tbuckley/cabot-search huggingface dataset:
Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation
Authors: Hui Xiong, Danling Wang, Linan Chen, Yeun Su Choo, Hong Ma, Chengyuan Tang, Kun Xia, Wei Jiang, Ze’ev Ronai, Xiaoxi Zhuang, Zhuohua Zhang
Journal: Journal of Clinical Investigation (2009)

Mutations in PARKIN, pten-induced putative kinase 1 (PINK1), and DJ-1 are individually linked to autosomal recessive early-onset familial forms of Parkinson disease (PD). Although mutations in these genes lead to the same disease state, the functional relationships between them and how their respective disease-associated mutations cause PD are largely unknown. Here, we show that Parkin, PINK1, and DJ-1 formed a complex (termed PPD complex) to promote ubiquitination and degradation of Parkin substrates, including Parkin itself and Synphilin-1 in neuroblastoma cells and human brain lysates. Genetic ablation of either Pink1 or Dj-1 resulted in reduced ubiquitination of endogenous Parkin as well as decreased degradation and increased accumulation of aberrantly expressed Parkin substrates. Expression of PINK1 enhanced Parkin-mediated degradation of heat shock-induced misfolded protein. In contrast, PD-pathogenic Parkin and PINK1 mutations showed reduced ability to promote degradation of Parkin substrates. This study identified a functional ubiquitin E3 ligase complex consisting of PD-associated Parkin, PINK1, and DJ-1 to promote degradation of un-/misfolded proteins and suggests that their PD-pathogenic mutations impair E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis.
Nervous and Ocular Disorders in Children with Cholestasis and Vitamin A and E Deficiencies
Authors: Fernando Alvarez, Pierre Landrieu, Paul Laget, Frédérique Lemonnier, Michel Odièvre, Daniel Alagille
Journal: Hepatology (2007)

Thirteen children, aged 10 months to 20 years, presenting with chronic cholestasis from the first month of life and with low serum levels of vitamins A and/or E, have been investigated for neurological and ophthalmological symptoms. Clinical findings consisted of 4 types: peripheral neuropathy; cerebellar dysfunction; abnormalities of eye movement, and retinal degenerative changes. The results of electrophysiological and morphological studies of muscle and nerves were consistent with jieurono-axonal degeneration. Electrical abnormalities of the retina, especially a decrease of the b wave of electroretinogram, appear to be the first sign of the syndrome, allowing early detection. Evidence for vitamin deficiency (E or E+A) suggests substitutive parenteral treatment in such patients.
Intestinal permeability to polyethyleneglycol 600 in relation to macromolecular 'closure' in the neonatal pig.
Authors: B Westrom, J Svendsen, C Tagesson
Journal: Gut (1984)

The intestinal permeability of different sized molecules in the neonatal pig was investigated. Piglets of varying age (0-168 h) were given a mixture of different sized polyethyleneglycols (414-942 dalton polyethyleneglycols) together with ovalbumin and bovine serum albumin by stomach tube, and the serum concentrations were determined two hours after feeding. Considerable amounts of ovalbumin and bovine serum albumin were found in the serum of animals up to 24 hours of age, whereas very little or none at all was found in sera from older animals. By contrast, an intestinal permeability barrier to polyethyleneglycols in the 414-942 dalton range was found not only in the older animals but in all pigs investigated, including the newborn, unsuckled. In addition, the permeability barrier to polyethyleneglycols was found in a pig which was starved to prevent macromolecular closure and, therefore, absorbed considerable amounts of bovine serum albumin and ovalbumin. These findings indicate that 414-942 dalton polyethyleneglycols cross the intestinal mucosa at different rates due to size regardless of age of the animals and regardless of whether the mucosa is permeable to protein or not. This suggests that low molecular weight molecules like 414-942 dalton polyethyleneglycols and macromolecules (proteins) cross the neonatal gut wall through different routes.
Hospital Admission Through the Emergency Department
Authors: Gregg A. Pane
Journal: JAMA (1992)

<h3>To the Editor.</h3> —In their article on ED admissions, Stern et al<sup>1</sup>found that, even after adjusting for diagnosis related group severity and socioeconomic status, patients admitted through the ED stayed 27% longer and incurred 13% higher charges than other patients. An additional important variable to consider is delay in seeking care prior to hospitalization. Another study by Weissman et al<sup>2</sup>found that hospitalized patients who reported a delay had a 9% longer hospital stay compared with others. In a study of ED admissions at our teaching hospital,<sup>3</sup>patients admitted through the ED who initially delayed seeking care had markedly (approximately 25%) longer lengths of stay and higher hospital charges than patients in the ED who did not delay. The overriding message from these studies is that patients admitted via the ED often use more health care resources than do other patients. The key underlying factors include
Loss of NPP1 induces cartilage remodelling into bone and OA-like changes in mice
Authors: J. Bertrand, M. Furst, W. Ruther, F. Rutsch, Y. Nitschke, F. Dell'Accio, T. Pap
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Cartilage calcification is common in osteoarthritis (OA) and correlates with the severity of cartilage breakdown. Nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) contributes to maintain an optimal balance of pyrophosphate (PPi) and phosphate (Pi) in the extracellular matrix, thereby, together with the phosphate regulating molecules progressive ankylosis protein (ANK) and tissue nonspecific alkaline phosphatase (TNAP), preventing the generation of calcium crystals. Previous data have demonstrated regulation of NPP1 expression by inflammatory mediators and linked it to pathological cartilage calcification. <h3>Methods</h3> Cartilage explants were obtained from 120 consecuitve patients with OA undergoing joint replacement. Experimental OA was induced in mice by resection of the anterior cruciate ligament. Cartilage calcification was evaluated in human explants by digital contact radiography and in mice by fluorid positron emission tomography (PET)-scanning and μCT. The expression of NPP1, ANK and TNAP was performed by quantitative real time RT-PCR in human cartilage samples and by immunohistochemistry in experimental murine OA. Von Kossa-safranin-O staining was used to measure cartilage and meniscal calcification in mice carrying a homozygous loss of function mutation of <i>enpp1</i>. The severity of OA was quantified using the Mankin Score. Cartilage remodelling was investigated using immunohistological stainings for collagen type I, collagen type X, osteopontin and TRAP. <h3>Results</h3> In OA patients, the expression of NPP1, but not ANK and TNAP, inversely correlated with cartilage calcification (p&lt;0.05). Such inverse correlation was confirmed in vivo in experimental murine OA. Using Fluoride PET, the authors showed enhanced calcification activity in joints as well as in cartilage of non-weight bearing areas, including ear cartilage, in NPP1<sup>−/−</sup> mice, thereby suggesting that mechanical stress is not required for induction of calcification. NPP1<sup>−/−</sup> mice developed typical OA changes as evaluated by histological analysis and in vivo imaging. Intriguingly, calcification processes were associated with increased expression of the hypertrophic marker collagen X and the bone marker collagen I. Finally, the authors detected osteoclasts at the interface between bone and cartilage. <h3>Conclusion</h3> NPP1 is an important player in OA-associated cartilage calcification. Pathologic calcification in the NPP1<sup>−/−</sup> mice leads to cartilage remodelling into bone, thereby resembling aspects of hypertrophic maturation. Taken together, the data suggest that OA is characterised by the reactivation of molecular signalling cascades associated with endochondral ossification.
Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood
Authors: Joris C. Verster, Edmund R. Volkerts, Armand W.A.A. van Oosterwijck, Mounir Aarab, Saskia I.R. Bijtjes, A.Marit De Weert, Erik J.E. Eijken, Marinus N. Verbaten
Journal: Journal of Allergy and Clinical Immunology (2003)
Specific IgE antibodies to vespids in the course of immunotherapy with <i>Vespula germanica</i> administered to patients sensitized to <i>Polistes dominulus</i>
Authors: C. Juarez, M. Blanca, A. Miranda, F. Sanchez, M. J. Carmona, M. J. Avila, S. Fernandez, J. Fernandez, S. Terrados
Journal: Allergy (1992)

Sera from a group of 12 patients with anaphylactic reactions to vespids were studied. Field observations and RAST values suggested that the offending insect was Polistes dominulus (PD). Specific IgE antibodies to PD appeared in all cases and to Vespula germanica (VG) in nine. Absorption studies in these basal sera showed that IgE antibodies to VG were due to cross‐reactivity with PD. The RAST value to both venoms was higher after immunotherapy (IT) in six cases. IgE antibodies increased to determinants common to both vespids, and in 41% of the cases to specific epitopes of VG venom allergens not initially detected in the basal sera. In one case antibodies increased only to VG without a corresponding rise to PD. These results indicate that if the correct venom to which the individuals are sensitized is not administered IgE antibodies may appear which were not initially detected in the patients's era. The levels of these antibodies declined during the course of IT.
Reduction of Tumorigenicity of Cigarette Smoke
Authors: Ernest L. Wynder
Journal: JAMA (1965)

A study of different types of cigarettes has demonstrated that the tumorigenic activity of cigarette smoke condensate for the experimental animal can be significantly reduced through practical means. It has been shown that a combination of modifications in the makeup of cigarettes, with respect to reduction of total smoke condensate yield, selective reduction of tumorigenic agents, and selective reduction of ciliotoxic agents, can significantly lower the tumorigenic as well as the ciliotoxic activity of cigarette smoke condensate established to a variety of animals and animal tissue. It has been stressed that long-term epidemiologic studies on man are necessary to determine the effect of these changes on the development of those types of cancer considered to be associated with cigarette smoking.
Prospective Study of Hyperglycemia and Cancer Risk
Authors: Pär Stattin, Annekatrin Lukanova, Bernt Lindahl, Göran Hallmans, Rudolf Kaaks
Journal: Diabetes Care (2007)

There are many possible mechanisms underlying the association between hyperglycemia and cancer risk (1); however, they were not discussed in our recent article (2), due to format limitations. At a cellular level, glucose may lead to activation of energy sensing mechanisms, which in turn favor cellular growth and proliferation. Additionally, elevated glucose concentrations may also stimulate cancer growth through increased formation of advanced glycation end products. As noted by Bowker and Johnson (3), increased …
Impact of a Real-Time Computerized Duplicate Alert System on the Utilization of Computed Tomography
Authors: Elliot J. Wasser, Luciano M. Prevedello, Aaron Sodickson, Wenhong Mar, Ramin Khorasani
Journal: JAMA Internal Medicine (2013)

The use of high-cost imaging modalities is rising rapidly. From 1995 through 2007, use of computed tomographic (CT) scans in the United States increased more than 4-fold1,2; by 2006, CT and magnetic resonance imaging examinations were the fastest-growing physician-directed Medicare expenditure.3,4 An uncertain proportion of these examinations represent overuse.5

There are little published data on the frequency of duplicated high-cost imaging examinations,6 but economic modeling suggests that cost savings from reducing redundant radiologic testing would be substantial.7 Because unnecessary duplication of CT examinations contributes to an increasingly strained medical payment system and exposes patients to unnecessary potential risks of radiation and intravenous contrast,2,8,9 we sought to determine whether alerting an ordering health care provider to the presence of a potentially redundant recent CT examination via decision support in a computerized physician order entry system (CPOE) can reduce repeated testing.
Future Practice Alternatives in Medicine
Authors: Henry M. Tufo
Journal: JAMA (1988)

Editor Dr David B. Nash and colleagues have written a provocative and useful book, a collection of essays about change and alternatives. The book's central thesis is that medicine is experiencing great change, and one of the results is a broadening of career opportunities that the emerging professional should at least examine. The essays describe the social and economic changes that are occurring, their impact on the profession, and the problems and opportunities that will result. We have been conditioned by the experience of the last 30 years to think of career opportunities shaped solely by the rapid advances in the biologic sciences. We forget that in other times and places the MD degree was a passport to a wide range of careers. One of the values of this book is that it reminds us of the inherent strength of the doctor of medicine degree. The essays are thought-provoking and
Abstract P2-10-13: CD4 positive tumor-infiltrating lymphocytes are associated with improved prognosis in node-negative breast cancer
Authors: M Schmidt, L van de Sandt, D Boehm, I Sicking, M Battista, A Lebrecht, C Solbach, H Koelbl, M Gehrmann, J Rahnenführer, JG Hengstler
Journal: Cancer Research (2012)

Abstract Background: The prognostic significance of CD8 positive cytotoxic lymphocytes in breast cancer is well accepted. However, the role of CD4 positive lymphocytes is ambiguous. We examined the prognostic relevance of CD4 positive tumor-infiltrating lymphocytes in previously published node-negative breast cancer cohorts using RNA expression. Methods: Microarray based gene-expression data for CD4 (203547_at) were analyzed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n = 824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CD4 on metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes (ER+/HER2−, ER−/HER2−, HER2+). Independent prognostic relevance was analyzed using multivariate Cox regression. Results: Higher RNA expression of CD4 was related to better MFS in a meta-analysis of the whole cohort (HR 0.66, 95% CI 0.49–0.90, p = 0.0074). Prognostic significance was most pronounced in the HER2+ positive molecular subtype (HR 0.32, 95% CI 0.14–0.75, p = 0.0091) as compared to ER+/HER2− (HR 0.62, 95% CI 0.29–1.32, P&amp;gt;0.05) and ER−/HER2− (HR 0.61, 95% CI 0.28–1.35, P&amp;gt;0.05) carcinomas of the breast. CD4 showed independent prognostic significance (HR 0.60, 95% CI 0.37–0.96, p = 0.032) in multivariate analysis. In addition to CD4, only histological grade of differentiation (HR 2.43, 95% CI 1.50–3.94, P &amp;lt; 0.001) and tumor size (HR 1.87, 95% CI 1.19–2.94, p = 0.007), but not age, HER2 status or hormone receptor status retained an independent prognostic association with MFS. Conclusion: CD4 positive tumor-infiltrating lymphocytes have independent prognostic significance in node-negative breast cancer. A higher expression is associated with improved outcome. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-13.
Carcinoma of the Breast: Assorted Problems
Authors: Philip Rubin
Journal: JAMA (1967)

Breast cancer is more than one disease. The garden variety of adenocarcinoma with varying degrees of differentiation constitutes the majority of cases, but many types of neoplasms occur. Some neoplasms as colloid carcinoma, medullary cancer with stromal invasion, and intraductal cancer can reach large dimensions with a low incidence of axillary nodal or vascular invasion and carry an improved prognosis.<sup>1</sup>A more ominous and less well-understood group are the sarcomas of the breast because of their patterns of spread and their biological behavior. The host rather than the cancer itself may dominate and express the course of the disease. Inflammatory cancer represents an unusual mode of spread into dermal lymphatics, but may indicate poor host defenses as well as an aggressive tumor. There is a particular concern with the young woman who develops cancer because emotional reactions are understandably heightened —the fear of disfigurement, inability to function completely as
The Golgi Associated Calcium Pumps in Human Breast Cancer.
Authors: D. Grice, H. Faddy, P. Kenny, G. Monteith, S. Roberts-Thomson
Journal: Cancer Research (2009)

Abstract The Golgi apparatus, located within the cell, is an intracellular calcium store. Golgi calcium is implicated in roles including post-translational modification, cell signalling and cellular proliferation. In breast cancer, there is evidence of aberrations in Golgi-dependent processes, some of which are linked to calcium regulated enzymes and Golgi structure. Previous studies show that Golgi-associated calcium pumps sequester calcium into the Golgi apparatus via an active transport mechanism requiring ATP. We investigated Golgi-associated calcium pumps in the context of breast cancer. Analysis of clinical breast sample and breast cancer cell line microarray databases indicates that different breast cancer subtypes may be characterized by alterations in Golgi calcium signalling. To explore this further, we assessed calcium transporter transcription in a bank of breast cancer-derived cell lines and non-malignant-derived breast cell lines using real time RT-PCR. The consequences of silencing Golgi calcium transporter expression were assessed using Dharmacon Smartpool On Target Plus siRNA. Inhibition (greater than 90%) was confirmed with real time RT-PCR 24, 72, 96 and 120 hours post transfection (P &amp;lt; 0.05). Effects of inhibition on calcium signalling, proliferation and induction and sensitization of breast cancer cells to endoplasmic reticulum stress via tunicamycin (0.1, 1, 10 µg/mL) was assessed. Endoplasmic reticulum stress was confirmed by measuring the induction of GRP94 mRNA expression. Effects on calcium signalling were characterized using a fluorescence imaging plate reader (FLIPR; Molecular DevicesTM) and a fluorescence calcium indicator. The nature of calcium responses to endoplasmic reticulum calcium mobilizing agents was assessed, agents included a sarcoplasmic-endoplasmic Ca2+-ATPase inhibitor, a purinergic agonist (ATP, 100 µM) and a protease activated receptor modulator. Collectively our results imply that some breast cancers are associated with a remodelling of Golgi calcium transport with functional consequences on calcium signalling in breast cancer cells. Modulators of Golgi calcium content in breast cancer may represent a novel therapeutic approach for some breast breast cancer subtypes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1129.
LUMBAR SYMPATHETIC BLOCKS AND ANTICOAGULANT THERAPY
Authors: J. Eugene Ruben
Journal: JAMA (1953)

<h3>To the Editor:</h3> —InThe Journal(May 30, 1953) there was an article entitled "Danger of Lumbar Sympathetic Blocks During Anticoagulant Therapy" by Robert P. Hohf, William S. Dye, and Ormand C. Julian. The authors reported retroperitoneal hemorrhage following paravertebral lumbar sympathetic block during anticoagulant therapy in three patients with peripheral vasospasm. In their comment they state, "It is apparent that there is no way to avoid this catastrophe by modifying the technique by which a block is performed or by regulating the therapeutic dose of anticoagulants." It has been shown that adequate lumbar sympathetic block may be obtained by the injection of dilute solutions of local anesthetics into the epidural space (Ruben, J. E.:<i>Anesth. &amp; Analg.</i><b>29</b>:296, 1950). This space may be entered for the purpose by the caudal or the interspinous route. A flexible needle (Hingson, R. A., and Southworth, J. L.:<i>Mil. Surgeon</i><b>100</b>:474,
Abstract 1731: TAK-701, a humanized monoclonal antibody to HGF, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an <i>EGFR</i> mutation
Authors: Wataru Okamoto, Isamu Okamoto, Kaoru Tanaka, Tokuzo Arao, Kazuto Nishio, Masahiro Fukuoka, Pasi Jänne, Kazuhiko Nakagawa
Journal: Cancer Research (2011)

Abstract Most non-small cell lung cancer (NSCLC) tumors with an activating mutation of the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib but ultimately develop resistance to these drugs. Hepatocyte growth factor (HGF) induces EGFR-TKI resistance in NSCLC cells with such a mutation. We investigated strategies to overcome gefitinib resistance induced by HGF. Human NSCLC cells with an activating EGFR mutation (HCC827 cells) were engineered to stably express HGF (HCC827-HGF cells). HCC827-HGF cells secreted large amounts of HGF and exhibited resistance to gefitinib in vitro to an extent similar to that of HCC827 GR cells, in which the gene for the HGF receptor MET is amplified. A MET-TKI reversed gefitinib resistance in HCC827-HGF cells as well as in HCC827 GR cells, suggesting that MET activation induces gefitinib resistance in both cell lines. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib inhibited the phosphorylation of MET, EGFR, ERK, and AKT in HCC827-HGF cells, resulting in suppression of cell growth and indicating that autocrine HGF-MET signaling contributes to gefitinib resistance in these cells. Combination therapy with TAK-701 and gefitinib also markedly inhibited the growth of HCC827-HGF tumors in vivo. The addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation. 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 1731. doi:10.1158/1538-7445.AM2011-1731
Clinical assessment of bronchodilator drugs delivered by aerosol
Authors: G. M. Shenfield, J. W. Paterson
Journal: Thorax (1973)

A method is described for the early clinical evaluation of bronchodilator aerosols. It is simple to perform, and an accurate estimate of potency can be obtained in a small number of patients. Using this method, three new sympathomimetic drugs, Th 1165a, salmefamol, and rimiterol, have been tested. All proved to be active bronchodilators and were equipotent with isoprenaline or salbutamol.