tbuckley/cabot-search huggingface dataset:
Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
Authors: Manuel AR Ferreira, Melanie C Matheson, David L Duffy, Guy B Marks, Jennie Hui, Peter Le Souëf, Patrick Danoy, Svetlana Baltic, Dale R Nyholt, Mark Jenkins, Catherine Hayden, Gonneke Willemsen, Wei Ang, Mikko Kuokkanen, John Beilby, Faang Cheah, Eco JC de Geus, Adaikalavan Ramasamy, Sailaja Vedantam, Veikko Salomaa, Pamela A Madden, Andrew C Heath, John L Hopper, Peter M Visscher, Bill Musk, Stephen R Leeder, Marjo-Riitta Jarvelin, Craig Pennell, Dorret I Boomsma, Joel N Hirschhorn, Haydn Walters, Nicholas G Martin, Alan James, Graham Jones, Michael J Abramson, Colin F Robertson, Shyamali C Dharmage, Matthew A Brown, Grant W Montgomery, Philip J Thompson
Journal: The Lancet (2011)
Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in sera from patients with polymyositis-scleroderma overlap.
Authors: T Mimori, M Akizuki, H Yamagata, S Inada, S Yoshida, M Homma
Journal: Journal of Clinical Investigation (1981)

Autoantibodies in the serum from a patient with connective tissue disease have been used to define a high molecule weight acidic nuclear protein antigen. The antigen tentatively termed Ku, after the first two letters of patient's name, has distinct physicochemical properties and immunological specificities that distinguish it from previously reported antigens. The Ku antigen has an apparent 300,000 mol wt as determined by gel filtration and sucrose density gradient ultracentrifugation techniques. The antigen is destroyed by trypsin, mild heating, and pH variations greater than 10 and less than 5. Treatment with ribonuclease or deoxyribonuclease did not affect the antigenic reactivity. The Ku antigen was demonstrated in the soluble extracts of human, calf, and rabbit, but not of rat tissues. Purified antibody localized the Ku antigen within the nuclei of human liver where a "reticular" pattern of immunofluorescence was seen. Of 330 patients with various connective tissue diseases, 9 had precipitating antibodies to the Ku antigen. Preliminary results of clinical analysis indicated that antibody to the Ku antigen might become a useful marker for a group of patients with clinical characteristics of both polymyositis and scleroderma with a good prognosis.
Reducing dynamin 2 expression rescues X-linked centronuclear myopathy
Authors: Belinda S. Cowling, Thierry Chevremont, Ivana Prokic, Christine Kretz, Arnaud Ferry, Catherine Coirault, Olga Koutsopoulos, Vincent Laugel, Norma B. Romero, Jocelyn Laporte
Journal: Journal of Clinical Investigation (2014)

Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1–/y). Generation of Mtm1–/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle–specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.
A comparison of the cardiovascular actions of indoramin, propranolol, lignocaine, and quinidine
Authors: B. J. ALPS, E. T. BORROWS, E. S. JOHNSON, M. W. STANIFORTH, A. B. WILSON
Journal: Cardiovascular Research (1972)

Indoramin hydrochloride lowered blood pressure to a significantly greater and more prolonged extent than propranolol. It induced bradycardia and reduced peak left ventricular dp/dt, concomitant with a decrease in peripheral resistance. Propranolol reflexly increased peripheral resistance, thus accounting for the transient nature of its vasodepressor action. The sustained nature of the hypotensive action of indoramin was related to its α-adrenoceptor blocking property in the periphery. The cardiovascular actions of indoramin also differed from those of lignocaine and quinidine.
Prolonged, But Not Acute, Glutathione Depletion Promotes Fas–Mediated Mitochondrial Permeability Transition and Apoptosis in Mice
Authors: Delphine Haouzi, Mounia Lekehal, Marina Tinel, Nathalie Vadrot, Laure Caussanel, Philippe Lettéron, Alain Moreau, Gérard Feldmann, Daniel Fau, Dominique Pessayre
Journal: Hepatology (2001)

Glutathione depletion either decreased or increased death-receptor-mediated apoptosis in previous studies. Comparison of the durations of glutathione depletion before death-receptor stimulation in these studies might suggest a different effect of prolonged versus acute thiol depletion. We compared the effects of the prolonged glutathione depletion caused by a sulfur amino acid-deficient (SAA(-)) diet and the acute depletion caused by a single dose of phorone on hepatic apoptosis triggered by the administration of an agonistic anti-Fas antibody. The chronic SAA(-) diet did not affect hepatic Fas or Bcl-XL, but increased p53 and Bax, and exacerbated Fas-mediated mitochondrial membrane depolarization, electron-microscopy-proven outer mitochondrial membrane rupture, cytochrome c translocation to the cytosol, and caspase 3 activation. These effects were prevented by cyclosporin A, an inhibitor of mitochondrial permeability transition. The SAA(-) diet increased internucleosomal DNA fragmentation, the percentage of apoptotic hepatocytes, serum alanine transaminase (ALT) activity, and mortality after Fas stimulation. Despite a similar decrease in hepatic glutathione, administration of a single dose of phorone 1 hour before the anti-Fas antibody did not change p53 or Bax, and did not enhance Fas-induced mitochondrial permeability transition and toxicity. However, 4 repeated doses of phorone (causing more prolonged glutathione depletion) increased Bax and Fas-mediated toxicity. In conclusion, a chronic SAA(-) diet, but not acute phorone administration, increases p53 and Bax, and enhances Fas-induced mitochondrial permeability transition and apoptosis. Thiol depletion could cause oxidative stress that requires several hours to increase p53; the latter induces Bax, which translocates to mitochondria after Fas stimulation.
Killing of Dendritic Cells
Authors: Franca Ronchese, Ian F. Hermans
Journal: The Journal of Experimental Medicine (2001)

Although we normally think of dendritic cells (DCs; references ([1][1]) and ([2][2])) as the “initiators” of immune responses and of their activity as confined largely to interaction with naive T cells in secondary lymphoid organs, there is emerging evidence that DCs are also important players
Antigen-Specific Inhibition of Effector T Cell Function in Humans after Injection of Immature Dendritic Cells
Authors: Madhav V. Dhodapkar, Ralph M. Steinman, Joseph Krasovsky, Christian Munz, Nina Bhardwaj
Journal: The Journal of Experimental Medicine (2001)

Immunostimulatory properties of dendritic cells (DCs) are linked to their maturation state. Injection of mature DCs rapidly enhances antigen-specific CD4+ and CD8+ T cell immunity in humans. Here we describe the immune response to a single injection of immature DCs pulsed with influenza matrix peptide (MP) and keyhole limpet hemocyanin (KLH) in two healthy subjects. In contrast to prior findings using mature DCs, injection of immature DCs in both subjects led to the specific inhibition of MP-specific CD8+ T cell effector function in freshly isolated T cells and the appearance of MP-specific interleukin 10-producing cells. When pre- and postimmunization T cells were boosted in culture, there were greater numbers of MP-specific major histocompatibility complex tetramer-binding cells after immunization, but these had reduced interferon production and lacked killer activity. These data demonstrate the feasibility of antigen-specific inhibition of effector T cell function in vivo in humans and urge caution with the use of immature DCs when trying to enhance tumor or microbial immunity.
Intracellular multiplication of Legionnaires' disease bacteria (Legionella pneumophila) in human monocytes is reversibly inhibited by erythromycin and rifampin.
Authors: M A Horwitz, S C Silverstein
Journal: Journal of Clinical Investigation (1983)

We have previously reported that virulent egg yolk-grown Legionella pneumophila, Philadelphia 1 strain, multiplies intracellularly in human blood monocytes and only intracellularly under tissue culture conditions. In this paper, we have investigated the effect of erythromycin and rifampin on L. pneumophila-monocyte interaction in vitro; erythromycin and rifampin are currently the drugs of choice for the treatment of Legionnaires' disease. The intracellular multiplication of L. pneumophila is inhibited by erythromycin and rifampin, as measured by colony-forming units, whether the antibiotics are added just before or just after infection of monocytes with L. pneumophila, or 2 d after infection when L. pneumophila is in the logarithmic phase of growth in monocytes. Intracellular multiplication of L. pneumophila is inhibited by 1.25 microgram/ml but not less than or equal to 0.125 microgram/ml erythromycin and 0.01 microgram/ml but not less than or equal to 0.001 microgram/ml rifampin. These concentrations of antibiotics are comparable to those that inhibit extracellular multiplication of L. pneumophila under cell-free conditions in artificial medium; the minimal inhibitory concentration is 0.37 microgram/ml for erythromycin and 0.002 microgram/ml for rifampin. Multiplication of L. pneumophila in the logarithmic phase of growth in monocytes is inhibited within 1 h of the addition of antibiotics. Intracellular bacteria inhibited from multiplying by antibiotics are not killed. By electron microscopy, the bacteria appear intact within membrane-bound vacuoles, studded with ribosomelike structures. L. pneumophila multiplying extracellularly on artificial medium is killed readily by relatively low concentrations of erythromycin and rifampin; the minimal bactericidal concentration is 1 microgram/ml for erythromycin and 0.009 microgram/ml for rifampin. In contrast, L. pneumophila multiplying intracellularly is resistant to killing by these concentrations of erythromycin and rifampin or by concentrations equal to or greater than peak serum levels in humans. Extracellular L. pneumophila in stationary phase is also resistant to killing by erythromycin and rifampin. These findings, taken together with our previous work, indicate that, in vivo, L. pneumophila is resistant to killing by erythromycin and rifampin. Inhibition of L. pneumophila multiplication in monocytes by antibiotics is reversible; when the antibiotics are removed from infected monocyte cultures after 2 d, L. pneumophila resumes multiplication. This study indicates that patients with Legionnaires' disease under treatment with erythromycin and rifampin require host defenses to eliminate L. pneumophila, and that inadequate host defenses may result in relapse after cessation of therapy.
Too much is spent on older people's healthcare and too little on their social care, MPs are told
Authors: A. O'Dowd
Journal: BMJ (2011)

The present system for funding social care of adults is unsustainable and “nuts,” and far too much is spent on healthcare, the man who led a high profile inquiry into care has told MPs.

The respected economist Andrew Dilnot, chairman of the Commission on Funding of Care and Support—the body that recently reviewed the funding system for care and support in England—emphasised that the current system was in dire need of an overhaul when he appeared before the parliamentary health select committee on 6 December.

The Dilnot inquiry, which reported in July ( BMJ 2011;343:d4261, doi:10.1136/bmj.d4261), recommended a cap on individuals’ personal contributions to the costs of social care of around £35 000 (€41 000; $55 000) …
Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility
Authors: Luisa F. Escobar-Hoyos, Ruchi Shah, Lucia Roa-Peña, Elizabeth A. Vanner, Nilofar Najafian, Anna Banach, Erik Nielsen, Ramsey Al-Khalil, Ali Akalin, David Talmage, Kenneth R. Shroyer
Journal: Cancer Research (2015)

Abstract Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27KIP1 as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27KIP1. We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27KIP1 during G1 phase of the cell cycle. p27KIP1 lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27KIP1, whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27KIP1. In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27KIP1 were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27KIP1 to influence cervical cancer pathogenesis. Cancer Res; 75(17); 3650–62. ©2015 AACR.
The capillary transport system for free fatty acids in the heart.
Authors: C A Goresky, W Stremmel, C P Rose, S Guirguis, A J Schwab, H E Diede, E Ibrahim
Journal: Circulation Research (1994)

The nature of the process by which free fatty acids, which are tightly bound to albumin, traverse the endothelium of cardiac capillaries to reach the cardiac muscle cells, so that they are extracted to a net extent of approximately 40%, needs clarification. Previous studies have indicated that a membrane fatty acid-binding protein provides for carrier-mediated uptake of free fatty acids by isolated hepatocytes, cardiomyocytes, and jejunal mucosal cells. A monoclonal monospecific antibody was prepared against purified membrane fatty acid-binding protein from rat liver. Multiple-indicator dilution experiments were carried out in the isolated rat heart with labeled albumin, sucrose, and palmitate in the presence of control perfusate or perfusate containing either specific antibody or comparable nonspecific myeloma cell supernatant (each of the latter containing additional albumin, in identical concentrations). Analysis of the labeled-sucrose curves provided a permeability-surface area product for sucrose to which that for palmitate could be compared. In comparison with control supernatants, myeloma supernatant produced a minor inhibition of palmitate uptake, as a result of the increase in albumin concentration. The specific antibody, which contained identical albumin concentrations, produced a major inhibition of palmitate uptake, significantly greater than with the myeloma supernatant. The data indicate that the membrane fatty acid-binding protein mediates the transfer of free fatty acid across the endothelial cells of cardiac capillaries for presentation to heart muscle. Passive intramembrane lateral diffusion of palmitate could not provide an explanation for the findings.
A closer look at non-Hodgkin's lymphoma cases in a national Swedish systemic lupus erythematosus cohort: a nested case-control study
Authors: B Lofstrom, C Backlin, C Sundstrom, A Ekbom, I E Lundberg
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To investigate risk factors for non-Hodgkin's lymphoma (NHL) and analyse NHL subtypes and characteristics in patients with systemic lupus erythematosus (SLE). <h3>Methods:</h3> A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case control study on SLE patients who developed NHL during this observation period was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed. Tissue specimens on which the lymphoma diagnosis was based were retrieved and reclassified according to the WHO classification. NHLs of the subtype diffuse large B cell lymphoma (DLBCL) were subject to additional immunohistochemical staining using antibodies against bcl-6, CD10 and IRF-4 for further subclassification into germinal centre (GC) or non-GC subtypes. <h3>Results:</h3> 16 patients with SLE had NHL, and the DLBCL subtype dominated (10 cases). The 5-year overall survival and mean age at NHL diagnosis were comparable with NHL in the general population—50% and 61 years, respectively. Cyclophosphamide or azathioprine use did not elevate lymphoma risk, but the risk was elevated if haematological or sicca symptoms, or pulmonary involvement was present in the SLE disease. Two patients had DLBCL-GC subtype and an excellent prognosis. <h3>Conclusions:</h3> NHL in this national SLE cohort was predominated by the aggressive DLBCL subtype. The prognosis of NHL was comparable with that of the general lymphoma population. There were no indications of treatment-induced lymphomas. Molecular subtyping could be a helpful tool to predict prognosis also in SLE patients with DLBCL.
Therapeutic Synergism of Hyperthermia-cis-Platinum in a Mouse Tumor Model&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: D.S. Alberts, Y.M. Peng, H.S.G. Chen, T.E. Moon, T.C. Cetas, J.D. Hoeschele
Journal: JNCI Journal of the National Cancer Institute (1980)

A small-animal model was developed as a guide to whole-body hyperthermia in cancer patiens. Anesthetized DBA/2 mice were secured to a platform, and their hindlimbs were immersed in a 42.3 degrees C water bath for 30-60 minutes. Hindlimb hyperthermia reulted in steady-state rectal and femoral bone marrow and muscle temperatures of 42 degrees C and upper extremity muscle and esophagus temperatures of 41 degrees C. With this hyper thermia technique, the mouse spleen colony assay could be used to quantitate the lethality of hyperthermia and/or cis-dichloro-diammineplatinum(II) (cis-platinum) on clonogenic bone marrow and leukemia cells. Hyperthermia prior to cis-platinum administration increased cis-platinum inhibition of leukemia colony formation as much as 2 logs; however, antileukemia synergism ws greatest when cis-platinum administration immediately preceded hyperthermia and no evidence existd of synergism against normal bone marrow colonies. Correlative in vivo drug uptake studies showed a marked increase in leukemia cell uptake of 195mPt-cis-platinum at elevated temperatures, which suggested a potential mechanism for the apparent antileukemia synergism of cis-platinum and heat.
CYCLOSPORIN A IN OLIGURIC RENAL TRANSPLANT RECIPIENTS
Authors: BruceM. Hall, DavidJ. Tiller, A.G.R. Sheil, GeoffreyG. Duggin, JohnS. Horvath, JamesR. Johnson, MichaelS. Stephen, James May, JohnP. Rogers, JohnF. Thompson, John Boulas
Journal: The Lancet (1981)
Design of Folate-Linked Liposomal Doxorubicin to its Antitumor Effect in Mice
Authors: Atsushi Yamada, Yukimi Taniguchi, Kumi Kawano, Takashi Honda, Yoshiyuki Hattori, Yoshie Maitani
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Tumor cell targeting is a promising strategy for enhancing the therapeutic potential of chemotherapy agents. Polyethylene glycol (PEG)-coated (sterically stabilized) liposomes show enhanced accumulation on the surface of tumors, but steric hindrance by PEGylation reduces the association of the liposome-bound ligand with its receptor. To increase folate receptor (FR) targeting, we optimized the concentration and PEG spacer length of folate-PEG-lipid in liposomes. Experimental Design: Three types of folate-linked liposomal doxorubicin were designed and prepared by optimizing the concentration and PEG spacer length of folate-PEG-lipid in PEGylated or non-PEGylated liposomes and by masking folate-linked liposomes where the folate ligand is “masked” by adjacent PEG spacers. The liposome targeting efficacy was evaluated in vitro and in vivo. Results: In human oral carcinoma KB cells, which overexpress FR, modification with sufficiently long PEG spacer and a high concentration of folate ligand to non-PEGylated liposomes increased the FR-mediated association and cytotoxicity more than with PEGylated and masked folate-linked liposomes. On the contrary, in mice bearing murine lung carcinoma M109, modification with the folate ligand in PEGylated and masked folate-linked liposomes showed significantly higher antitumor effect than with non-PEGylated liposomes irrespective of the length of time in the circulation after intravenous injection. Conclusions: The results of this study will be beneficial for the design and preparation of ligand-targeting carriers for cancer treatment.
TNF-α blockade in chronic granulomatous disease–induced hyperinflammation: Patient analysis and murine model
Authors: Christine Deffert, Maria L. Olleros, Yuan Huiping, François R. Herrmann, Dina Zekry, Irene Garcia, Karl-Heinz Krause, Michela G. Schäppi
Journal: Journal of Allergy and Clinical Immunology (2011)
CLINICAL AND ANGIOGRAPHIC RESULTS AFTER HYBRID CORONARY REVASCULARIZATION: A NEW PARADIGM FOR THE TREATMENT OF SELECTED PATIENTS WITH MULTIVESSEL CORONARY DISEASE
Authors: Michael E. Halkos, John D. Puskas, John S. Douglas, Thomas Vassiliades, Chandan Devireddy, Aloke Finn, Robert A. Guyton, Henry Liberman
Journal: Journal of the American College of Cardiology (2013)