tbuckley/cabot-search huggingface dataset:
WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited
Authors: Luke Boulter, Rachel V. Guest, Timothy J. Kendall, David H. Wilson, Davina Wojtacha, Andrew J. Robson, Rachel A. Ridgway, Kay Samuel, Nico Van Rooijen, Simon T. Barry, Stephen J. Wigmore, Owen J. Sansom, Stuart J. Forbes
Journal: Journal of Clinical Investigation (2015)

Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.
Small-intestinal and Gastric Changes in Ulcerative Colitis: A Biopsy Study
Authors: S. N. Salem, S. C. Truelove, W. C. D. Richards
Journal: BMJ (1964)

We decided to make an objective study of the state of the stomach and small intestine in this disease, with special reference to the histological picture as judged by peroral biopsy specimens. In addition to obtaining gastric and small-intestinal specimens, it was our intention to make some studies of small-intestinal function. The full range of tests available for the study of this function takes a considerable time. In dealing with an attack of ulcerative colitis it is essential that treatment be given without undue delay, and, in addition, the patient is often not fit to withstand any disturbing investigation. It has therefore been necessary for us to restrict the tests to one or two which can be carried out in the course of a few days and which do not cause any upset. In the event it has proved possible to estimate the faecal fat excretion and the absorption of vitamin B12 without inconveniencing the patient. Some patients were already on corticosteroid treatment at the time of our studies, but others with first attacks of the disease or with a recent relapse were studied before specific treatment was instituted. The object of this paper is to present the results obtained in a pilot study along the lines just discussed and to consider future possibilities.
Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo
Authors: Cornelia Grebe, Theda-Maria Klingebiel, Simon Philipp Grau, Karl Toischer, Michael Didié, Claudius Jacobshagen, Christian Dullin, Gerd Hasenfuss, Tim Seidler
Journal: Cardiovascular Research (2011)

The calcineurin and nuclear factor of activated T cells (NFAT) pathway can mediate pro-hypertrophic signalling in the heart. Recently, it has been shown that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates NFAT, which limits calcineurin/NFAT signal transduction in T cells and hypertrophy in cultured cardiomyocytes. The hypothesis tested in this study was that DYRK1A prevents calcineurin/NFAT-mediated cardiac hypertrophy in vivo.In cultured rat cardiomyocytes, adenovirus-mediated overexpression of DYRK1A antagonized calcineurin-mediated nuclear NFAT translocation and the phenylephrine-induced hypertrophic growth response. To test the ability of DYRK1A to reduce hypertrophic cardiac growth in vivo, we created tetracycline-repressible Dyrk1a transgenic mice to avoid the cardiac developmental defects associated with embryonic DYRK1A expression. However, in the mouse model, histological determination of myocyte diameter, heart weight/body weight ratio, and echocardiographic measurements revealed that myocardial expression of DYRK1A failed to reduce hypertrophy induced via aortic banding or co-expression of calcineurin. This discrepancy is explained, at least in part, by insufficient long-term inhibition of NFAT and the activation of DYRK1A-resistant maladaptive genes in vivo.Isolated augmentation of DYRK1A can be compensated for in vivo, and this may significantly limit anti-hypertrophic interventions aimed at enhancing DYRK1A activity.
Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule.
Authors: H F Cheng, B N Becker, K D Burns, R C Harris
Journal: Journal of Clinical Investigation (1995)

Angiotensin II (Ang II) is an important regulator of proximal tubule salt and water reabsorption. Recent studies indicate that rabbit proximal tubule angiotensin II receptors are the type-1 (AT1R) subtype. We studied the effect of Ang II on proximal tubule receptor expression. Rabbits were treated with either angiotensin converting enzyme inhibitors or a low salt diet to modulate endogenous Ang II levels. In captopril-treated rabbits, liver and glomerular AT1R mRNA levels increased 242 +/- 125 and 141 +/- 60%, respectively (n = 6-7; P < 0.05), as determined by quantitative PCR. In contrast, proximal tubule AT1R mRNA levels decreased 40 +/- 11% (n = 6; P < 0.05). Binding of 125I Ang II to renal cortical basolateral membranes of captopril-treated rabbits decreased from 2.9 +/- 0.55 to 1.4 +/- 0.17 fmol/mg protein (n = 6; P < 0.025). In rabbits fed a sodium chloride-deficient diet for 4 wk, AT1R mRNA levels decreased 52 +/- 11% in liver and 43 +/- 7% in glomeruli (n = 4-5; P < 0.05), whereas they increased 141 +/- 85% (n = 5; P < 0.05) in proximal tubule. In basolateral membranes from rabbits on the sodium chloride-deficient diet, specific binding of 125I Ang II increased from 2.1 +/- 0.2 to 4.3 +/- 1.1 fmol/mg protein (n = 7; P < 0.05). To determine whether Ang II directly regulates expression of proximal tubule AT1 receptors, further studies were performed in cultured proximal tubule cells grown from microdissected S1 segments of rabbit proximal tubules and immortalized by transfection with a replication-defective SV40 vector. Incubation of these cells with Ang II (10(-11) to 10(-7) M) led to concentration-dependent increases in both AT1R mRNA levels and specific 125I Ang II binding. Pretreatment with pertussis toxin inhibited Ang II stimulation of AT1R mRNA. AT1R mRNA expression was decreased by either forskolin or a nonhydrolyzable cAMP analogue (dibutryl cAMP). Simultaneous Ang II administration overcame the inhibitory effect of forskolin but not dibutryl cAMP. These results indicate that proximal tubule AT1R expression is regulated by ambient Ang II levels, and Ang II increases AT1R mRNA at least in part by decreasing proximal tubule cAMP generation through a pertussis toxin-sensitive mechanism. Upregulation of proximal tubule AT1R by Ang II may be important in mediating enhanced proximal tubule sodium reabsorption in states of elevated systemic or intrarenal Ang II.
Scleroderma (Progressive Systemic Sclerosis) Associated with Cancer of the Lung
Authors: Sigmundur M. Jonsson, Joseph M. Houser
Journal: New England Journal of Medicine (1956)

AS early as 1891 Dinkier1 pointed out that scleroderma is a systemic disease that may affect the connective tissue of many organs. Therefore, a more appropriate name would be, "progressive systemic sclerosis," as proposed by Goetz.2 This name, however, has not been generally adopted.The following case is considered to be of particular interest because of the development of cancer of the lung in association with scleroderma.Case ReportJ.Z., a 31-year-old woman, had a chest film taken in a community x-ray survey in November, 1951, that showed fine reticular strands in both lungs. For this reason she was referred . . .
72 PREOPERATIVE CALORIE RESTRICTION REDUCES HEPATIC TUMOUR LOAD AFTER EXPOSURE TO CIRCULATING COLONCARCINOMA TUMORCELLS IN A MOUSE MODEL
Authors: T.M. van Ginhoven, J.W. van den Berg, W.A. Dik, J.N.M. IJzermans, R.W.F. de Bruin
Journal: Journal of Hepatology (2010)
Book: The Regulation of Privacy and Data Protection in the Use of Electronic Health Information
Authors: R. Anderson
Journal: BMJ (2002)

An International Perspective and Reference Source on Regulatory and Legal Issues Related to Person-Identifiable Health Databases 

Roberto J Rodrigues, Petra Wilson, Stephen J Schanz    ![][1] 

Pan American Health Information, pp 217

To order, email rrodrigues@paho.org

Rating: 0

My first reaction on leafing through this book was excitement—at seeing sections on the law and practice of medical informatics in dozens of countries. E-medicine throws up many hard regulatory problems, and we should not all have to waste time reinventing the same square old wheels. For example, I am writing this in Boston, and last night had a debate with local medical ethicists about the definition of anonymous data. The United States is now learning the hard way about many of the problems with de-identifying data—and, in particular, how easy supposedly anonymous records …

 [1]: /embed/graphic-1.gif
Intermittent Erlotinib in Combination with Pemetrexed: Phase I Schedules Designed to Achieve Pharmacodynamic Separation
Authors: Angela M. Davies, Cheryl Ho, Laurel Beckett, Derick Lau, Sidney A. Scudder, Primo N. Lara, Natasha Perkins, David R. Gandara
Journal: Journal of Thoracic Oncology (2009)
Ligation of the T cell receptor complex results in activation of the Ras/Raf-1/MEK/MAPK cascade in human T lymphocytes.
Authors: R A Franklin, A Tordai, H Patel, A M Gardner, G L Johnson, E W Gelfand
Journal: Journal of Clinical Investigation (1994)

Stimulation of T cells with antibodies directed towards the T cell receptor complex results in the activation of mitogen-associated protein kinase (MAPK). Two pathways have been described in other cell types that can lead to MAPK activation. One of these pathways involves the activation of Ras, leading to the activation of Raf-1, and the subsequent activation of MEK (MAPK or ERK kinase). The contribution of this pathway in T cells for anti-CD3 or phorbol myristate acetate (PMA)-mediated MAPK activation was examined. We detected the kinase activities of Raf-1 and MEK towards their substrates (MEK for Raf-1 and MAPK for MEK) in this pathway leading to the activation of MAPK. Stimulation of the T cells with either anti-CD3 antibody or PMA resulted in a rapid activation of both Ras and Raf-1. MEK activity towards kinase-active or -inactive recombinant MAPK also increased upon stimulation. In addition, both MAPK and p90rsk were activated in these cells. We suggest that activation of MAPK and the subsequent activation of ribosomal S6 kinase (p90rsk) occurs by the Ras/Raf-1/MEK cascade in T lymphocytes stimulated by ligation of the T cell receptor complex.
Cardiac lipoprotein lipase in the spontaneously hypertensive rat
Authors: N Sambandam
Journal: Cardiovascular Research (1997)

Objective: The objectives of the present study were to determine functional (i.e., heparin-releasable) and intracellular (i.e., heparin-non-releasable) cardiac lipoprotein lipase (LPL) activity during the development of hypertension in spontaneously hypertensive (SHR) rats. Methods: Male WKY and SHR rats were killed before (7–8 weeks of age) and following (15–16 weeks of age) the development of severe hypertension in SHR rats. LPL activity in coronary perfusates was determined by retrogradely perfusing the hearts with heparin (5 U/ml). Cardiac myocytes were also isolated from the two groups of rats by collagenase digestion, and surface-bound and intracellular LPL activity measured. Results: With the development of hypertension in SHR rats, there was a concomitant and progressive reduction in the heparin-releasable coronary endothelial LPL activity. Neither insulin action nor cell-associated enzyme activity could explain this low LPL activity in coronary blood vessels. However, acute vasodilation with nifedipine (a Ca2+ influx blocker) or CGS-21680 (A2-purinergic receptor agonist) increased the peak heparin-releasable LPL activity in hearts isolated from SHR rats. Conclusions: Our results indicate that hypertension per se may play a significant role in regulating cardiac LPL activity, and hence fatty acid supply to the hypertensive SHR rat heart.
A novel micelle-encapsulated platinum(II) anticancer agent
Authors: Vithal B. Jadhav, Yong Joo Jun, Ju Hee Song, Min Kyoung Park, Ji Hyun Oh, Song Wha Chae, In-Sun Kim, Soo-Jin Choi, Hwa Jeong Lee, Youn Soo Sohn
Journal: Journal of Controlled Release (2010)
A Pregnancy-Prevention Program in Women of Childbearing Age Receiving Isotretinoin
Authors: Allen A. Mitchell, Carla M. Van Bennekom, Carol Louik
Journal: New England Journal of Medicine (1995)

Isotretinoin is effective in treating severe acne, but it is also teratogenic. To minimize pregnancies among exposed women, the manufacturer, together with the U.S. Food and Drug Administration, implemented a multicomponent Pregnancy Prevention Program in 1988. We report the results of an ongoing survey designed to assess compliance with this program.
Treatment of Primary Breast Cancer
Authors: Jerome A. Urban
Journal: JAMA (1980)

IT WAS my privilege to participate in the Consensus Development Conference on "The Treatment of Primary Breast Cancer—Management of Local Disease," held in Washington, DC, June 1979.<sup>1</sup>The purpose of this meeting was above reproach: "to bring together a varied group of physicians, surgeons, scientists, and consumers in order to achieve a general agreement on the optimum approach to the control of breast cancer." Although the consensus meeting pertained mainly to surgery, only three of the ten panelists were practicing surgeons. The majority report presented elsewhere in this issue (p 797) does not include some factual data presented at the meeting concerning several issues that influence the treatment of breast cancer. These include the long-term importance of the multicentricity of breast cancer and the therapeutic effect of adequate axillary node dissection. The majority report assumes that all breast cancer is systemic from its inception.<sup>2</sup>It intimates that all
Causality assessment in drug-induced liver injury using a structured expert opinion process: Comparison to the Roussel-Uclaf causality assessment method
Authors: Don C. Rockey, Leonard B. Seeff, James Rochon, James Freston, Naga Chalasani, Maurizio Bonacini, Robert J. Fontana, Paul H. Hayashi
Journal: Hepatology (2010)

Drug-induced liver injury (DILI) is largely a diagnosis of exclusion and is therefore challenging. The US Drug-Induced Liver Injury Network (DILIN) prospective study used two methods to assess DILI causality: a structured expert opinion process and the Roussel-Uclaf Causality Assessment Method (RUCAM). Causality assessment focused on detailed clinical and laboratory data from patients with suspected DILI. The adjudication process used standardized numerical and descriptive definitions and scored cases as definite, highly likely, probable, possible, or unlikely. Results of the structured expert opinion procedure were compared with those derived by the RUCAM approach. Among 250 patients with suspected DILI, the expert opinion adjudication process scored 78 patients (31%) as definite, 102 (41%) as highly likely, 37 (15%) as probable, 25 (10%) as possible, and 8 (3%) as unlikely. Among 187 enrollees who had received a single implicated drug, initial complete agreement was reached for 50 (27%) with the expert opinion process and for 34 (19%) with a five-category RUCAM scale ( P = 0.08), and the two methods demonstrated a modest correlation with each other (Spearman's r = 0.42, P = 0.0001). Importantly, the RUCAM approach substantially shifted the causality likelihood toward lower probabilities in comparison with the DILIN expert opinion process. Conclusion : The structured DILIN expert opinion process produced higher agreement rates and likelihood scores than RUCAM in assessing causality, but there was still considerable interobserver variability in both. Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed. Hepatology 2010
Sun Exposure, Sun Protection, and Vitamin D
Authors: June K. Robinson
Journal: JAMA (2005)

Objectives: To examine during what behaviors people apply sunscreen and to assess the relationship to UV exposure monitored by personal dosimetry and diaries.Design: Open prospective observational study.Setting: University hospital.Participants: A convenience sample of 340 Danish volunteers: children, adolescents, indoor workers, sun worshippers, golfers, and gardeners (age range, 4-68 years).Intervention: Subjects recorded sunscreen use and sun-exposure behavior in diaries and carried personal, electronic UV dosimeters, measuring time-stamped UV doses continuously, during a median of 119 days covering 346 sun-years (1 sun-year equals 1 subject participating during 1 summer season).Main Outcome Measures: Associations between sunscreen use and age, sex, skin type, occupation, sunburn, UV exposure doses, and behavior; and adequate application density and sun protection factor required to prevent sunburn.Results: There were great variations in sunscreen use, which was highly correlated with risk behavior (sunbathing or exposing the upper body) (r = 0.39; P&lt;.001). Sunscreens were used on a median of 5 days per sun-year (range, 1 day for gardeners to 16 days for sun worshippers). Ten percent of females and 41% of males never used sunscreens. Females used sunscreens more but also had more unprotected risk behavior than males (8 days vs 4 days; P&lt;.001). Sunscreen use was not correlated with age, and children had as much unprotected risk behavior as adults. Sunscreens were used on 86% of the days with risk behavior in southern Europe vs 20% in northern Europe (P&lt;.001). The UV doses were significantly higher on days with sunscreen (P≤.03) and on sunburn days (P&lt;.001). The median sun protection factor was 10.5. The sun-protecting effect corresponded to an application density of 0.5 mg/cm2.Conclusions: Days with sunscreen correlated not with days without risk behavior, but with days “sunbathing with the intention to tan,” indicating that sunscreens were used as tanning aids to avoid sunburn.
Statistical issues in carcinogenic risk assessment.
Authors: H E Rockette
Journal: Environmental Health Perspectives (1991)

Considerable progress has been made on the development of a variety of analytical methods to aid in the carcinogenic risk associated with exposure to both occupational and environmental agents. Although the development of these methods has been accompanied by consideration of many statistical issues, there are many areas where additional effort could be directed if these analytical methods are to provide the most appropriate interpretation of risk. These issues include methods of combining multiple studies to obtain an overall risk estimate, the robustness of the statistical model, methods of selection among competing models, an assessment of the effect of different measures of exposure on the estimated dose-response relationship, and development of surveillance methodology. These issues are discussed, and productive areas of future research are indicated.
VEGF121b and VEGF165b are weakly angiogenic isoforms of VEGF-A
Authors: Raúl Catena, Leyre Larzabal, Marta Larrayoz, Eva Molina, Jose Hermida, Jackeline Agorreta, Ramon Montes, Ruben Pio, Luis M Montuenga, Alfonso Calvo
Journal: Molecular Cancer (2010)

Different isoforms of VEGF-A (mainly VEGF₁₂₁, VEGF₁₆₅ and VEGF189) have been shown to display particular angiogenic properties in the generation of a functional tumor vasculature. Recently, a novel class of VEGF-A isoforms, designated as VEGF(xxx)b, generated through alternative splicing, have been described. Previous studies have suggested that these isoforms may inhibit angiogenesis. In the present work we have produced recombinant VEGF₁₂₁/₁₆₅b proteins in the yeast Pichia pastoris and constructed vectors to overexpress these isoforms and assess their angiogenic potential.Recombinant VEGF₁₂₁/₁₆₅b proteins generated either in yeasts or mammalian cells activated VEGFR2 and its downstream effector ERK1/2, although to a lesser extent than VEGF₁₆₅. Furthermore, treatment of endothelial cells with VEGF₁₂₁/₁₆₅b increased cell proliferation compared to untreated cells, although such stimulation was lower than that induced by VEGF₁₆₅. Moreover, in vivo angiogenesis assays confirmed angiogenesis stimulation by VEGF₁₂₁/₁₆₅b isoforms. A549 and PC-3 cells overexpressing VEGF₁₂₁b or VEGF₁₆₅b (or carrying the PCDNA3.1 empty vector, as control) and xenotransplanted into nude mice showed increased tumor volume and angiogenesis compared to controls. To assess whether the VEGF(xxx)b isoforms are differentially expressed in tumors compared to healthy tissues, immunohistochemical analysis was conducted on a breast cancer tissue microarray. A significant increase (p < 0.05) in both VEGF(xxx)b and total VEGF-A protein expression in infiltrating ductal carcinomas compared to normal breasts was observed. A positive significant correlation (r = 0.404, p = 0.033) between VEGF(xxx)b and total VEGF-A was found.Our results demonstrate that VEGF₁₂₁/₁₆₅b are not anti-angiogenic, but weakly angiogenic isoforms of VEGF-A. In addition, VEGF(xxx)b isoforms are up-regulated in breast cancer in comparison with non malignant breast tissues. These results are to be taken into account when considering a possible use of VEGF₁₂₁/₁₆₅b-based therapies in patients.
Labeling and Intracellular Tracking of Functionally Active Plasmid DNA with Semiconductor Quantum Dots
Authors: Charudharshini Srinivasan, Jeunghoon Lee, Fotios Papadimitrakopoulos, Lawrence K. Silbart, Minhua Zhao, Diane J. Burgess
Journal: Molecular Therapy (2006)

Semiconductor nanocrystal quantum dots (QDs) allow long-term imaging in the cellular environment with high photostability. QD biolabeling techniques have previously been developed for tagging proteins and peptides as well as oligonucleotides. In this contribution, QD-decorated plasmid DNA was utilized for the first time for long-term intracellular and intranuclear tracking studies. Conjugation of plasmid DNA with phospholipid-coated QDs was accomplished using a peptide nucleic acid (PNA)–N-succinimidyl-3-(2-pyridylthio) propionate linker. Gel electrophoresis and confocal and atomic force microscopy (AFM) were used to confirm the structure of QD–DNA conjugates. AFM imaging also revealed that multiple QDs were attached in a cluster at the PNA-reactive site of the plasmid DNA. These QD–DNA conjugates were capable of expressing the reporter protein, enhanced green fluorescent protein, following transfection in Chinese hamster ovary (CHO-K1) cells with an efficiency of ca. 62%, which was comparable to the control (unconjugated) plasmid DNA.
PLASTIC REAGENT BOTTLES FOR ALKALIS
Authors: Theodore Cornbleet
Journal: JAMA (1953)

<h3>To the Editor:—</h3> Anyone who uses strong alkalis, such as sodium hydroxide solution—and this includes most practitioners and medical technicians—wishes at times to avoid somehow the etching properties of these reagents. Because of the etching properties, the inner surface of a glass bottle is dissolved and smudged. The reagent itself becomes a complex suspending a brackish waste that interferes with proper usage. I found it necessary to renew the sodium hydroxide solution in my laboratory every two weeks, and that became a nuisance. These strong alkali reagents are by far the most useful in the everyday hunt for fungi when examining and diagnosing cutaneous lesions and eruptions and excretions from the bronchial tree, lungs, and gastrointestinal tract. Numerous other tests and procedures in the medical and chemical laboratory depend on the availability of a supply of strong alkali solution. Plastics today are commonplace and are fashioned into a thousand and