tbuckley/cabot-search huggingface dataset:
A rat knock out model of human familial adenomatous polyposis
Authors: James Amos-Landgraf, Lawrence Kwong, Jill Haag, Michael Gould, William Dove
Journal: Cancer Research (2006)

4844   Humans with mutations in the Adenomatous Polyposis Coli (APC) gene get hundreds to thousands of adenomas in the colon and develop colorectal cancer, however current mouse models of human intestinal cancer, including the ApcMin model developed at the McArdle Laboratory, develop lesions primarily in the small intestine and have never been observed to metastasize. We have generated a rat knock out of Apc in which the animals develop primarily colonic tumors by 90 days of age. We have termed this allele Pirc for polyposis in rat colon. Our group has recently developed the technology to knock out rat genes of interest through mutagenesis with N-ethyl-N-nitrosourea (ENU). We screened 2530 base pairs of exon 15 of the rat Apc gene from genomic DNA in the offspring of mutagenized Fisher-344 inbred rats using a universal vector gap repair yeast truncation assay (Biotechniques. 2004 Sep;37(3):383-8). Screening of 1360 progeny yielded a single mutant with an A to T transversion changing a lysine to a stop codon at amino acid position 1137. Upon abstract submission the founder male is 260 days old, remains fertile, and has successfully transmitted the mutation to 60 progeny. Ten of the resulting mutant N1 animals were brother-sister mated and their offspring confirmed that the ApcPirc allele is homozygous lethal. Necropsy of six N1 ApcPirc heterozygotes, three at 90 days and three at 130 days of age, identified an average of 6 visible adenomatous polyps in the colon, while six wild type age-matched littermates were tumor-free. Histological immunofluorescence staining of four of the tumors for β-catenin confirmed the tumor-associated relocalization of β-catenin from the lateral membrane to the cytoplasm and nucleus. The affected animals showed neither visible lesions nor β-catenin relocalization in the small intestine. Pirc/+ animals treated somatically with ENU at 2 weeks of age develop in excess of 100 microadenomas in the distal small intestine and colon by 60 days post injection. No lesions were seen in the ENU treated non-carriers. ApcPirc was successfully crossed to Wistar-Furth and intercrossing of the F1 carriers determined that the ApcPirc allele was homozygous lethal in the F2 progeny. Ongoing studies include the examination of tumor number and distribution in older carrier N1 and F1 animals as well as the effects of a high fat diet on N1 animals. The primary localization of tumors to the colon recapitulates human intestinal cancer, addressing one of the major drawbacks of ApcMin and other mouse models that have a primarily small-intestinal distribution. The colonic phenotype and longer life span of the ApcPirc rat combined with the growing resources of rat genetics, genomics and biology indicate that the rat may be an advantageous model for human tumor progression and experimental treatment of colon cancer.
Abstract 3132: Paraoxonase-1 Activity Is not Independently Related with the Risk of Future Coronary Artery Disease
Authors: Rakesh S Birjmohun, Menno Vergeer, Erik S Stroes, Michael W Tanck, Nicholas J Wareham, Robert Luben, Manjinder S Sandhu, John J Kastelein, Kay-Tee Khaw, S M Boekholdt
Journal: Circulation (2008)

Background Paraoxonase-1 (PON1) is a potent antioxidant enzyme bound to high-density lipoprotein (HDL). Its activity, but not its concentration, is controlled by the PON1 Q192R polymorphism. PON1 is considered to protect against atherogenesis, but it is unclear whether this relation is independent of its carrier, HDL. Objective To evaluate the predictive value of PON1 for coronary artery disease (CAD) we assessed PON1 activity and genotype (Q192R polymorphism) in a large cohort. Methods and results We performed a case-control study nested in the prospective EPIC-Norfolk cohort. Cases (n = 1138) were apparently healthy men and women aged 45–79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n=2237) were matched by age and sex. Serum PON1 activity was lower in cases vs. controls (59.9 ± 44.6 U/L vs. 63.4 ± 46.7 U/L, p=0.020) and correlated with HDL cholesterol (r= 0.16, p&lt;0.0001). Whereas the PON1 Q192R polymorphism strongly controlled PON1 activity (QQ: 27 ± 9, QR: 87 ± 27 and RR 152 ± 44 U/L), it was not related to the risk of future CAD (Odds Ratio [OR] per R allele 0.98 [0.84–1.15], p=0.84). Using conditional logistic regression, quartiles of PON1 activity showed a modest inverse relation with CAD risk (OR for the highest vs. the lowest quartile 0.77 [0.63– 0.95], p=0.013; p for trend over quartiles 0.064). PON1 activity adjusted for Q192R genotype - a proxy for PON1 concentration -correlated better with HDL cholesterol (r=0.29, p&lt;0.0001) and strongly predicted CAD risk (OR for the highest versus the lowest quartile 0.72 (0.58 – 0.91), p for trend over quartiles = 0.005). However, this relation was abolished after adjustment for HDL related parameters (HDL particle number, HDL cholesterol, HDL size and apolipoprotein A-I; OR for highest vs. lowest quartile 0.87 [0.66 –1.16], p for trend over quartiles = 0.13). Conclusion In the largest prospective study to date, we show that PON1 activity inversely relates to CAD risk, but not independently of HDL, presumably due to its close association with the HDL particle. Since the Q192R polymorphism profoundly affects lifelong PON1 activity, our inability to demonstrate a relation between the Q192R polymorphism and CAD risk suggests that PON1 activity is not a causal factor in atherogenesis.
Thioridazine and sexual dysfunction
Authors: J Kotin, D E Wilbert, D Verburg, S M Soldinger
Journal: American Journal of Psychiatry (1976)

The authors found a 60% incidence of difficulties in sexual functioning in 57 male patients who had taken thioridazine. Ejaculatory problems were the most frequent dysfunction; a third of these patients experienced retrograde ejaculation. The incidence of sexual difficulties in 64 patients who had taken other major tranquilizers was only 25%. None of the latter group experienced retrograde ejaculation-most had difficulty achieving and maintaining erection. The authors recommend consideration of the possibility of sexual dysfunction in patients given thioridazine.
Effect of Acetaminophen on CGM Glucose in an Outpatient Setting
Authors: David M. Maahs, Daniel DeSalvo, Laura Pyle, Trang Ly, Laurel Messer, Paula Clinton, Emily Westfall, R. Paul Wadwa, Bruce Buckingham
Journal: Diabetes Care (2015)

Acetaminophen (paracetamol) interferes with continuous glucose monitor (CGM) sensing, resulting in falsely elevated CGM glucose values in both sensors currently approved by the U.S. Food and Drug Administration (FDA). In amperometric glucose biosensors, particularly those measuring hydrogen peroxide, acetaminophen’s phenolic moiety is oxidized at the sensing electrode, producing an electrochemical signal not related to glucose (1). Limited published data exist documenting the magnitude of the effect of acetaminophen on CGM glucose (2), especially in the outpatient setting with contemporary sensor technology. Currently, the FDA recommends that insulin dosing decisions are based on blood glucose (BG) meter values, not CGM glucose values. Given the common use of acetaminophen, its interference with CGM sensing has significant clinical implications for patients who use CGM. To better understand this effect, we performed an acetaminophen challenge as part of an outpatient study designed to investigate the potential challenges to closed-loop systems, which use CGM sensor …
Peripheral blood cell signatures as novel breast cancer biomarkers
Authors: Heather LaBreche, Eran Andrechek, Jeffrey Marks, Joseph Nevins
Journal: Clinical Cancer Research (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

B13 

Background: In 2007, over 40,000 women died from breast cancer in the United States alone. Detecting breast cancer at an early stage, or when the tumor is small, dramatically increases chances for survival, but current technologies, including mammography, have limited sensitivity and specificity. Our approach has been to use peripheral blood cells (PBCs) as a means of early breast cancer detection. PBCs act as biosensors by responding to both physiological changes and environmental exposures. These responses can be detected by microarray analysis as specific gene expression patterns, or signatures, that reflect the presence of a tumor. Methods: We used Affymetrix M430 2.0 Gene Chips to analyze gene expression in peripheral blood cell samples collected from either transgenic mice with spontaneous mammary adenocarcinomas (n= 15) or tumor-free, matched control mice (n= 15). In addition, we used Affymetrix Human U133 Plus 2.0 Gene Chips to analyze gene expression in peripheral blood cell samples collected from patients diagnosed by biopsy with either invasive breast cancer (n= 15) or a benign breast abnormality (n= 15). Expression data was subject to binary regression analysis, including leave-one-out crossvalidation, as well as validation in an independent sample set. Optimal cutoffs for predicted probabilities were calculated using receiver-operator characteristic curves. Results: We identified a 250-probe signature associated with the presence of spontaneous tumors in a transgenic mouse model of breast cancer. This signature is capable of accurately distinguishing tumor-bearing mice from tumor-free controls in a leave-one-out crossvalidation. The signature was validated in an independent sample set, where it performed with an overall accuracy of 100%. We have also developed a human breast cancer signature, which is able to accurately distinguish patients with invasive breast cancer from those with benign breast abnormalities in a leave-one-out crossvalidation. Conclusions: Our findings indicate that gene expression signatures can be derived from PBCs and can be used to not only distinguish between breast cancer patients and disease-free individuals, but also to predict cancer status. We describe breast cancer signatures derived from both mouse and human peripheral blood cells, demonstrating for the first time that this phenomenon is common to both species, suggesting that mouse models represent an opportunity to complement human biomarker studies, as well as a system in which mechanisms of tumor and PBC interaction may be revealed. These results support the concept of using blood-derived signatures as clinical diagnostic tests, although further investigation is needed to establish the specificity of such tests. We believe this is an approach to the development of clinical biomarkers for accurate, effective and noninvasive breast cancer detection.
Shape-directed compartmentalized delivery of a nanoparticle-conjugated small-molecule activator of an epigenetic enzyme in the brain
Authors: Piyush Chaturbedy, Manoj Kumar, Krishnachary Salikolimi, Sadhan Das, Sarmistha Halder Sinha, Snehajyoti Chatterjee, B.S. Suma, Tapas K. Kundu, Muthusamy Eswaramoorthy
Journal: Journal of Controlled Release (2015)
Increased vitamin D levels at birth and in early infancy increase offspring allergy risk—evidence for involvement of epigenetic mechanisms
Authors: Kristin M. Junge, Tobias Bauer, Stefanie Geissler, Frank Hirche, Loreen Thürmann, Mario Bauer, Saskia Trump, Matthias Bieg, Dieter Weichenhan, Lei Gu, Jan-Philipp Mallm, Naveed Ishaque, Oliver Mücke, Stefan Röder, Gunda Herberth, Ulrike Diez, Michael Borte, Karsten Rippe, Christoph Plass, Carl Hermann, Gabriele I. Stangl, Roland Eils, Irina Lehmann
Journal: Journal of Allergy and Clinical Immunology (2015)
Abstract 19502: A Human Induced Pluripotent Stem Cell-derived Cardiomyocyte Model of Pompe Disease.
Authors: Kunil K Raval, Chad H Koonce, Jianhua Zhang, Junying Yu, Timothy Kamp, James A Thomson
Journal: Circulation (2010)

Background: Infantile Pompe disease is an autosomal recessive genetic disorder characterized by a lack of acid alpha glucosidase (GAA) activity, the sole enzyme responsible for degrading glycogen w...
Abstract 4182: Unhealed Plaque Ruptures After Stenting in Acute Myocardial Infarction Assessed by Intracoronary Optical Coherence Tomography: Incidence, Predictors, and Clinical Implication
Authors: Takashi Kubo, Hiram G Bezera, Giulio Guagliumi, Vasile Sirbu, Giuseppe Musumeci, Orazio Valsecchi, Alessandro Aprile, Hiroyuki Kyono, Satoko Tahara, Akiko Maehara, Gary S Mintz, Alexandra J Lansky, Ovidiu Dressler, Roxana Mehran, Marco Costa, Gregg W Stone
Journal: Circulation (2009)
Abstract 17492: Alirocumab, a Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibody, Reduces Cholesterol Concentrations of Serum Remnant Lipoprotein Fractions, Very Low-Density Lipoproteins and Triglycerides
Authors: Peter P Toth, Sara Hamon, Steven R Jones, Seth S Martin, Parag H Joshi, Dan Gipe, Corinne Hanotin
Journal: Circulation (2013)

Introduction: Increased very low-density lipoprotein (VLDL) levels form part of a pattern of atherogenic dyslipidemia which predisposes to premature atherosclerosis. Remnant lipoproteins are produc...
Abstract 11397: PDE4 Controls Basal Cyclic AMP Levels and Beta-Adrenergic Signalling in Human Atrium
Authors: Cristina E Molina, Jerome Leroy, Wito Richter, Moses Xie, Colleen Scheitrum, Illkyu Lee, Christoph Maack, Catherine Rucker-Martin, Patrick Donzeau-Gouge, Leif Hove-Madsen, Ignacio Verde, Marco Conti, Gregoire Vandecasteele, Rodolphe Fischmeister
Journal: Circulation (2010)

Genetic studies have identified SNPs in the gene encoding the type 4D cAMP-specific phosphodiesterase (PDE4D) that confer an increased risk of cardioembolic stroke. Affected individuals were shown to exhibit a lower mRNA expression level for several PDE4D isoforms in their B-lymphocytes. However, the molecular and cellular basis for the association between a reduced PDE4D expression and stroke remains unknown. Because atrial fibrillation (AF) is the most common cause of cardioembolic stroke, we hypothesized that PDE4 inhibition in human atrial muscle might provide a rationale for AF and, in extension, cardioembolic stroke. Here we provide evidence that PDE4 is expressed in human atrial myocytes. PDE4D represents only a small portion of the total PDE activity in human atrium. However, of the four PDE4 subtypes (PDE4A-D), PDE4D is the major form expressed in this tissue. Pharmacological PDE4 inhibition with Ro 20–1724 (Ro, 10 µM) causes an increase in basal L-type Ca2+ channel current, ICa,L. Live cell imag...
Session II: Primary Hyperuricaemia and Gout: Comparison of Allopurinol and Probenecid
Authors: J. J. R. Duthie, J. T. Scott
Journal: Annals of the Rheumatic Diseases (1966)

After the introduction of allopurinol by the previous speakers, other clinical trials were carried out, and our own preliminary experience at the Postgraduate Medical School was presented to this Society 2 years ago (Hall, Holloway, and Scott, 1964).These studies confirmed the ability of allopurinol to lower the levels of serum uric acid (SUA) and urinary uric acid (UUA) rapidly with an increase in urinary oxypurine excretion.This increase, however, was not as large as the fall in UUA, so that there was a fall in overall purine excretion.In one or two patients severe gouty arthritis followed the commencement of therapy.Our further clinical investigations have followed two directions:(a) A therapeutic trial comparing the long-term effects of allopurinol with those of conventional uricosuric treatment in patients with uncomplicated gout;
Australia: government subsidises long term care by up to £22000 a year
Authors: Christopher Zinn
Journal: BMJ (2002)

The federal government is largely responsible for funding residential care for old people in Australia, helped by a combination of flat user fees and income tested fees.

Care homes for elderly people (known as “aged care homes”) can charge up to ${type:entrez-nucleotide,attrs:{text:A66000,term_id:4537990,term_text:A66000}}A66000 (£25300; $38000; €39000) a year to look after a high care resident, with the government paying a subsidy of up to ${type:entrez-nucleotide,attrs:{text:A57500,term_id:3713365,term_text:A57500}}A57500 (£22000) and the elderly person making up the difference, in what are known as “basic daily care fees.”

Residents thus contribute about 13% of the cost of their accommodation and care from their private income, savings, and pension. Those who do not have the full means tested pension may also have to pay an income tested fee, and high care residents with enough assets could also have to pay an accommodation charge.

High care patients with sufficient assets and income are expected to contribute a quarter of the cost of their accommodation and care.
Advances in H<sub>1</sub>-Antihistamines
Authors: F Estelle R Simons
Journal: New England Journal of Medicine (2004)

Histamine has an important role as a chemical messenger in physiologic responses, neurotransmission, allergic inflammation, and immunomodulation by way of the H1-receptor. Most H1-antihistamines, which are useful in treating these effects, possess similar efficacy in allergic rhinoconjunctivitis and chronic urticaria. However, there are clinically relevant differences among them in their pharmacology and safety profiles.
Rates of Clinically Apparent Venous Thromboembolism and Death Resulting from Pulmonary Embolism among Unselected Hospitalized Acutely Ill Medical Patients Versus Rates Predicted from Clinical Studies.
Authors: Franco Piovella, Frederick A. Anderson, Hervé Decousus, Gordon FitzGerald, Jean-François Bergmann, Ajay K. Kakkar, Alex C. Spyropoulos, Rainer B. Zotz, Frederick A. Spencer, Alexander G.G. Turpie
Journal: Blood (2005)
Prognostic Value of Sequencing-Based Minimal Residual Disease Detection in Multiple Myeloma
Authors: Hiroyuki Takamatsu, Ryoichi Murata, Jianbiao Zheng, Martin Moorhead, Naoki Takezako, Shigeki Ito, Toshihiro Miyamoto, Kenji Yokoyama, Kosei Matsue, Tsutomu Sato, Toshiro Kurokawa, Hideo Yagi, Yasushi Terasaki, Kinya Ohata, Takashi Yoshida, Malek Faham, Shinji Nakao
Journal: Blood (2014)
Reconfiguring acute hospital services
Authors: R. Smith
Journal: BMJ (1999)

Education and debate p 845 

Acute hospital services throughout the NHS need to be reconfigured, but it's unclear how best to do so. We can, however, probably agree on some principles. That was perhaps the main message from a meeting in held in Cambridge last year by the Anglia and Oxford region of the NHS Executive. The meeting, and also a series that starts today in the BMJ (p 845), make it clear that a national master plan, like the one that set up district general hospitals, is neither wanted nor probably possible.

Those at the conference took a show of hands on what was driving the need for reconfiguring acute services. Almost everybody thought that what should be driving it was the need to improve quality but that what actually was driving it was the need to reduce costs and cope with staffing problems, new technology, and public expectations The medical profession—represented by the BMA, the Royal College of Physicians of London, and Royal College of Surgeons of England—is convinced that “Comprehensive medical and surgical care of the highest quality requires the concentration of resources and skills into larger organisational units.”1 …
Session III: Secondary Hyperuricaemia: Allopurinol in the Prevention of Hyperuricaemia Secondary to the Treatmient of Neoplastic Diseases with Alkylating Agents, Adrenal Steroids, and Radiation Therapy
Authors: W. S. C. Copeman, I. H. Krakoff, M. Earl Balis
Journal: Annals of the Rheumatic Diseases (1966)

Previous speakers have testified to the effectiveness % NORMAL MYELOID of allopurinol in blocking uric acid production and % ERYTHROID to its usefulness in the management of gout.Experi-% /.STEM CELLS, LYMPHOCYTES ence with this compound to date has indicated that it COMPOUND F 75 MG METICORTEN 75 MG is equally useful in the prevention-and treatment of the hyperuricaemia which often o&urs as a result of BONE MARROW the rapid lysis of leukaemic or jymphoma cells by ____ES~2 6 10 2x raysor chemotherapeutic ag~mts (Krakoff and POLATLES ~529 464 0 258
Immunofluorescent Study on the Interaction between Collagen and Calcium Oxalate Crystals in the Renal Tubules
Authors: Kenjiro Kohri, Mitsumasa Kodama, Yasuaki Ishikawa, Yoshikazu Katayama, Hisao Matsuda, Masaaki Imanishi, Masahiko Takada, Yoshinari Katoh, Kiyoneri Kataoka, Takahide Akiyama, Masanori Iguchi, Takashi Kurita
Journal: European Urology (1991)
AN UNUSUAL HISTORY OF ECTOPIC PREGNANCIES
Authors: A H Bartley
Journal: JAMA (1921)

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Abstract 11343: High Density Lipoprotein (HDL) From Patients with Early Kidney Disease (CKD) Exerts Adverse Endothelial Effects
Authors: Timo Speer, Lucia Rohrer, Nicolle Kraenkel, Yi Shi, Alexander Akhmedov, Kira Kuschnerus, Gabriel Wernicke, Andreas Jung, Arnold von Eckardstein, Danilo Fliser, Thomas F Luscher, Ferdinand H Bahlmann, Ulf Landmesser
Journal: Circulation (2011)

Background Patients with chronic kidney disease (CKD) have a particularly high cardiovascular morbidity and mortality. High-density lipoprotein (HDL) from healthy subjects has been observed to exer...