tbuckley/cabot-search huggingface dataset:
Genotype-phenotype correlations with <i>TGM1</i> : clustering of mutations in the bathing suit ichthyosis and self-healing collodion baby variants of lamellar ichthyosis
Authors: B.C. Hackett, D. Fitzgerald, R.M. Watson, F.A. Hol, A.D. Irvine
Journal: British Journal of Dermatology (2009)

Journal Article Genotype–phenotype correlations with TGM1: clustering of mutations in the bathing suit ichthyosis and self‐healing collodion baby variants of lamellar ichthyosis Get access B.C. Hackett, B.C. Hackett Department of Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland Search for other works by this author on: Oxford Academic Google Scholar D. Fitzgerald, D. Fitzgerald Department of Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland Search for other works by this author on: Oxford Academic Google Scholar R.M. Watson, R.M. Watson Department of Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland Search for other works by this author on: Oxford Academic Google Scholar F.A. Hol, F.A. Hol Department of Human Genetics, Radboud University, Nijmegen Medical Center, Nijmegen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar A.D. Irvine A.D. Irvine Department of Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, IrelandDepartment of Clinical Medicine, Trinity College Dublin, Dublin, Ireland Alan D. Irvine. E‐mail: irvinea@tcd.ie Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 162, Issue 2, 1 February 2010, Pages 448–451, https://doi.org/10.1111/j.1365-2133.2009.09537.x Published: 01 February 2010
Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production.
Authors: N Karin, D J Mitchell, S Brocke, N Ling, L Steinman
Journal: The Journal of Experimental Medicine (1994)

An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87-99), is a major target of T cells in lesions of multiple sclerosis (MS) and in experimental allergic encephalomyelitis (EAE). T cells found in EAE lesions bear the same amino acids in the third complementary determining region of the T cell receptor (TCR) as those found in MS lesions. We analyzed the trimolecular interactions between MBP p87-99, class II major histocompatibility complex (MHC), and TCR, and designed soluble inhibitors for therapy. F, N, I, and V at positions 90, 92, 93, and 94 interact with MHC, whereas K, T, and P at positions 91, 95, and 96 interact with TCR. The peptides, p87-99[95T &amp;gt; A] and p87-99[96P &amp;gt; A] could compete more effectively with p87-99 for binding to MHC and could antagonize the in vitro response to T cells to p87-99 more effectively than p87-99[91K &amp;gt; A]. However, only p87-99[91K &amp;gt; A] prevented and reversed EAE, indicating that the extent of MHC or TCR competition does not predict success in treating EAE. To elucidate the mechanism of inhibition of EAE, draining lymph node cells from rats immunized with the native peptide alone or together with each of the three TCR antagonists were challenged in vitro with p87-99. Administration of p87-99[91K &amp;gt; A], but not p87-99 [95T &amp;gt; A] or p87-99[96P &amp;gt; A], reduced the production of tumor necrosis factor (TNF)- alpha and interferon (IFN) gamma. IFN-gamma and TNF-alpha are two cytokines that are critical in the pathogenesis of EAE and MS.
ANTXR1, a Stem Cell-Enriched Functional Biomarker, Connects Collagen Signaling to Cancer Stem-like Cells and Metastasis in Breast Cancer
Authors: Daohong Chen, Poornima Bhat-Nakshatri, Chirayu Goswami, Sunil Badve, Harikrishna Nakshatri
Journal: Cancer Research (2013)

Cancer stem-like cells are thought to contribute to tumor recurrence. The anthrax toxin receptor 1 (ANTXR1) has been identified as a functional biomarker of normal stem cells and breast cancer stem-like cells. Primary stem cell-enriched basal cells (CD49f(+)/EpCAM(-)/Lin(-)) expressed higher levels of ANTXR1 compared with mature luminal cells. CD49f(+)/EpCAM(-), CD44(+)/EpCAM(-), CD44(+)/CD24(-), or ALDEFLUOR-positive subpopulations of breast cancer cells were enriched for ANTXR1 expression. CD44(+)/CD24(-)/ANTXR1(+) cells displayed enhanced self-renewal as measured by mammosphere assay compared with CD44(+)/CD24(-)/ANTXR1(-) cells. Activation of ANTXR1 by its natural ligand C5A, a fragment of collagen VI α3, increased stem cell self-renewal in mammosphere assays and Wnt signaling including the expression of the Wnt receptor-lipoprotein receptor-related protein 6 (LRP6), phosphorylation of GSK3α/β, and elevated expression of Wnt target genes. RNAi-mediated silencing of ANTXR1 enhanced the expression of luminal-enriched genes but diminished Wnt signaling including reduced LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity, and metastasis. ANTXR1 silencing also reduced the expression of HSPA1A, which is overexpressed in metastatic breast cancer stem cells. Analysis of public databases revealed ANTXR1 amplification in medullary breast carcinoma and overexpression in estrogen receptor-negative breast cancers with the worst outcome. Furthermore, ANTXR1 is among the 10% most overexpressed genes in breast cancer and is coexpressed with collagen VI. Thus, ANTXR1:C5A interactions bridge a network of collagen cleavage and remodeling in the tumor microenvironment, linking it to a stemness signaling network that drives metastatic progression.
How to Revive Breakthrough Innovation in the Pharmaceutical Industry
Authors: Bernard H. Munos, William W. Chin
Journal: Science Translational Medicine (2011)

Over the past 20 years, pharmaceutical companies have implemented conservative management practices to improve the predictability of therapeutics discovery and success rates of drug candidates. This approach has often yielded compounds that are only marginally better than existing therapies, yet require larger, longer, and more complex trials. To fund them, companies have shifted resources away from drug discovery to late clinical development; this has hurt innovation and amplified the crisis brought by the expiration of patents on many best-selling drugs. Here, we argue that more breakthrough therapeutics will reach patients only if the industry ceases to pursue "safe" incremental innovation, re-engages in high-risk discovery research, and adopts collaborative innovation models that allow sharing of knowledge and costs among collaborators.
Altruistic Discourse and Therapeutic Misconception in Research Informed Consent
Authors: Steven Joffe
Journal: The American Journal of Bioethics (2006)

"Altruistic Discourse and Therapeutic Misconception in Research Informed Consent." The American Journal of Bioethics, 6(5), pp. 53–54 ACKNOWLEDGMENT Dr. Joffe receives support from the National Cancer Institute (CA 96872).
Expression of DBC1 and SIRT1 Is Associated with Poor Prognosis of Gastric Carcinoma
Authors: Eun Jung Cha, Sang Jae Noh, Keun Sang Kwon, Chan Young Kim, Byung-Hyun Park, Ho Sung Park, Ho Lee, Myoung Ja Chung, Myoung Jae Kang, Dong Geun Lee, Woo Sung Moon, Kyu Yun Jang
Journal: Clinical Cancer Research (2009)

SIRT1 (silent mating-type information regulation 2 homologue 1) expression has been reported to predict poor survival in some cancers. We therefore investigated the expression levels of SIRT1 and its negative regulator, DBC1 (deleted in breast cancer 1), in gastric cancer patients.We evaluated immunohistochemical expression of DBC1, SIRT1, and p53 using 3-mm tumor cores from 177 gastric cancer patients for tissue microarray.Positive expressions of DBC1 and SIRT1 were seen in 62% (109 of 177) and in 73% (130 of 177) of patients, respectively. Expression of DBC1 was significantly correlated with tumor stage (P = 0.007), lymph node metastasis (P < 0.001), tumor invasion (P = 0.001), venous invasion (P = 0.001), histologic types (P < 0.001), p53 expression (P < 0.001), and SIRT1 expression (P < 0.001). SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001). In addition, expression of DBC1 was significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P < 0.001 and P < 0.001, respectively). SIRT1 expression was also significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P = 0.001 and P = 0.001, respectively). Multivariate analysis showed that tumor stage and expression of DBC1 were independent prognostic factors significantly associated with overall survival and relapse-free survival.This study shows that expression of DBC1 and SIRT1 is a significant prognostic indicator for gastric carcinoma patients.
Hybrid Transgenic Mice Reveal In Vivo Specificity of G Protein–Coupled Receptor Kinases in the Heart
Authors: Andrea D. Eckhart, Sandra J. Duncan, Raymond B. Penn, Jeffrey L. Benovic, Robert J. Lefkowitz, Walter J. Koch
Journal: Circulation Research (2000)

Abstract —G protein–coupled receptor kinases (GRKs) phosphorylate activated G protein-coupled receptors, including α 1B -adrenergic receptors (ARs), resulting in desensitization. In vivo analysis of GRK substrate selectivity has been limited. Therefore, we generated hybrid transgenic mice with myocardium-targeted overexpression of 1 of 3 GRKs expressed in the heart (GRK2 [commonly known as the β-AR kinase 1], GRK3, or GRK5) with concomitant cardiac expression of a constitutively activated mutant (CAM) or wild-type α 1B AR. Transgenic mice with cardiac CAMα 1B AR overexpression had enhanced myocardial α 1 AR signaling and elevated heart-to-body weight ratios with ventricular atrial natriuretic factor expression denoting myocardial hypertrophy. Transgenic mouse hearts overexpressing only GRK2, GRK3, or GRK5 had no hypertrophy. In hybrid transgenic mice, enhanced in vivo signaling through CAMα 1B ARs, as measured by myocardial diacylglycerol content, was attenuated by concomitant overexpression of GRK3 but not GRK2 or GRK5. CAMα 1B AR-induced hypertrophy and ventricular atrial natriuretic factor expression were significantly attenuated with either concurrent GRK3 or GRK5 overexpression. Similar GRK selectivity was seen in hybrid transgenic mice with wild-type α 1B AR overexpression concurrently with a GRK. GRK2 overexpression was without effect on any in vivo CAM or wild-type α 1B AR cardiac phenotype, which is in contrast to previously reported in vitro findings. Furthermore, endogenous myocardial α 1 AR mitogen-activated protein kinase signaling in single-GRK transgenic mice also exhibited selectivity, as GRK3 and GRK5 desensitized in vivo α 1 AR mitogen–activated protein kinase responses that were unaffected by GRK2 overexpression. Thus, these results demonstrate that GRKs differentially interact with α 1B ARs in vivo such that GRK3 desensitizes all α 1B AR signaling, whereas GRK5 has partial effects and, most interestingly, GRK2 has no effect on in vivo α 1B AR signaling in the heart.
Intravenous administration of phosphorylated acid alpha-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice.
Authors: A T Van der Ploeg, M A Kroos, R Willemsen, N H Brons, A J Reuser
Journal: Journal of Clinical Investigation (1991)

The lysosomal storage disorder glycogenosis type II is caused by acid alpha-glucosidase deficiency. In this study we have investigated the possible applicability of mannose 6-phosphate receptor-mediated enzyme replacement therapy to correct the enzyme deficiency in the most affected tissues. Bovine testes acid alpha-glucosidase containing phosphorylated mannose residues was intravenously administered to mice and found to be taken up by heart (70% increase of activity) and skeletal muscle (43% increase); the major target organs. The uptake of nonphosphorylated human placenta acid alpha-glucosidase by heart and skeletal muscle appeared to be significantly less efficient, whereas uptake of dephosphorylated bovine testes enzyme was not detectable. The phosphorylated bovine testes acid alpha-glucosidase remained present in mouse skeletal muscle up to 9-15 d after administration, with a half-life of 2-4 d. Besides being measured in skeletal muscle and heart, uptake of phosphorylated bovine testes and nonphosphorylated human placenta acid alpha-glucosidase was measured in several other organs, but not in brain. The increase of acid alpha-glucosidase activity was highest in liver and spleen. We concluded that application of mannose 6-phosphate receptor-mediated enzyme replacement therapy may offer new perspectives for treatment of glycogenesis type II.
Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study
Authors: Emanuele Zucca, Annarita Conconi, Daniele Laszlo, Armando López-Guillermo, Reda Bouabdallah, Bertrand Coiffier, Catherine Sebban, Fabrice Jardin, Umberto Vitolo, Franck Morschhauser, Stefano A. Pileri, Christiane Copie-Bergman, Elias Campo, Andrew Jack, Irene Floriani, Peter Johnson, Maurizio Martelli, Franco Cavalli, Giovanni Martinelli, Catherine Thieblemont
Journal: Journal of Clinical Oncology (2013)

Purpose Apart from localized gastric disease, there is no consensus on standard initial treatment of mucosa-associated lymphoid tissue lymphoma. The IELSG-19 study (Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) was launched to compare chlorambucil alone versus chlorambucil plus rituximab in patients not previously given systemic anticancer therapy. Patients and Methods Patients not responding to or not suitable for local therapy were eligible. In arm A, chlorambucil was given daily 6 mg/m 2 orally (PO) for 6 weeks. Responding patients and those with stable disease continued to be given daily chlorambucil 6 mg/m 2 PO for 14 consecutive days every 28 days for four cycles. In arm B, intravenous rituximab 375 mg/m 2 per day was added on days 1, 8, 15, 22, 56, 84, 112, and 140. After completion of the planned accrual, the protocol was amended to introduce a third arm with rituximab alone. We report the planned final analysis of the first two arms (113 patients in arm A and 114 in arm B). Results At a median follow-up of 62 months, the 5-year event-free survival (EFS) was significantly better for the patients treated in arm B (68% v 50%; P = .002) who, despite similar overall response rates (90% v 87%), achieved a higher complete remission rate (78% v 65%; P = .025). Progression-free survival was also improved but it did not reach statistical significance (P = .057). Five-year overall survival (OS) was 89% in both arms. Both treatments were well tolerated without unexpected toxicities. Conclusion Both treatments were active; the better response rate and EFS obtained with the addition of rituximab did not translate into improved OS.
Identifying Priority Health Conditions, Environmental Data, and Infrastructure Needs: A Synopsis of the Pew Environmental Health Tracking Project
Authors: Jill Litt, Nga Tran, Kristen Chossek Malecki, Roni Neff, Beth Resnick, Thomas Burke
Journal: Environmental Health Perspectives (2004)

In this article we describe the methodologic approaches of the Pew Environmental Health Commission at the Johns Hopkins Bloomberg School of Public Health used to identify priority environmental health conditions and develop recommendations to establish a national environmental public health tracking network. We present the results of a survey of public health and environmental practitioners to uncover state and local health tracking needs and priorities. We describe the steps that combined the findings from the state and local health tracking survey and a review of the state of the science on environmental impacts on health to identify priority health end points. Through an examination of national health and health care databases, we then describe trends and public health effects of those diseases that may be linked to the environment. Based on this analysis, respiratory diseases and neurologic diseases are recommended as priorities for tracking. Specific end points recommended for tracking include asthma and chronic respiratory diseases, and chronic neurodegenerative diseases such as multiple sclerosis. Based on trends in reported prevalence, consideration should also be given to developmental disabilities, reproductive disorders, and endocrine/metabolic disorders. Strengthening of current efforts to track cancer and birth defects should also be included as components of a nationwide health tracking network. Finally, we present the recommendations for environmental public health tracking. These recommendations provided the groundwork for the development of the Centers for Disease Control and Prevention's National Environmental Public Health Tracking Progam that now includes 21 states, three cities, and three academic centers throughout the nation.
Development of mucoid Pseudomonas aeruginosa coincides with pulmonary deterioration in cystic fibrosis
Authors: D Derry
Journal: Thorax (2005)

▴ Li Z, Kosorok MR, Farrell PM, et al . Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA2005;293:581–8 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] This longitudinal study correlates acquisition of non-mucoid and mucoid phenotypes of Pseudomonas aeruginosa with respiratory symptoms, quantitative chest radiography, pulmonary function tests, and anti-pseudomonal antibodies in cystic fibrosis (CF). 56 children identified by the Wisconsin CF neonatal screening project between 1985 and 1994 were followed from diagnosis (median age 6.9 weeks) … [1]: {openurl}?query=rft.jtitle%253DJAMA%26rft.stitle%253DJAMA%26rft.issn%253D0002-9955%26rft.aulast%253DLi%26rft.auinit1%253DZ.%26rft.volume%253D293%26rft.issue%253D5%26rft.spage%253D581%26rft.epage%253D588%26rft.atitle%253DLongitudinal%2BDevelopment%2Bof%2BMucoid%2BPseudomonas%2Baeruginosa%2BInfection%2Band%2BLung%2BDisease%2BProgression%2Bin%2BChildren%2BWith%2BCystic%2BFibrosis%26rft_id%253Dinfo%253Adoi%252F10.1001%252Fjama.293.5.581%26rft_id%253Dinfo%253Apmid%252F15687313%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1001/jama.293.5.581&link_type=DOI [3]: /lookup/external-ref?access_num=15687313&link_type=MED&atom=%2Fthoraxjnl%2F60%2F4%2F334.atom [4]: /lookup/external-ref?access_num=000226694200021&link_type=ISI
Pulmonary Complications of Collagen Vascular Disease
Authors: J P Lynch, G W Hunninghake
Journal: Annual Review of Medicine (1992)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis
Authors: Shahin Shafiani, Glady’s Tucker-Heard, Ai Kariyone, Kiyoshi Takatsu, Kevin B. Urdahl
Journal: The Journal of Experimental Medicine (2010)

The ability of the adaptive immune system to restrict Mycobacterium tuberculosis (Mtb) is impeded by activated Foxp3+ regulatory T (T reg) cells. The importance of pathogen-specific T reg cells in this process has not been addressed. We show that T reg cell expansion after aerosol Mtb infection does not occur until Mtb is transported to the pulmonary lymph node (pLN), and Mtb-specific T reg cells have an increased propensity to proliferate. Even small numbers of Mtb-specific T reg cells are capable of delaying the priming of effector CD4+ and CD8+ T cells in the pLN and their subsequent accumulation in the lung, the primary site of infection. This delay likely prolongs the initial phase of bacterial expansion and explains the higher bacterial burden observed in these mice. Thus, T reg cells recognizing Mtb-derived antigens specifically and potently restrict protective immune responses during tuberculosis.
Serious long-term health consequences of Q-fever and Legionnaires' disease
Authors: Joris A.F. van Loenhout, Hein H.M.M. van Tiel, Jet van den Heuvel, Jan H. Vercoulen, Hans Bor, Koos van der Velden, W. John Paget, Jeannine L.A. Hautvast
Journal: Journal of Infection (2014)
Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice
Authors: Sara Gardenghi, Pedro Ramos, Maria Franca Marongiu, Luca Melchiori, Laura Breda, Ella Guy, Kristen Muirhead, Niva Rao, Cindy N. Roy, Nancy C. Andrews, Elizabeta Nemeth, Antonia Follenzi, Xiuli An, Narla Mohandas, Yelena Ginzburg, Eliezer A. Rachmilewitz, Patricia J. Giardina, Robert W. Grady, Stefano Rivella
Journal: Journal of Clinical Investigation (2010)

Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.
ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi
Authors: A. Chowdhary, J.F. Meis, J. Guarro, G.S. de Hoog, S. Kathuria, M.C. Arendrup, S. Arikan-Akdagli, M. Akova, T. Boekhout, M. Caira, J. Guinea, A. Chakrabarti, E. Dannaoui, A. van Diepeningen, T. Freiberger, A.H. Groll, W.W. Hope, E. Johnson, M. Lackner, K. Lagrou, F. Lanternier, C. Lass-Flörl, O. Lortholary, J. Meletiadis, P. Muñoz, L. Pagano, G. Petrikkos, M.D. Richardson, E. Roilides, A. Skiada, A.M. Tortorano, A.J. Ullmann, P.E. Verweij, O.A. Cornely, M. Cuenca-Estrella
Journal: Clinical Microbiology and Infection (2014)