tbuckley/cabot-search huggingface dataset:
Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2.
Authors: J D Horton, I Shimomura, M S Brown, R E Hammer, J L Goldstein, H Shimano
Journal: Journal of Clinical Investigation (1998)

We produced transgenic mice that express a dominant-positive truncated form of sterol regulatory element-binding protein-2 (SREBP-2) in liver and adipose tissue. The encoded protein lacks the membrane-binding and COOH-terminal regulatory domains, and it is therefore not susceptible to negative regulation by cholesterol. Livers from the transgenic mice showed increases in mRNAs encoding multiple enzymes of cholesterol biosynthesis, the LDL receptor, and fatty acid biosynthesis. The elevations in mRNA for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase were especially marked (13-fold and 75-fold, respectively). As a result, the transgenic livers showed a 28-fold increase in the rate of cholesterol synthesis and a lesser fourfold increase in fatty acid synthesis, as measured by intraperitoneal injection of [3H]water. These results contrast with previously reported effects of dominant-positive SREBP-1a, which activated fatty acid synthesis more than cholesterol synthesis. In adipose tissue of the SREBP-2 transgenics, the mRNAs for cholesterol biosynthetic enzymes were elevated, but the mRNAs for fatty acid biosynthetic enzymes were not. We conclude that SREBP-2 is a relatively selective activator of cholesterol synthesis, as opposed to fatty acid synthesis, in liver and adipose tissue of mice.
Survivorship care plans in research and practice
Authors: Talya Salz, Kevin C. Oeffinger, Mary S. McCabe, Tracy M. Layne, Peter B. Bach
Journal: CA A Cancer Journal for Clinicians (2012)

Abstract The Institute of Medicine (IOM) recommends the use of survivorship care plans (SCPs) for all cancer survivors. Developing useful SCPs requires understanding what survivors and their providers need and how SCPs can be implemented in practice. Published studies investigating the perspectives of stakeholders (survivors, primary care providers, and oncology providers) were reviewed regarding the content and use of SCPs. All National Cancer Institute (NCI)‐designated cancer centers were surveyed concerning the extent to which SCPs for survivors of breast and colorectal cancers are in use, their concordance with the IOM's recommendation, and details about SCP delivery. Survivors and primary care providers typically lack the information the IOM suggested should be included in SCPs. Oncology providers view SCPs favorably but express concerns about the feasibility of their implementation. Fewer than one‐half (43%) of NCI‐designated cancer centers deliver SCPs to their breast or colorectal cancer survivors. Of those that do, none deliver SCPs that include all components recommended by the IOM. Survivors' and providers' opinions about the use of SCPs are favorable, but there are barriers to implementation. SCPs are not widely used in NCI‐designated cancer centers. Variation in practice is substantial, and many components recommended by the IOM framework are rarely included. CA Cancer J Clin 2012; © 2012 American Cancer Society.
SCL/TAL1-mediated Transcriptional Network Enhances Megakaryocytic Specification of Human Embryonic Stem Cells
Authors: Miguel G Toscano, Oscar Navarro-Montero, Veronica Ayllon, Veronica Ramos-Mejia, Xiomara Guerrero-Carreno, Clara Bueno, Tamara Romero, Mar Lamolda, Marien Cobo, Francisco Martin, Pablo Menendez, Pedro J Real
Journal: Molecular Therapy (2014)

Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs; however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that stem cell leukemia (SCL) overexpression accelerates the emergence of hemato-endothelial progenitors from hESCs and promotes their subsequent differentiation into blood cells with higher clonogenic potential. Given that SCL participates in megakaryocytic commitment, we hypothesized that it may potentiate megakaryopoiesis from hESCs. We show that ectopic SCL expression enhances the emergence of megakaryocytic precursors, mature megakaryocytes (MKs), and platelets in vitro. SCL-overexpressing MKs and platelets respond to different activating stimuli similar to their control counterparts. Gene expression profiling of megakaryocytic precursors shows that SCL overexpression renders a megakaryopoietic molecular signature. Connectivity Map analysis reveals that trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), both histone deacetylase (HDAC) inhibitors, functionally mimic SCL-induced effects. Finally, we confirm that both TSA and SAHA treatment promote the emergence of CD34(+) progenitors, whereas valproic acid, another HDAC inhibitor, potentiates MK and platelet production. We demonstrate that SCL and HDAC inhibitors are megakaryopoiesis regulators in hESCs.
HH Salter (1860s): taking cold as original cause and provocative of attacks of asthma
Authors: Carl Persson, Lena Uller
Journal: Thorax (2013)

Henry Hyde Salter's pioneering contributions and unsurpassed descriptions regarding many facets of asthma and its treatments1 are increasingly recognised during the last 50 years.2 ,3 Indeed, reference to Salter is frequent in current discussions on asthma. However, Salter's intriguing observations inferring roles of respiratory infection in asthma remain little noticed. Yet, common cold, predominantly rhinovirus infections, is now acknowledged as leading cause of exacerbations of asthma. Respiratory viral infection is also major contender as original inciter of asthma (reviewed in ref. 4).

A centennial before discovery of cold virus5 …
Abstract B97: The role of JNK isoforms in adenovirus-induced autophagy: Implications for cancer immunotherapy using oncolytic adenoviruses.
Authors: Sarah R. Klein, Hong Jiang, Sujan Piya, Zhimin Lu, Candelaria Gomez-Manzano, Juan Fueyo
Journal: Cancer Research (2013)

Abstract Glioblastoma multiforme is the most common and lethal form of primary brain tumor in adults. Targeted immunotherapy using recombinant oncolytic viruses is a promising strategy for the treatment of brain tumors. Delta-24-RGD is a highly selective and potent oncolytic adenovirus that induces autophagy in malignant gliomas. Data from our ongoing clinical trial suggested Delta-24-RGD initiated an anti-tumor immune response in patients. Importantly, autophagy promotes the presentation of viral antigens for activation of immune cells; therefore, we sought to elucidate the molecular mechanisms by which adenoviruses induce autophagy. Adenoviral replication induced phosphorylation of JNK that was required for autophagy. Our results indicated that JNK regulates autophagy through Bcl-2 phosphorylation and consequent dissociation of Bcl-2 and beclin 1. Contrary to starvation-induced autophagy, adenovirus-mediated autophagy was facilitated by both JNK1 and JNK2 isoforms of JNK. Moreover, our data indicated that adenoviral antigens were presented at the cell surface, which was ablated upon down-regulation of JNK or autophagy. We propose a JNK/autophagy-dependent mechanism for the immune presentation of viral antigens that can be leveraged when developing recombinant adenoviruses for the advancement of anti-tumor immunotherapy. Thus, we developed a genetically-modified Delta-24 adenovirus expressing an EGFRvIII epitope that is aberrantly expressed in gliomas. The majority (&amp;gt;80%) of cells infected with Delta-24-FvIII presented the fiber-bound EGFRvIII epitope on their surface, an effect that was diminished upon inhibition of autophagy. Our data demonstrated that oncolytic adenoviruses can be modified to present cancer antigens for an anti-tumor immune response that may be enhanced by positively regulating autophagy. Citation Format: Sarah R. Klein, Hong Jiang, Sujan Piya, Zhimin Lu, Candelaria Gomez-Manzano, Juan Fueyo. The role of JNK isoforms in adenovirus-induced autophagy: Implications for cancer immunotherapy using oncolytic adenoviruses. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B97.
Survey of colourings and preservatives in drugs.
Authors: I. Pollock, E. Young, M. Stoneham, N. Slater, J. D. Wilkinson, J. O. Warner
Journal: BMJ (1989)

OBJECTIVE--To assess the prevalence of colourings and preservatives in drug formulations in the United Kingdom. DESIGN--Postal survey. PARTICIPANTS--All pharmaceutical manufacturers in the United Kingdom were requested to supply data on drug formulations with particular regard to the content of colourings and preservatives. MAIN OUTCOME MEASURE--Prevalence in proprietary drugs of colourings or preservatives, or both, that have been implicated in adverse reactions. Computation of a list of formulations of bronchodilators, antihistamines, and antibiotics that are free of such additives. RESULTS--A total of 118 out of 120 pharmaceutical companies supplied the data requested. In all, 2204 drug formulations were analysed and found to contain 419 different additives, of which 52 were colourings and preservatives that have been implicated in adverse reactions; 930 formulations contained such an additive. Tartrazine was the fourth most commonly occurring colouring, being present in 124 drug formulations. CONCLUSION--Many drugs contain additives that help to identify them and prolong their shelf life but are implicated in adverse reactions in some people. Some form of labelling of drug additives would enable these people to avoid drugs containing such additives.
Using Information Technology to Improve the Monitoring of Outpatient Prescribing
Authors: Alan J. Forster, Claudine Auger, for the ISTOP ADE Investigators
Journal: JAMA Internal Medicine (2013)

Dr Doshi received €1500 from the European Respiratory Society in support of his travel to the society's September 2012 annual congress, where he gave an invited talk on oseltamivir.Dr Jefferson receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, none of which are on clinical study reports.In 2011-2012, Dr Jefferson acted as an expert witness in a litigation case related to an antiviral (oseltamivir phosphate; Tamiflu [Roche]).Dr Jefferson is on a legal retainer for expert advice on litigation for influenza vaccines in health care workers.
Molecular genetic confirmatory testing from newborn screening samples for the common African‐American, Asian Indian, Southeast Asian, and Chinese β‐thalassemia mutations
Authors: Urvashi Bhardwaj, Yao‐Hua Zhang, Fred Lorey, Linda L. McCabe, Edward R.B. McCabe
Journal: American Journal of Hematology (2005)

Abstract β‐Thalassemia is a serious health problem in the United States, especially in California, due to increased Asian immigration. Neonatal screening by using high‐performance liquid chromatography (HPLC) or isoelectric focusing (IEF) may lead to confusion due to interactions of various hemoglobinopathies with β‐thalassemia. Our purpose was to develop single‐tube multiplexed PCR assays using original neonatal screening specimens to identify the mutations responsible for β‐thalassemia in order to expedite diagnostic confirmation. Primers were designed for two to six common ethnic‐specific mutations using the amplification refractory mutation system (ARMS). This multiplex ARMS approach was standardized using DNA samples with known mutations for β‐thalassemia in those of Asian (Southeast Asian, Chinese, and Asian Indian) and African‐American descent. Specimens from African‐American neonates were tested for two mutations (−88 and −29); Asian Indians for five mutations (IVSI‐1, IVSI‐5, codons (Cd) 41/42, Cd 8/9, and 619‐bp deletion); Chinese, Taiwanese, and Southeast Asians for seven mutations (Cd 41/42, Cd 17, −28, IVSII‐654, Cd 71/72, IVSI‐5, and IVSI‐1). We identified each of these β‐thalassemia mutations in multiplexed ARMS from positive control samples. We tested 25 anonymized dried blood specimens from neonates who had been diagnosed with β‐thalassemia and who also belonged to these ethnic groups. We detected a mutation specific to the neonate's ethnic group using the ARMS approach in nearly all specimens, and the results were confirmed by sequencing. Multiplexed ARMS for ethnic‐specific β‐thalassemia mutations from the original newborn screening dried blood specimens is a rapid and efficient approach for diagnostic confirmation. Am. J. Hematol. 78:249–255, 2005. © 2005 Wiley‐Liss, Inc.
Inhibition of the Bicarbonate Exit Step in Urinary Acidification by a Disulfonic Stilbene
Authors: Loren H. Cohen, Allan Mueller, Philip R. Steinmetz
Journal: Journal of Clinical Investigation (1978)

Acidification of the luminal solution by the isolated turtle bladder involves H+ secretion by a pump at the luminal membrane. The OH− dissociated in this process reacts with CO2 and forms HCO3− which moves passively out of the cell across the serosal cell membrane. In the present study, this exit step for HCO3− was inhibited by serosal addition of the disulfonic stilbene, SITS, an agent which is thought to bind to a transport protein at the serosal cell membrane. 90 min after serosal addition of 0.5 mM SITS, H+ secretion decreased by > 80%. In contrast, luminal addition of SITS had no effect. During inhibition of H+ secretion by serosal SITS, overall cell pH, measured by the 5, 5-dimethyl-2, 3-oxazolidinedione method, increased from 7.48±0.03 to 7.61±0.02. This increase of 0.13±0.02 pH U was associated with a much larger regional pH increase as judged from the decrement in the attainable pH gradient across the epithelium. After serosal SITS, this gradient was reduced from 2.88±0.06 to 2.09±0.11 pH U. In the absence of evidence for increased H+ permeability or a change in the force of the H+ pump, the gradient decrement of 0.79±0.08 U reflects a similar pH increment on the cytoplasmic side of the pump.
The Cesarean Section Rate-Reply
Authors: Randall S. Stafford
Journal: JAMA (1990)

<h3>In Reply.—</h3> A premise of my review was that further increases in cesarean section rates are not warranted. Dr Overhulse's call for the universal adoption of cesarean section contradicts this prevailing consensus<sup>1</sup>and perhaps illustrates why there is so frequently a tenuous connection between clinical practice and the medical literature. Although maternal mortality is now rare, cesarean section nevertheless carries an increased risk of death compared with vaginal delivery, even for planned cesarean sections.<sup>2</sup>In addition, postcesarean infection occurs in approximately 15% of cesarean deliveries even with antibiotic prophylaxis.<sup>3</sup>Hospital stays are twice as long following cesarean section compared with vaginal delivery. Although the physical and emotional hardships of laboring women cannot be minimized, the statement that "the mortality and morbidity rates of planned cesarean section... are as low as those of vaginal delivery" is not supported by the literature. Dr Overhulse's implication that late pelvic relaxation
Do CD4+ T Cell Functional Responses to Epstein–Barr Virus Provide Protective Immunity Against CNS Lymphoma in AIDS?
Authors: Mark A Jacobson
Journal: PLoS Medicine (2007)

Since highly active antiretroviral treatment (HAART) regimens became widely available in North America and Europe in 1996, the incidence of AIDS-defining opportunistic infections and malignancies has declined dramatically. This decline has been attributed to restoration of protective immunity by HAART since HAART improves many of the deficits in T and B cell function that are caused by uncontrolled HIV infection. Some of these deficits include diminished antigen-specific T cell proliferation and cytokine expression, decreased production of new naive T cells by the thymus, and abnormally high levels of CD4+ and CD8+ T cell and B cell activation [1–3]. However, the causal link between the reversal or prevention of these T and B cell functional abnormalities and immune protection against AIDS-defining opportunistic infections and malignancies remains largely hypothetical at present.
A revised score for predicting PE
Authors: M Rajpopat
Journal: Thorax (2006)

▴ Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med2006;144:165–71[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Clinical variables were derived and validated in two independent cohorts of patients suspected of having a pulmonary … [1]: {openurl}?query=rft.jtitle%253DAnnals%2Bof%2BInternal%2BMedicine%26rft.stitle%253DANN%2BINTERN%2BMED%26rft.aulast%253DLe%2BGal%26rft.auinit1%253DG.%26rft.volume%253D144%26rft.issue%253D3%26rft.spage%253D165%26rft.epage%253D171%26rft.atitle%253DPrediction%2Bof%2BPulmonary%2BEmbolism%2Bin%2Bthe%2BEmergency%2BDepartment%253A%2BThe%2BRevised%2BGeneva%2BScore%26rft_id%253Dinfo%253Adoi%252F10.7326%252F0003-4819-144-3-200602070-00004%26rft_id%253Dinfo%253Apmid%252F16461960%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.7326/0003-4819-144-3-200602070-00004&link_type=DOI [3]: /lookup/external-ref?access_num=16461960&link_type=MED&atom=%2Fthoraxjnl%2F61%2F8%2F662.atom [4]: /lookup/external-ref?access_num=000235074800002&link_type=ISI
Homocyst(e)ine and Cardiovascular Disease
Authors: Alan S. Feiner
Journal: Annals of Internal Medicine (2000)

Letters18 April 2000Homocyst(e)ine and Cardiovascular DiseaseAlan S. Feiner, MDAlan S. Feiner, MDRose Medical Center; Denver, CO 80220 (Feiner)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-132-8-200004180-00017 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Eikelboom and colleagues (1) and others have described a possible association between high levels of homocyst(e)ine and cardiovascular disease and clotting. I wonder why an increased incidence of clotting or cardiovascular disease has not been reported in patients with pernicious anemia and high homocyst(e)ine levels.Reference1. Eikelboom JW, Lonn L, Genest J, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999;131:363-75. LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Rose Medical Center; Denver, CO 80220 (Feiner) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHomocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence John W. Eikelboom , Eva Lonn , Jacques Genest Jr. , Graeme Hankey , and Salim Yusuf Homocyst(e)ine and Cardiovascular Disease John W. Eikelboom , Eva Lonn , and Salim Yusuf Metrics Cited byIs Subclinical Hypothyroidism Associated With Hyperhomocysteinemia?Reducing global risk for cardiovascular disease: Using lifestyle changes and pharmacotherapy 18 April 2000Volume 132, Issue 8Page: 676KeywordsCardiovascular diseasesPernicious anemia Issue Published: 18 April 2000 Copyright & PermissionsCopyright © 2000 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
An Address on the Analogies of Menstruation and Pregnancy and Labour, in Some of their Physiological and Pathological Relations
Authors: R. Barnes
Journal: BMJ (1889)

THE analogy between menstruation and pregnancy and labour is traceable in detail.The history of the menstrual process is a necessary introduction to the history of gestation.'t has long been held that in both cases the primum mobile resides in the ovary.Of 'late years the dominion of the ovary over the uterine phenomena of menstruation has been to some extent challenged.It would carry me beyond the scope of this memoir to investigate minutely the grounds upon which this challenge is founded.For the present purpose I will simply state what cannot be questioned, namely, that the ovary is certainly a necessary factor in reproduction and gestation.The old dictum, " omne vivum ex ovo," has not 1.Local.-Spasms followed by paralysis, resulting from tear'n,
Abstract 613: Increased PI3K/AKT activity, which confers resistance to trastuzumab, can be overcome by lapatinib
Authors: Neil A. O'Brien, YuHua Wang, Lucy Chow, Karen Wilcox, Brigid Browne, John Crown, Jane Arboleda, Charles Ginther, Michael J. Duffy, Norma O'Donovan, Dennis J. Slamon
Journal: Cancer Research (2010)

Abstract Trastuzumab and lapatinib provide clinical benefit to women with HER2 positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. There are no clinically validated biomarkers of resistance to therapy. We evaluated responses to trastuzumab and lapatinib in a panel of 17 HER2-amplified cell lines in both two and three dimensional culture and investigated the role of receptor tyrosine kinase (RTK) signaling and PI3K/AKT pathway activation in resistance. We also conditioned four cell lines to acquire trastuzumab resistance, and two additional cell lines to acquire lapatinib resistance. The SUM-225, HCC-1419, HCC-1954, UACC-893, HCC-1569, UACC-732, JIMT-1 and MDA-453 cell lines are innately resistant to trastuzumab, whereas the MDA-361, MDA-453, HCC-1569, UACC-732, JIMT-1, HCC-202 and UACC-893 cells are innately lapatinib resistant. Lapatinib is active in both de novo (SUM-225, HCC-1419 and HCC-1954) and acquired trastuzumab resistant cell lines. Increased phosphorylation of HER2, EGFR, HER3 and IGF-1R correlated with response to lapatinib but not trastuzumab. p95HER2 levels correlated with response to lapatinib, however p95HER2 levels also correlated with levels of full length HER2, indicating that p95HER2 may not be an independent marker of lapatinib response. A decrease in AKT phosphorylation in response to trastuzumab or lapatinib treatment correlated significantly with response to either agent, indicating that loss of pAKT is a biomarker of response to both HER2-targeted therapeutics. Accordingly, trastuzumab treatment of trastuzumab resistant cells had little effect on AKT phosphorylation, whereas treatment of these cells by lapatinib significantly reduced pAKT levels. Thus, lapatinib retains its activity in trastuzumab resistance via continued dephosphorylation of AKT. We also observed that loss of PTEN or the presence of activating mutations in PI3K marked resistance to trastuzumab yet lapatinib response was independent of these factors. Thus, increased activation of the PI3K/AKT pathway confers resistance to trastuzumab which can be overcome by lapatinib. In conclusion, pharmacological targeting of the PI3K/AKT pathway may provide benefit to HER2 positive breast cancer patients who are resistant to trastuzumab therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 613.