tbuckley/cabot-search huggingface dataset:
Abstract IA15: Predicting drug sensitivity from cancer cell lines
Authors: Adam Arne Margolin, In Sock Jang, Stephen Friend
Journal: Cancer Research (2012)

Abstract High-throughput molecular characterization technologies have enabled detailed genetic and genomic characterization of large panels of cancer cell lines, including profiling of gene expression, copy number variation (CNV), SNP, mutation, and RNA-seq. The same cell lines have also been profiled for sensitivity to potential anti-cancer compounds, allowing development of computational models used to predict genotype-specific drug treatments linked to tumor molecular subtypes. Inferring such models is challenging because the model inputs contain far more features than observations, known as the p&amp;gt;&amp;gt;n problem, precluding the use of classical statistical models such as least squares (a.k.a. multiple linear regression). Recently, generalized linear models or penalized linear models have been proposed and extended for feature selection and overcoming the p&amp;gt;&amp;gt;n. Bayesian extension of such methods have also been developed, using algorithms such as Metropolis-Hasting and Markov Chain Monte Carlo, and demonstrated to improve prediction accuracy at the expense of increased computing cost. A comprehensive evaluation of predictive modeling techniques is essential to leverage cell line studies to infer the most accurate genetic predictors of drug sensitivity, which can then be used to inform patient selection strategies in clinical trials and to identify functional genetic determinants of drug sensitivity or resistance. In this study, we evaluate state-of-the-art predictive models which utilize dimension reduction methods (e.g., partial least square, support vector machine, principal component regression), feature selection (e.g., LASSO, RIDGE, and elastic-net), and Bayesian feature selection (e.g., Bayesian LASSO and Bayesian RIDGE). We assess each method based on 1) the accuracy of sensitivity predictions in a cross validation setting and in an independent dataset, and 2) the biological coherence of inferred predictive features by comparison to publicly available pathway databases. Citation Format: Adam Arne Margolin, In Sock Jang, Stephen Friend. Predicting drug sensitivity from cancer cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA15.
"Old age" can be appropriate on death certificates
Authors: B. Mansfield
Journal: BMJ (2001)

EDITOR—I cannot let Kafetz's assertions that “old age” should not be acceptable on death certificates join the growing list of ex cathedra statements arising from the actions of one wayward practitioner [Harold Shipman].1 One of the roles I still consider I have as a general practitioner is to protect my patients from overzealous investigation, …
826 OPTIMIZATION OF THE BIOMASS GROWTH FOR THE DEVELOPMENT OF A CLINICAL SCALE BIOARTIFICIAL LIVER USING A HUMAN DERIVED CELL LINE WITHIN ENCAPSULATED ALGINATE
Authors: E. Erro, J. Bundy, I. Massie, A. Gander, S.A. Chalmers, R. Molls, M. Zhou, P. Sharrat, B. Fuller, H. Hodgson, C. Selden
Journal: Journal of Hepatology (2010)
Effects of Prolonged Ethanol Intake: Production of Fatty Liver Despite Adequate Diets*
Authors: Charles S. Lieber, Don P. Jones, Leonore M. DeCarli
Journal: Journal of Clinical Investigation (1965)

Although the association of alcoholism and fatty liver was described as early as 1836 (3), the pathogenesis of this disorder is still the subject of controversy.Among the problems at issue is the question of whether the fatty liver observed after prolonged alcohol intake is due only to nu- tritional deficiencies associated with alcoholism or whether it is caused by alcohol itself (4-6).In the present study an attempt was made to dissociate the effect of ethanol per se from se- quelae of dietary deficiencies.It was found, both in man and in rats, that ethanol ingestion produces fatty livers, despite maintenance of adequate diets. Methods A. Clinical studiesSubjects.Five individuals were studied under meta- bolic unit conditions.The subjects varied in age be- tween 36 and 62 years; all but one were males.All had a history of alcoholism, but they had abstained from al- chohol for periods varying from 30 days to 2 years.At the time of the study, none had clinical evidence of liver disease, and liver function tests were normal (Ta- ble I).The subjects had a history of previous alcoholic fatty liver, documented by liver biopsy, but at the time of *
Activator Protein 2α Inhibits Tumorigenicity and Represses Vascular Endothelial Growth Factor Transcription in Prostate Cancer Cells
Authors: Maribelis Ruiz, Curtis Pettaway, Renduo Song, Oliver Stoeltzing, Lee Ellis, Menashe Bar-Eli
Journal: Cancer Research (2004)

Abstract Activator protein-2α (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells. We have shown previously that although AP-2 is expressed highly in normal prostatic epithelium, its expression is lost in high-grade prostatic intraepithelial neoplasia and prostate cancer, suggesting that loss of AP-2 plays a role in prostate cancer development. We demonstrate that forced AP-2 expression in the prostate cancer cell line LNCaP-LN3 (AP-2 negative) inhibited dramatically tumor incidence in nude mice. To identify the genes that might have been responsible for this effect, we used microchip expression array. We found several genes known to be involved in malignancy were deregulated, including the vascular endothelial growth factor (VEGF) gene. Because VEGF was down-regulated by 14.7-fold in the AP-2-transfected cells and because it is a major angiogenic factor in prostate cancer development and progression, we chose to examine the AP-2-VEGF interaction. Our evidence suggests that AP-2 repressed transcriptionally the VEGF promoter by competing with the transcriptional activator Sp3. Loss of AP-2 in prostate cancer cells reduced the AP-2:Sp3 ratio and activated VEGF expression. AP-2 acts as a tumor-suppressor gene in prostate cancer. Elucidating the molecular events resulting from loss of AP-2 in the prostate epithelium has implications for the understanding and prevention of the onset of prostate cancer.
Patient power on the march
Authors: J. Warden
Journal: BMJ (1988)

Perhaps doctors should beware, but the old idea that the needs of the patient are paramount is now so attractive to politicians that they are in danger of believing that they thought of it first.Listen, for instance, to John Moore, Social Services Secretary, referring last week to the review of the National Health Service:"Above all we will bear in mind that our paramount concern is and always will be the interest of the individual patient."The sentiment is commonplace enough today, but it was not always so.The founders ofthe NHS did not identify the needs of the individual patient as a prime objective above all others.There was
Effectiveness of salmeterol<i>versus</i>ipratropium bromide on exertional dyspnoea in COPD
Authors: M.L. Ayers, R. Mejia, J. Ward, T. Lentine, D.A. Mahler
Journal: European Respiratory Journal (2001)

The hypothesis of the study was that salmeterol and ipratropium would have similar dyspnoea ratings during steady-state cycle ergometry at 1 h, but that salmeterol would reduce dyspnoea at 6 h after administration in patients with chronic obstructive pulmonary disease (COPD). The study design was a randomized, double-blind trial in 16 patients (aged 63±11 yrs) with symptomatic COPD. Two days after familiarization with testing procedures, patients were randomly assigned to receive either two puffs (42 µg) of salmeterol and two puffs of placebo inhaler, or two puffs (36 µg) of ipratropium from each of two inhalers (total, 72 µg). Two days later, patients received the alternative medication. During exercise at 60% of peak oxygen consumption patients rated dyspnoea and performed inspiratory capacity manoeuvres each minute. Forced expiratory volume in one second was 1.13±0.48 L (37±13% predicted). Dyspnoea ratings were similar for salmeterol and ipratropium at 1 and 6 h. Inspiratory capacity was similar for salmeterol and ipratropium at 1 h, but significantly higher for salmeterol at 6 h (Δ=120 mL; p=0.03). It is concluded that with the doses used, salmeterol and ipratropium provided similar dyspnoea ratings during exercise at 1 and 6 h after administration.
Some patients stop treatment when variables improve
Authors: K Kain, A J Catto
Journal: BMJ (2005)

The General Medical Council and the future of revalidation GMC member respondsEditor-Esmail and Kmietowicz give an inaccurate account of the General Medical Council's policy development on revalidation, ignoring an iterative process with interested parties since 1998 in an attempt to introduce the most fundamental change to medical regulation since its foundation in 1858. 1 2 The GMC clearly has had regard to the legitimate interests of three principal groups-government and the NHS, patients and the public, and the various tribes that make up the UK medical profession.Despite suggestions to the contrary, an initial exploratory meeting on revalidation convened by Sir Donald Irvine in June 1998 was held in the context of a high profile professional conduct case, but well before the Bristol inquiry report and absolutely nothing to do with Rodney Ledward or, indeed, Harold Shipman.It was recognised then that some doctors were not keeping fully up to date nor were they indulging in reflective practice.Irvine correctly proposed that there was a need to make registration with the GMC more meaningful to the public than a mere recognition that doctors had reached a certain standard of professional knowledge in their early 20s.Both articles promote the idea that the doctors' regulator should be filling the vacuum within the NHS created by its failing to fulfil its public responsibility to monitor doctors' clinical standards.Clinical governance is now, slowly, being developed and eventually will extend from systems and teams to individuals-but is it reasonable, as both authors postulate, that such monitoring should become the financial and moral responsibility of the GMC sitting in London and Manchester rather than local managers at the coalface?Although revalidation is a continuing process, it becomes summative only every five years.The NHS and its local systems must not be allowed to abrogate their responsibility for the safety of patients on a day to day basis.Nor should they demand that the GMC and its prime function of assuring fitness to practise and the meaning of the medical register be inappropriately promoted as the first line of defence for the maintenance of clinical quality and safety.
<i>NBS1</i> Expression as a Prognostic Marker in Uveal Melanoma
Authors: Justis P. Ehlers, J. William Harbour
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Up to half of uveal melanoma patients die of metastatic disease. Treatment of the primary eye tumor does not improve survival in high-risk patients due to occult micrometastatic disease, which is present at the time of eye tumor diagnosis but is not detected and treated until months to years later. Here, we use microarray gene expression data to identify a new prognostic marker. Experimental Design: Microarray gene expression profiles were analyzed in 25 primary uveal melanomas. Tumors were ranked by support vector machine (SVM) and by cytologic severity. Nbs1 protein expression was assessed by quantitative immunohistochemistry in 49 primary uveal melanomas. Survival was assessed using Kaplan-Meier life-table analysis. Results: Expression of the Nijmegen breakage syndrome (NBS1) gene correlated strongly with SVM and cytologic tumor rankings (P &amp;lt; 0.0001). Further, immunohistochemistry expression of the Nbs1 protein correlated strongly with both SVM and cytologic rankings (P &amp;lt; 0.0001). The 6-year actuarial survival was 100% in patients with low immunohistochemistry expression of Nbs1 and 22% in those with high Nbs1 expression (P = 0.01). Conclusions: NBS1 is a strong predictor of uveal melanoma survival and potentially could be used as a clinical marker for guiding clinical management.
TURNOVER OF S35-SULFATE IN EPIPHYSES AND DIAPHYSES OF SUCKLING RATS
Authors: Dominic D. Dziewiatkowski, N. Di Ferrante, F. Bronner, Gladys Okinaka
Journal: The Journal of Experimental Medicine (1957)

S(35)-sulfate was injected intraperitoneally- into 7-day-old rats and their long bones were removed after intervals of time. The epiphyses were separated from the diaphyses for analysis. From the diaphyses freed of bone marrow about 82 per cent of the S(35) which they contained was extracted with a 2.5 N solution of sodium hydroxide. More, about 91 per cent of the S(35), was thus extracted from the epiphyses. Dialysis of the extracts against water showed that the fraction of S(35) which was dialyzable decreased rapidly with time. After 1 hour about 80 per cent and 50 per cent of the S(35) in the extracts of diaphyses and epiphyses, respectively were found in the dialysates, after 24 hours about 20 per cent and 4 per cent, and after 120 hours 12 per cent and 1 per cent. Similar values for the S(35) in inorganic sulfate were found when the extracts were chromatographed on an anion exchange resin, dowex-2. The S(35), other than inorganic sulfate, was in the form of bound sulfate, which was released by acid hydrolysis. Uronic acid and hexosamines, primarily galactosamine, were associated with the S(35). Indeed, on paper electrophoretograms and paper chromatograms the major S(35)-labelled component which was seen resembled chondroitin sulfate in its mobility. On the paper chromatograms, also a second S(35)-labelled component with a mobility lower than that of chondroitin sulfate was found. It is unlikely that the latter is a breakdown product of chondroitin sulfate, produced in the course of extraction with the sodium hydroxide solution. In fact, both components were also found in sodium versenate homogenates which had been dialyzed extensively against water. On the basis of these results it is suggested that the greatest part of the S(35)-labelled materials previously demonstrated by autoradiography to be progressively deposited in the metaphyses after 24 hours,-as the concentration of S(35)-sulfate concurrently decreased in the epiphyseal cartilage plates,-are akin to the chondroitin sulfate of the epiphyseal cartilage plates and are derived from the latter.
Thrombocythemia
Authors: Herbert Fanger, Louis J. Cella, Henry Litchman
Journal: New England Journal of Medicine (1954)

IN the past study of the myeloproliferative disorders of the bone marrow has been devoted to the red-cell and white-cell series. To be sure, some attention has been paid to the relation of the megakaryocytes to thrombocytopenia, but, strangely enough, there have been few observations of excessively high platelet counts and megakaryocytic hyperplasia. Tocantins1 has described moderate increases in the platelet count from various stimuli — for example, fractures, operations, hypochromic anemia and dermatoses. This increase is called thrombocytosis and is probably not uncommon. Little is known about the histology of the bone marrow in such conditions.In contrast there . . .
Setting priorities New Zealand-style
Authors: J. Dixon, B. New
Journal: BMJ (1997)

What is the best way to ration health services? We have had debate: between those who argue that the government should define a package of services available on the NHS1 and those who instead prefer fuzziness–leaving rationing decisions largely up to clinicians.2 But whatever the services available, there is general agreement that more could be done to ensure that effective treatments are provided.

The approach taken by the British government has been mixed. On the one hand it has decided not to define a list of core services available on the NHS and has left it up to purchasers to decide.3 To help, it has provided information to purchasers on the effectiveness of a range of treatments.4 On the other, it has developed several policies with direct bearing on rationing, such as curtailing free eye testing on the NHS, allowing adult dentistry to drift out of the NHS, and requiring purchasers to …
A simple and rapid micromethod for genomic DNA extraction from jugal epithelial cells
Authors: Y. Aron, E. Swierezewski, A. Lockhart
Journal: Allergy (1994)

We describe a rapid and reliable micromethod for DNA isolation from buccal epithelial cells from the interior mouth mucosa. This convenient, noninvasive method could be applied to genetic typing in a small number of cells (about 2000 cells per cheek). We have shown that DNA released by this method is suitable for further amplification by polymerase chain reaction (PCR). Using this protocol, coupled with the PCR‐RFLP (restriction fragment length polymorphism) method, we analyzed the allelic sequence diversity of the human lymphocyte antigen (HLA) class II genes in an extended family of 33 persons containing 14 asthmatic or atopic members. Six of eight DQA1 alleles, and 11 DQB1, 20 DPB1, and 10 DR haplotypes could be identified in a single DNA sample. Our results suggest that the DR53 group haplotype is frequently associated with allergic asthma and atopy. The micromethod described here may be useful in genetic epidemiology, especially in family studies involving small children.
Continuous rapid atrial pacing to control recurrent or sustained supraventricular tachycardias following open heart surgery.
Authors: A L Waldo, W A MacLean, R B Karp, N T Kouchoukos, T N James
Journal: Circulation (1976)

A technique is described to control recurrent or sustained supraventricular tachycardia associated with rapid ventricular rates following open heart surgery. The technique utilizes a pair of temporarily implanted atrial epicardial wire electrodes to pace the heart. In one group of patients with recurrent atrial flutter and 2:1 A-V conduction, continuous rapid atrial pacing at 450 beats/min produced and sustained atrial fibrillation. The ventricular response rate immediately slowed when compared to that during atrial flutter, and if further slowing was required, it was easily accomplished by the administration of digitalis. Another group of patients with different arrhythmias (recurrent paroxysmal atrial tachycardia, sustained ectopic atrial tachycardia, or sinus rhythm with premature atrial beats which precipitated runs of atrial fibrillation) was treated with continuous rapid atrial pacing to produce 2:1 A-V block. In all instances, the continuous rapid atrial pacing suppressed the supraventricular tachycardia and maintained the ventricular response rate in a therapeutically desirable range. It was demonstrated that the technique is safe, effective, and reliable.
Landmark perspective: Mass vaccination against polio
Authors: A. R. Hinman
Journal: JAMA (1984)

<h3>The Introduction of Oral Vaccine</h3> Although the introduction and immediate widespread use of inactivated polio vaccine (IPV) in 1955 was accompanied by an abrupt decline in the reported number of cases of poliomyelitis in the United States, there was considerable excitement in the late 1950s about the impending availability of attenuated live (oral) poliovirus vaccine (OPV).<sup>1-3</sup>This excitement stemmed both from anticipated advantages of OPV and from some disappointment with the performance of IPV. The anticipated advantages of OPV included its potential to induce effective and long-lasting protection after only one dose, obviating the need for boosters, its ability to pass to contacts of vaccinees, thereby extending the effects of the vaccine beyond those directly vaccinated, and the fact that the protection induced embraces both infection and disease. The disappointment with IPV resulted from the fact that, after a record low of 2,499 cases of paralytic poliomyelitis in 1957,
A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus
Authors: Annarosa Floreani, Isabella Carderi, Angela Variola, Erik Rosa Rizzotto, James Nicol, Nora V. Bergasa
Journal: Hepatology (2006)

A single nucleotide polymorphism characterized by the substitution of valine for glutamate (V1188E) in exon 25 of the multidrug resistance protein 2 gene was found in a group of patients with primary biliary cirrhosis. This heterozygous mutation was significantly associated with the presence of pruritus.
Abstract 3514: LT-00673, a highly potent PARP inhibitor, shows antitumor activity against tumor cells with DNA repair deficiencies
Authors: Yuqiao Jerry Shen, Ying Feng, Bing Wang, Daniel Chu, Peter Myers, Leonard Post
Journal: Cancer Research (2010)

Abstract Poly (ADP-ribose) polymerases (PARP) −1 and −2 are key nuclear enzymes that are activated by DNA damage and play a critical role in the base excision DNA repair (BER) pathway. Previous studies have indicated that inhibitors of PARP-1 and −2 could enhance the tumor cytotoxicity of DNA damaging agents by preventing cancer cells from repairing DNA damage. In addition, PARP inhibitors have been shown to selectively kill cancer cells that are deficient in BRCA-1 or BRCA-2 function. More recently, it was further suggested that other genetic deficiencies, such as PTEN gene mutation and malfunction of DNA mismatch repair, may also sensitize cells to cytotoxicity of PARP inhibitors. We have previously reported a novel PARP inhibitor, called LT-00673, that inhibits PARP-1 with IC50 of 0.58 nM. LT-00673 is also a potent inhibitor of PARP-2, but does not inhibit poly (ADP-ribose) glycohydrolase (PARG). In cell culture studies, LT-00673 potentiates chemotherapeutic agents such as temozolomide and SN-38, and displays potent single-agent cytotoxicity in BRCA-1 and BRCA-2 mutant cells. In xenograft tumor model studies, daily oral dosing of LT-00673 significantly enhances the antitumor effects of cytotoxic therapies in a dose-dependent manner. Furthermore, once daily oral dosing of LT-00673 at 0.33 mg/kg/day results in tumor regression in the MX-1 model (BRCA-1 deficient). In the current study, we further investigated the pharmacokinetic properties of LT-00673 in dogs and rats, and compared antitumor efficacies of different dosing schedules of LT-00673 using xenograft tumor models. We also demonstrated that several PTEN-deficient human cancer cell lines are highly sensitive to LT-00673 as a single agent. 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 3514.