tbuckley/cabot-search huggingface dataset:
Long-term Physiologically Regulated Expression of the Low-density Lipoprotein Receptor In Vivo Using Genomic DNA Mini-gene Constructs
Authors: Olivia C Hibbitt, Eileen McNeil, Michele MP Lufino, Len Seymour, Keith Channon, Richard Wade-Martins
Journal: Molecular Therapy (2009)

Familial hypercholesterolemia (FH) is a condition caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Expression of LDLR is highly regulated and excess receptor expression is cytotoxic. To incorporate essential gene regulation into a gene therapy vector for FH, we generated vectors in which the expression of therapeutic human LDLR gene, or luciferase reporter gene, is driven by 10 kb of human LDLR genomic DNA encompassing the promoter region including elements essential for physiologically regulated expression. Using luciferase expression and specific LDL binding and internalization assays, we have shown in vitro that the genomic promoter element confers long-term, physiologically regulated gene expression and complementation of receptor deficiency in culture for 240 cell-generations. This was demonstrated in the presence of sterols or statins, modifiers of LDLR promoter activity. In vivo, we demonstrate efficient liver-specific delivery and expression of luciferase following hydrodynamic tail-vein injection and confirm that expression from the LDLR promoter element is sensitive to statin administration. We also demonstrate long-term LDLR expression from the 10-kb promoter element up to 9 months following delivery. The vector system that we describe provides the efficient delivery, long-term expression, and physiological regulation required for a successful gene therapy intervention for FH.
ETC-1002 LOWERS LDL-C MORE THAN EZETIMIBE IN PATIENTS WITH HYPERCHOLESTEROLEMIA WITH OR WITHOUT STATIN INTOLERANCE AND HAS A SIMILAR SAFETY AND TOLERABILITY PROFILE
Authors: Paul Thompson, Christie Ballantyne, James McKenney, David Orloff, Diane MacDougall, Janice Margulies, Jeffrey Hanselman, Roger Newton
Journal: Journal of the American College of Cardiology (2015)
DETECTION OF EXTRASYSTOLE OF HEART IN RELATION TO DISEASES OF BILE PASSAGES AND DUODENAL ULCER
Authors: Moses Behrend
Journal: JAMA (1924)

<h3>To the Editor:</h3> —The important contribution of Drs. Straus and Hamburger inThe Journal, March 1, is timely and of considerable practical value. In July, 1923, I read a paper entitled "Some Problems in Gallbladder Disease, Their Operative Treatment and Complications," before the Lake Keuka Medical and Surgical Association, Lake Keuka, N. Y. In this paper it was stated that a diseased gallbladder may act as a source of focal infection, acting on the heart, producing what is known as an extrasystole. After the operation of cholecystectomy, the extrasystole entirely disappeared. In one of the cases there was a coexistent duodenal ulcer. The cardiographic work was performed by Dr. Joseph Wolffe. The paper, which has been in the hands of the publishers for the last six months, will appear shortly.
Biocompatibility and buffers: Effect of bicarbonate-buffered peritoneal dialysis fluids on peritoneal cell function
Authors: Achim Jörres, Thorsten O. Bender, André Finn, Janusz Witowski, Sibylle Fröhlich, Gerhard M. Gahl, Ulrich Frei, Heiko Keck, Jutta Passlick-Deetjen
Journal: Kidney International (1998)
Protective Role of IgA
Authors: Kim M. Debelak-Fehir
Journal: JAMA (1974)

<h3>To the Editor.—</h3> Binkley and Stigler (228:1228, 1974) have suggested an interesting maternal-fetal relationship in regard to transfer-factor deficiency in neonatal infectious disease. However, they have neglected to mention the role of IgA, the major immunoglobulin coating mucous membranes. IgA provides a primary defense mechanism against bacterial and viral infections. It has been shown that the transfer of specific immunity via milk will prevent diarrhea caused by pathogenic types of<i>Escherichia coli (Adv Immunol</i>9:1, 1968). Furthermore, Campbell et al (<i>Science</i>125:932, 1957) have shown that immunization of the mammary gland to bacteria in the infant's mouth can induce specific antibody in milk within eight hours. Although transfer factor may possibly be transferred via the placenta or colostrum, the role of IgA in providing protection to the neonate should not be overlooked.
ON THE TREATMENT OF CIRRHOSIS OF THE LIVER.
Authors: J. H. MUSSER
Journal: JAMA (1901)

Cirrhosis of the liver—often called alcoholic cirrhosis —is seen under the following circumstances: 1, without symptoms, the patient having died from other causes; 2, without symptoms until a climax is reached in the sudden outbreak of gastric or intestinal hemorrhage, terminating the life of the patient; 3, with symptoms due to obstruction of the portal vessels; 4, with those due to catarrh and obstruction of the bile ducts; 5, with combined portal and duct symptoms; 6, in very rare instances, a certain ill-defined cachexia, symptoms of auto-intoxication and the physical signs of a contracted liver, may suggest in a patient of alcoholic habits the presence of this form of cirrhosis. We will defer the consideration of the symptomatic treatment until a later portion of the paper. The morbid process in alcoholic cirrhosis is clearly defined and if the diagnosis of the first stage, so-called, could be positively determined indications for
The Microorganism
Authors: WEN LAN LOU WANG
Journal: Annals of Internal Medicine (1979)

The Legionnaires' disease (LD) bacterium can now be readily cultured on artificial media. Studies were done to define the growth and survival of the LD bacterium in these media and ascertain its susceptibility to disinfecting agents. Growth-curve studies of the Philadelphia 1 strain using Mueller-Hinton broth with ferric pyrophosphate and L-cysteine (Feeley-Gorman broth) showed a lag phase of less than 24 h, a generation time of 3.8 h during the logarithmic phase, a plateau of 2 X 10' organisms per millilitre, and continued viability for as long as 110 d. Viability on chocolate agar with 1% hemoglobin and 2% IsoVitaleX® added reached 150 d. This strain was susceptible to a variety of commonly recommended hospital and laboratory disinfectants, often in low concentrations. These investigations suggest that prolonged survival may occur in natural as well as artificial milieus and that low concentrations of phenolics, quaternary ammonium compounds, glutaraldehyde, formaldehyde, and hypochlorite could eradicate potential reservoirs for human infection.
Thrombolytic profiles of clot-targeted plasminogen activators. Parameters determining potency and initial and maximal rates.
Authors: P Holvoet, M Dewerchin, J M Stassen, H R Lijnen, T Tollenaere, P J Gaffney, D Collen
Journal: Circulation (1993)

Targeting of plasminogen activators to the thrombus by means of fibrin-specific monoclonal antibodies may enhance their thrombolytic potency. The kinetics of clot binding of two human fibrin-specific monoclonal antibodies (MA-12B3 and MA-15C5) and of clot lysis with their chemical 1:1 stoichiometric complexes with recombinant single-chain urokinase-type plasminogen activator (rscu-PA) (rscu-PA/MA-12B3 and rscu-PA/MA-15C5) were determined in hamsters and rabbits. Thrombolytic potencies, maximal rates of clot lysis, and the duration of the lag phases before clot lysis of the antibody/rscu-PA conjugates were compared with those of rscu-PA and tissue-type plasminogen activator (rt-PA).Bolus injection of 7.5 micrograms of 125I-labeled antibody in rabbits with an extracorporeal arteriovenous loop containing a 0.3-mL human plasma clot produced clot-to-blood ratios of 6.6 +/- 1.0 (mean +/- SEM) for MA-12B3 and 1.1 +/- 0.15 for MA-15C5 (p < 0.001 versus MA-12B3) within 6 hours. Progressive digestion of the clot did not alter the binding of MA-12B3 but resulted in as much as a 10-fold increase of the binding of MA-15C5. The conjugates infused intravenously over 90 minutes in hamsters with a human plasma clot in the pulmonary artery produced dose-related in vivo clot lysis. Thrombolytic potencies (maximal slope of the percent lysis versus dose in milligrams of u-PA equivalent per kilogram body weight) were 2,500 +/- 440 for rscu-PA/MA-12B3, 3,600 +/- 640 for rscu-PA/MA-15C5 (p = NS vs. rscu-PA/MA-12B3), 60 +/- 8 for rscu-PA (p < 0.001 versus both conjugates), and 380 +/- 66 for rt-PA (p < 0.001 versus both conjugates). The plasma clearances of the conjugates were fourfold to sixfold slower than those of rscu-PA and rt-PA. Maximal rates of clot lysis, determined by continuous external radioisotope scanning over the thorax, were 0.90 +/- 0.13%, 0.91 +/- 0.17%, 0.84 +/- 0.12%, and 1.1 +/- 0.16% lysis per minute for rscu-PA/MA-12B3, rscu-PA/MA-15C5, rscu-PA, and rt-PA, respectively; these maximal rates were obtained with 0.016, 0.016, 1.0, and 0.25 mg/kg, respectively, and were associated with minimal lag phases of 18 +/- 3.2, 28 +/- 4.9, 34 +/- 3.7, and 25 +/- 3.9 minutes, respectively.The thrombolytic potency of the rscu-PA/antifibrin conjugates is determined by their clearance, as well as by rate and extent of initial binding to clots and by changes in binding during clot lysis. Clot targeting of rscu-PA with fibrin-specific antibodies increases its thrombolytic potency but does not alter the maximal rate or the minimal lag phase of clot lysis. These parameters appear to be independent of the nature of the plasminogen activator and of targeting.
Depression
Authors: Matthew Owen Howard
Journal: JAMA (2003)

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[757] UCP2 INDUCES MITOCHONDRIAL UNCOUPLING DURING NONALCOHOLIC STEATOHEPATITIS: AN ADAPTATIVE MECHANISM TO REDUCE OXIDATIVE STRESS BUT PRODUCING DEPLETION OF ATP
Authors: G. Serviddio, F. Bellanti, R. Tamborra, A.D. Romano, T. Rollo, N. Capitanio, G. Vendemiale, E. Altomare
Journal: Journal of Hepatology (2007)
Performance evaluation of a new rapid urine test for chlamydia in men: prospective cohort study
Authors: E.-C. Nadala, B. T Goh, J.-P. Magbanua, P. Barber, A. Swain, S. Alexander, V. Laitila, C.-E. Michel, L. Mahilum-Tapay, I. Ushiro-Lumb, C. Ison, H. H Lee
Journal: BMJ (2009)

To evaluate the performance of a rapid test for chlamydia with first void male urine samples as a potential tool for diagnosis and screening of chlamydial infection in men.Evaluation of test performance in prospective cohort study. Settings A young people's sexual health centre (site 1) and a genitourinary medicine clinic (site 2) in the United Kingdom.1211 men aged 16-73 attending either of the two sites.Sensitivity, specificity, positive predictive value, and negative predictive value of the Chlamydia Rapid Test versus polymerase chain reaction assay. Relation between the visual signal of the Chlamydia Rapid Test and organism load.Detection rates for Chlamydia trachomatis infection with polymerase chain reaction were 4.4% (20/454) at site 1 and 11.9% (90/757) at site 2. Compared with polymerase chain reaction assay, the resolved sensitivity, specificity, positive predictive value, and negative predictive value of the Chlamydia Rapid Test was 82.6% (90/109), 98.5% (1085/1102), 84.1% (90/107), and 98.3% (1085/1104), respectively. The organism load in first void urine samples that were positive for chlamydia ranged from 7.28x10(2) to 6.93x10(6) plasmids/ml and correlated significantly with the visual signal of the Chlamydia Rapid Test (r=0.7897, P<0.001).The performance of the new Chlamydia Rapid Test with first void male urine samples indicates that it would be an effective diagnostic tool for chlamydial infection in men. The availability of test results within an hour allows for immediate treatment and contact tracing, potentially reducing the risks of persistent infection and onward transmission. The test could also provide a simple and reliable alternative to nucleic acid amplification assays for testing of male urine in chlamydial screening programmes in high prevalence settings.
A Distinct Metabolic Signature of Human Colorectal Cancer with Prognostic Potential
Authors: Yunping Qiu, Guoxiang Cai, Bingsen Zhou, Dan Li, Aihua Zhao, Guoxiang Xie, Houkai Li, Sanjun Cai, Dong Xie, Changzhi Huang, Weiting Ge, Zhanxiang Zhou, Lisa X. Xu, Weiping Jia, Shu Zheng, Yun Yen, Wei Jia
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Metabolic phenotyping has provided important biomarker findings, which, unfortunately, are rarely replicated across different sample sets due to the variations from different analytical and clinical protocols used in the studies. To date, very few metabolic hallmarks in a given cancer type have been confirmed and validated by use of a metabolomic approach and other clinical modalities. Here, we report a metabolomics study to identify potential metabolite biomarkers of colorectal cancer with potential theranostic value. Experimental Design: Gas chromatography–time-of-flight mass spectrometry (GC–TOFMS)–based metabolomics was used to analyze 376 surgical specimens, which were collected from four independent cohorts of patients with colorectal cancer at three hospitals located in China and City of Hope Comprehensive Cancer Center in the United States. Differential metabolites were identified and evaluated as potential prognostic markers. A targeted transcriptomic analysis of 29 colorectal cancer and 27 adjacent nontumor tissues was applied to analyze the gene expression levels for key enzymes associated with these shared metabolites. Results: A panel of 15 significantly altered metabolites was identified, which demonstrates the ability to predict the rate of recurrence and survival for patients after surgery and chemotherapy. The targeted transcriptomic analysis suggests that the differential expression of these metabolites is due to robust metabolic adaptations in cancer cells to increased oxidative stress as well as demand for energy, and macromolecular substrates for cell growth and proliferation. Conclusions: These patients with colorectal cancer, despite their varied genetic background, mutations, pathologic stages, and geographic locations, shared a metabolic signature that is of great prognostic and therapeutic potential. Clin Cancer Res; 20(8); 2136–46. ©2014 AACR.
Abstract 4671: Radioguided detection of lymph node metastasis in non-small cell lung cancer.
Authors: Chukwumere Nwogu, Todd Demmy, Sai Yendamuri, Wei Tan, Paul Bogner, Elisabeth Dexter, Anthony Picone, Mark Hennon, Alan Hutson, Mary Reid, Richard Cheney, Alex Adjei
Journal: Cancer Research (2013)

Abstract Background: Lymph node staging provides the most important prognostic information in patients with loco-regional non-small cell lung cancer. We hypothesized that gamma radiation detection using an intra-operative hand-held gamma probe following intravenous 18F-fluorodeoxyglucose (FDG) injection would identify lymph nodes containing metastases in a much more sensitive manner than standard pathological practices. We compared the accuracy of detecting thoracic lymph node metastases using positron emission tomography- computed tomography (PET-CT) versus the gamma probe. Methods: One hundred patients with resectable lung cancers had pre-operative positron emission tomography-computed tomography (PET-CT) and mediastinoscopy. 10mCi of FDG was injected on the day of surgery. A handheld gamma probe detected increased FDG uptake within thoracic lymph nodes during pulmonary resection procedures. The lymph nodes that demonstrated increased FDG uptake, but were non-malignant by conventional H&amp;E staining underwent further serial sectioning, immunohistochemistry (IHC) and RT-PCR (reverse transcriptase - polymerase chain reaction). Sensitivity and specificity for lymph node metastasis detection by PET-CT and the gamma probe were calculated. Results: Three patients had metastatic lymphadenopathy detected at mediastinoscopy, so their procedures were aborted, while the others proceeded to lung resection and complete lymphadenectomy. Fifteen additional patients had lymph node involvement on routine pathologic analysis. IHC and RT-PCR detected micrometastatic lymph node disease in 4 and 29 patients, respectively. Using RT-PCR as the gold standard, the sensitivity and specificity of PET-CT for detection of lymph node metastasis were 11% and 98% respectively, in contrast to 38% and 50% respectively for the gamma probe. Conclusion: The intra-operative hand held gamma probe is more sensitive but less specific than PET-CT in detecting lymph node metastasis from lung cancer. Its overall accuracy was low, resulting in limited up-staging of patients. RT-PCR analysis of FDG-avid lymph nodes for epithelial markers increased the clinical utility of this probe in detecting micrometastasis. Such up-staged patients could derive a survival benefit from adjuvant chemotherapy. More specific radioisotopes are being developed to improve the clinical utility of this technique. Citation Format: Chukwumere Nwogu, Todd Demmy, Sai Yendamuri, Wei Tan, Paul Bogner, Elisabeth Dexter, Anthony Picone, Mark Hennon, Alan Hutson, Mary Reid, Richard Cheney, Alex Adjei. Radioguided detection of lymph node metastasis in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4671. doi:10.1158/1538-7445.AM2013-4671
Effect of alterations in the thyroid state on the intrinsic contractile properties of isolated rat skeletal muscle
Authors: Herman K. Gold, James F. Spann, Eugene Braunwald
Journal: Journal of Clinical Investigation (1970)

Contractile properties of soleus muscles isolated from 31 euthyroid (EU), 20 hyperthyroid (HT), and 18 myxedematous (MY) rats were studied in a myograph. At 100 stimuli/sec maximum isometric tension was essentially identical in EU (17.2 +/-0.5 g/mm(2)) and HT (17.7 +/-0.5 g/mm(2)) muscles, but was significantly depressed in MY muscles (11.5 +/-0.7 g/mm(2)). The rate of tension development was increased in HT (103 +/-4.5 g/sec per mm(2)) as compared to both EU (86.2 +/-4.6 g/sec per mm(2)) and MY (38.4 +/-2.2 g/sec per mm(2)) muscles, while the duration of the active state was shortened in HT (77.1 +/-2.3 msec) as compared to EU (105.1 +/-1.1 msec) muscles and was prolonged in MY muscles (153.3 +/-6.0 msec). The mean rate of isometric relaxation was 26.5 +/-4.9 g/mm(2) per sec in EU muscles, more rapid in HT muscles (33.1 +/-1.3 g/sec per mm(2)), and slower in MY muscles (16.0 +/- g/mm(2) per sec). The fusion frequency was greater in HT muscles, averaging 68.5 +/-3.6 stimuli/sec compared to EU muscles (38.1 +/-1.2 stimuli/sec) and to MY muscles (33.3 +/-4.0 stimuli/sec). At 40 stimuli/sec tension averaged 16.4 +/-0.8 g/mm(2) in EU muscles while at the same frequency tension was reduced in HT muscle, averaging 14.2 +/-0.5 g/mm(2). All differences were significant (P < 0.01). In conclusion, HT and MY result in profound alterations in the intrinsic contractile properties of skeletal muscle. While tension in HT muscles is maintained in vitro at a stimulus frequency of 100 stimuli/sec, the reduction in duration of active state may lower tension in vivo by preventing complete fusion of contractile events. In MY tension is reduced as a consequence of the lowered intensity of the active state. These changes explain, at least in part, the weakness of muscle activity in both HT and MY.
Productive Infection of Neonatal CD8+ T Lymphocytes by HIV-1
Authors: Liang Peng Yang, James L. Riley, Richard G. Carroll, Carl H. June, James Hoxie, Bruce K. Patterson, Yusei Ohshima, Richard J. Hodes, Guy Delespesse
Journal: The Journal of Experimental Medicine (1998)

CD8+ T lymphocytes confer significant but ultimately insufficient protection against HIV infection. Here we report that activated neonatal CD8+ T cells can be productively infected in vitro by macrophage-tropic (M-tropic) HIV-1 isolates, which are responsible for disease transmission, whereas they are resistant to T cell–tropic (T-tropic) HIV strains. Physiological activation of CD8-α/β+ CD4− T cell receptor–α/β+ neonatal T cells, including activation by allogeneic dendritic cells, induces the accumulation of CD4 messenger RNA and the expression of CD4 Ag on the cell surface. The large majority of anti-CD3/B7.1–activated cord blood CD8+ T cells coexpress CD4, the primary HIV receptor, as well as CCR5 and CXCR4, the coreceptors used by M- and T-tropic HIV-1 strains, respectively, to enter target cells. These findings are relevant to the rapid progression of neonatal HIV infection. Infection of primary HIV-specific CD8+ T cells may compromise their survival and thus significantly contribute to the failure of the immune system to control the infection. Furthermore, these results indicate a previously unsuspected level of plasticity in the neonatal immune system in the regulation of CD4 expression by costimulation.
Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions.
Authors: P S Seifert, F Hugo, J Tranum-Jensen, U Zâhringer, M Muhly, S Bhakdi
Journal: The Journal of Experimental Medicine (1990)

The major characteristics of human atherosclerotic lesions are similar to those of a chronic inflammatory reaction, namely fibrosis, mesenchymal cell proliferation, the presence of resident macrophages, and cell necrosis. Atherosclerosis exhibits in addition the feature of lipid (mainly cholesterol) accumulation. The results of the present report demonstrate that a specific cholesterol-containing lipid particle present in human atherosclerotic lesions activates the complement system to completion. Thus, lipid could represent a stimulatory factor for the inflammatory reaction, whose underlying mechanistic basis may be, at least in part, complement activation. The complement-activating lipid was purified from saline extracts of aortic atherosclerotic lesions by sucrose density gradient centrifugation followed by molecular sieve chromatography on Sepharose 2B. It contained little protein other than albumin, was 100-500 nm in size, exhibited an unesterified to total cholesterol ratio of 0.58 and an unesterified cholesterol to phospholipid ratio of 1.2. The lipid, termed lesion lipid complement (LCA), activated the alternative pathway of complement in a dose-dependent manner. Lesion-extracted low density lipoprotein (LDL) obtained during the purification procedure failed to activate complement. Specific generation of C3a desArg and C5b-9 by LCA indicated C3/C5 convertase formation with activation proceeding to completion. Biochemical and electron microscopic evaluations revealed that much of the C5b-9 present in atherosclerotic lesions is membraneous, rather than fluid phase SC5b-9. The observations reported herein establish a link between lipid insudation and inflammation in atherosclerotic lesions via the mechanism of complement activation.