term stable expression of therapeutic transgenes. As a step towards this goal, we have re-engineered a self-inactivating FIV-based vector to include features that are designed to optimize transgene expression in neurons, and to potentially increase vector safety. These features include elimination of the major splice donor site and mutation of the gag start site of translation. An internal promoter drives neural-specific transgene expression, and comprises an optimized TATA box and the initiator regulator from the Dntt gene coupled to enhancer sequences from the Syn1 gene. A shortened DNA central flap and the woodchuck hepatitis virus post-transcriptional regulatory element increase virus production and transgene expression. To reduce position effects the avian beta-globin locus HS4 insulator was inserted into the downstream LTR in place of the U3 region, and a CpG island element from the Aprt gene was added to the internal promoter. Using enhanced yellow fluorescent protein (EYFP) targeted to mitochondria as a marker gene, we have obtained robust EYFP expression in 84% of post-mitotic neurons from embryonic rat cortex in vitro. We are in the process of assessing the long-term stability of transgene expression in these neurons.
Controversies in Management: Only hospitals can provide the required skills
Authors: N B Lincoln
Journal: BMJ (1994)

previously for a more comprehensive rehabilitation approach with greater emphasis on psychosocial functioning.8This might be started in hospital, but its full realisation requires a community orientation. ConclusionHospital based care creates insoluble difficulties in addressing the key patient issues of long term treat- ment, handicap, and psychosocial functioning.Even in the best hospital centres, with patients carefully selected for the best recovery potential, the outcome in the medium term is poor.9Few districts currently provide stroke services that respond to the umbrella term "career in stroke disability."The shortfall is large, and although community rehabilitation is in its infancy, it has the best potential to fill this gap.
Attenuated portal hypertension in germ‐free mice: Function of bacterial flora on the development of mesenteric lymphatic and blood vessels
Authors: Sheida Moghadamrad, Kathy D. McCoy, Markus B. Geuking, Hans Sägesser, Jorum Kirundi, Andrew J. Macpherson, Andrea De Gottardi
Journal: Hepatology (2015)

Intestinal bacterial flora may induce splanchnic hemodynamic and histological alterations that are associated with portal hypertension (PH). We hypothesized that experimental PH would be attenuated in the complete absence of intestinal bacteria. We induced prehepatic PH by partial portal vein ligation (PPVL) in germ‐free (GF) or mice colonized with altered Schaedler's flora (ASF). After 2 or 7 days, we performed hemodynamic measurements, including portal pressure (PP) and portosystemic shunts (PSS), and collected tissues for histomorphology, microbiology, and gene expression studies. Mice colonized with intestinal microbiota presented significantly higher PP levels after PPVL, compared to GF, mice. Presence of bacterial flora was also associated with significantly increased PSS and spleen weight. However, there were no hemodynamic differences between sham‐operated mice in the presence or absence of intestinal flora. Bacterial translocation to the spleen was demonstrated 2 days, but not 7 days, after PPVL. Intestinal lymphatic and blood vessels were more abundant in colonized and in portal hypertensive mice, as compared to GF and sham‐operated mice. Expression of the intestinal antimicrobial peptide, angiogenin‐4, was suppressed in GF mice, but increased significantly after PPVL, whereas other angiogenic factors remained unchanged. Moreover, colonization of GF mice with ASF 2 days after PPVL led to a significant increase in intestinal blood vessels, compared to controls. The relative increase in PP after PPVL in ASF and specific pathogen‐free mice was not significantly different. Conclusion : In the complete absence of gut microbial flora PP is normal, but experimental PH is significantly attenuated. Intestinal mucosal lymphatic and blood vessels induced by bacterial colonization may contribute to development of PH. (H epatology 2015;61:1685‐1695)
Proteolytic activity and expression of the 20S proteasome are increased in psoriasis lesional skin
Authors: L. Henry, L. Le Gallic, G. Garcin, O. Coux, N. Jumez, P. Roger, T. Lavabre-Bertrand, J. Martinez, L. Meunier, P.E. Stoebner
Journal: British Journal of Dermatology (2011)

Background Deregulation of the proteasome pathway has been shown to be involved in the pathogenesis of several inflammatory disorders. To date limited information exists on proteasome and immunoproteasome expression and activity in psoriasis skin. Objectives To investigate the potential role of proteasomes in the pathogenesis of psoriasis. Methods Thirty‐six patients with psoriasis and 40 healthy subjects were included. The protein and mRNA expression levels and proteolytic activity of proteasome and immunoproteasome subunits were determined using immunohistochemistry, quantitative polymerase chain reaction and fluorogenic peptide substrate in lesional and nonlesional psoriasis skin. We additionally measured the plasmatic proteasome (p‐proteasome) levels using enzyme‐linked immunosorbent assay. Results We reveal an increased expression of proteasome and immunoproteasome subunits but stable mRNA levels in lesional psoriasis skin as compared with nonlesional psoriasis skin (n =19), suggesting that proteasome and immunoproteasome expression is regulated post‐transcriptionally. This proteasome overexpression was associated with a significant increase of the proteasomal chymotrypsin‐like activity that was threefold higher in lesional skin than in nonlesional skin (n =3). p‐Proteasome levels were enhanced in patients with psoriasis (mean ± SEM 3960 ± 299 ng mL−1, range 1484–8987) when compared with controls (2535 ± 187 ng mL−1, range 654–6446, P <0·001) and were significantly higher in psoriatic arthritis (4937 ± 572 ng mL−1, range 2600–8987). In addition, they were correlated to the body surface area involved and appeared thus as a new biomarker of psoriasis severity. Conclusions Altogether these results strongly suggest the involvement of the proteasome system in the pathogenesis of psoriasis and support the relevance of proteasome inhibitors in local or systemic treatment of psoriasis.