tbuckley/cabot-search huggingface dataset:
De-engineering in the NHS
Authors: C J Dickinson
Journal: BMJ (1996)

In 1986 the Chrysler Corporation of the United States recruited Robert Lutz to be its executive vice president. Later he was appointed president and chief operating officer. In a recent lecture he explained to the Royal Academy of Engineering how he had turned round the fortunes of what had been an ailing and unprofitable corporation by a process of what he described as “re-engineering”—incidentally making its cash reserves exceptionally attractive to predators.

When he arrived he discovered innumerable “little bureaucratic empires,” chock-full of what he called “redo loops— miscommunications, false starts, doubling back to do again what should have been done right first time because nobody really worked together as a team.” He created four “platform teams” (one for each main vehicle type), each under a single leader. Each was encouraged to help leaders of the other teams in every possible way. Each team was encouraged to view its suppliers as true extensions of the company rather than as “generic interchangeable vendors” whose only purpose in life was to do what they were told to do. “We've totally scrapped the age old system of auctioning off contracts to the lowest bidder. Instead we set what we call a ‘target cost’ for any given part or component, and work closely with trusted, preselected …
Neutral Endopeptidase Protein Expression and Prognosis in Localized Prostate Cancer
Authors: Iman Osman, Herman Yee, Samir S. Taneja, Benjamin Levinson, Anne Zeleniuch-Jacquotte, Caroline Chang, Craig Nobert, David M. Nanus
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Neutral endopeptidase (NEP) is a cell-surface peptidase that inactivates neuropeptide growth factors implicated in prostate cancer progression. The clinical significance of decreased NEP expression observed in prostate cancer is unclear. We investigated whether decreased NEP expression in localized prostate cancers is associated with prostate-specific antigen (PSA) relapse after radical prostatectomy. Experimental Design: NEP expression patterns were examined by immunohistochemistry in 223 men, who underwent radical prostatectomy between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) with available representative tissues and adequate follow up. We also examined whether hypermethylation of the NEP promoter contributes to down-regulation of NEP protein expression in a subset of patients that showed decreased NEP expression (n = 22). Results: Three patterns of NEP expression were observed: (a) membranous expression similar to benign prostate epithelium (n = 82; 37%); (b) complete loss of NEP expression in prostate cancer compared with adjacent benign prostate glands (n = 105; 47%); and (c) heterogeneous NEP expression (n = 36; 16%). In a multivariate analysis, complete loss of NEP expression was associated with PSA relapse after controlling for grade, stage, pretreatment PSA, and race simultaneously (hazard ratio, 1.99; 95% confidence interval, 1.13–3.52; two-sided χ2 P = 0.017). In addition, DNA hypermethylation of the NEP promoter was frequently (73%) identified in a subset of 22 of cases that showed decreased NEP expression. Conclusion: Our data suggest that decreased NEP expression might contribute to progression of localized prostate cancer after surgery. Data also suggest that methylation is an important mechanism of NEP protein silencing. Larger prospective studies are required for confirmation.
The Early Development of Homosexuality: A Study of Adolescent Lesbians
Authors: MALVINA W. KREMER, ALFRED H. RIFKIN
Journal: American Journal of Psychiatry (1969)

Twenty-five lesbian girls between the ages of 12 and 17 were investigated with special emphasis on family background and relationships. The reversed oedipal formulation that appears to describe many lesbians raised in intact nuclear families was not found. Findings from the study suggest that homosexuality may be a final common behavior pathway rather than a single entity with a single etiology.
Insulin-like growth factor-1 and its binding proteins during a low-protein diet in chronic renal failure.
Authors: D Fouque, Y Le Bouc, M Laville, F Combarnous, M O Joly, P Raton, P Zech
Journal: Journal of the American Society of Nephrology (1995)

The effects of a low-protein diet on the serum insulin-like growth factor (IGF)-1 and IGF binding proteins (IGFBP) were investigated during a 3-month controlled study in 12 adult chronic renal failure patients. Six patients were randomly supplemented with keto acids (Cetolog, Clintec, Velizy, France). Protein intake was prescribed so that both groups were isonitrogenous. Dietary survey included a monthly 3-day food record and a 24-h urinary urea measurement. After a 4- to 6-wk equilibrium period (1.11 g of protein, 32 kcal/kg body wt per day), patients reduced their protein intake to 0.71 g protein/kg body wt per day. Energy intake was kept constant (31 kcal/kg body wt per day) during the 3-month period. Serum IGF-1 levels were in normal range and, for 11 of the 12 patients, were correlated with the GFR (P = 0.01). These serum IGF-1 values did not decrease after reducing the protein intake. By Western ligand blotting, serum IGFBP1, IGFBP2, and IGFBP4 levels were significantly higher than normal adults, whereas the IGFBP3 level was not increased. IGFBP were not modified when protein intake was reduced. The IGFBP1 level was elevated despite a normal insulin level. IGFBP4 changes were inversely correlated with IGF-1 variations. There was no difference between groups receiving or not receiving the keto acids. Thus, in adult chronic renal failure, reducing protein intake by 40% did not modify the growth hormone/IGF-1/IGFBP axis.
Studies on the Mechanism of Isoantigenic Variant Formation in Heterozygous Mouse Tumors. IV. &lt;italic&gt;H-2&lt;/italic&gt; Component Analysis of an (A/Sn × A.SW)F&lt;sub&gt;1&lt;/sub&gt; Lymphoma 1&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: Harvey L. Ozer, George Klein, Joy H. Ozer
Journal: JNCI Journal of the National Cancer Institute (1966)

An A/Sn × A.SW lymphoma (LNSF) and isoantigenic variants derived from it were studied with the use of monocomponent isoantisera in vitro. Representative antigens of 3 classes were analyzed: those derived from A/Sn alone (4, 8, 11), from A.SW alone (7, 19), and from both A/Sn and A.SW (3, 5). Variants were obtained from mice in which selection was directed against 4, 8, 11 (A.SW), 4 alone (A.SW × C3H), or 11 alone (A.SW × DBA/2). All variants retained A.SW antigens whether in A.SW alone or both A/Sn and A.SW. A.SW and A.SW × C3H variants lost 4, 8, 11. Four A.SW × DBA/2 variants were 4, 8, −11, while one was 4, −8, −11. The segregation of 8 in these variants indicated that 8 is between 4 and 11 in the H-2 chromosomal region, that a chromosomal alteration is most likely responsible for variant formation in vivo, and that this method can be used for genetic analysis of the H-2.
Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model
Authors: Eline Menu, Helena Jernberg-Wiklund, Thomas Stromberg, Hendrik De Raeve, Leonard Girnita, Olle Larsson, Magnus Axelson, Kewal Asosingh, Kenneth Nilsson, Ben Van Camp, Karin Vanderkerken
Journal: Blood (2005)
Comparison of recombinant adenovirus vectors expressing antimigratory and antiproliferative proteins in a porcine coronary restenosis model
Authors: O. Varenne, P. Sinnaevo, H. Gillijns, V. Laurysens, A. Bout, K. Meurrens, C. Zurcher, J.E. van Dijk, D. Collen, S. Janssens, R.D. Gerard
Journal: Journal of the American College of Cardiology (1998)
IFNα-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells
Authors: Cristina Tecchio, Veronica Huber, Patrizia Scapini, Federica Calzetti, Daniela Margotto, Giuseppe Todeschini, Lorenzo Pilla, Giovanni Martinelli, Giovanni Pizzolo, Licia Rivoltini, Marco A. Cassatella
Journal: Blood (2004)
Telethonin Deficiency Is Associated With Maladaptation to Biomechanical Stress in the Mammalian Heart
Authors: Ralph Knöll, Wolfgang A. Linke, Peijian Zou, Snježana Miočiċ, Sawa Kostin, Byambajav Buyandelger, Ching-Hsin Ku, Stefan Neef, Monika Bug, Katrin Schäfer, Gudrun Knöll, Leanne E. Felkin, Johannes Wessels, Karl Toischer, Franz Hagn, Horst Kessler, Michael Didié, Thomas Quentin, Lars S. Maier, Nils Teucher, Bernhard Unsöld, Albrecht Schmidt, Emma J. Birks, Sylvia Gunkel, Patrick Lang, Henk Granzier, Wolfram-Hubertus Zimmermann, Loren J. Field, Georgine Faulkner, Matthias Dobbelstein, Paul J.R. Barton, Michael Sattler, Matthias Wilmanns, Kenneth R. Chien
Journal: Circulation Research (2011)

Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function.Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation.By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts.Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.
Increase in collateral blood flow following repeated coronary artery occlusion and nitroglycerin administration.
Authors: S Brazzamano, A E Mays, J C Rembert, J C Greenfield
Journal: Circulation Research (1984)

The effects of occlusion, reperfusion, reocclusion (n = 13), and nitroglycerin (n = 10) on regional transmural myocardial collateral blood flow was tested in conscious dogs in which collateral development was stimulated by partial stenosis of the left circumflex coronary artery. Hemodynamics and collateral blood flow were measured during the awake state using 9-micron radioactive microspheres. Regional transmural flow was measured during transient occlusion of the circumflex artery at 7 and at 14 days postoperatively. On the 14th postoperative day, two sets of circumflex occlusions and blood flow measurements were carried out. The first set consisted of two occlusions separated by 15 minutes. The second set performed 2 hours later included two occlusions, separated by 15 minutes, and nitroglycerin administration. Mean collateral blood flow increased significantly (P = 0.002) from 0.10 +/- 0.07 ml/min per g on day 7 to 0.25 +/- 0.18 ml/min per g on day 14. A significant increase in mean collateral blood flow from occlusion one to two was observed (0.28 +/- 0.17 to 0.37 +/- 0.22 ml/min per g, P = 0.005). Mean collateral flow increased significantly (P = 0.01) between pre- to post-nitroglycerin occlusions, 0.28 +/- 0.20 to 0.46 +/- 0.32 ml/min per g. Although this increase appeared to be greater than during the first set of occlusions, it did not reach statistical significance (P = 0.08). These data indicate that when immature collaterals are present, occlusions, reperfusion, and reocclusions of a major coronary artery produce augmentation in collateral flow. This must be considered in evaluating interventions which may alter collateral flow.
Changes in bronchoalveolar lavage fluid proteins in sarcoidosis: a proteomics approach
Authors: F. Sabounchi-Schütt, J. Åström, U. Hellman, A. Eklund, J. Grunewald
Journal: European Respiratory Journal (2003)

In sarcoidosis, an inflammatory lung disease, the protein profile of bronchoalveolar lavage fluid (BALF) is altered. To study the BALF protein pattern changes in sarcoidosis, samples from six patients and four healthy individuals were analysed by two-dimensional polyacrylamide gel electrophoresis. A comparison of the protein-spot patterns showed a significantly higher number of protein spots in the pH range 5.5–6.7 in patients compared to controls (472 <i>versus</i> 384). Furthermore, the number of protein spots in the patients were significantly decreased in the acidic pH range 4.5–5.5 (399 <i>versus</i> 518). Measurement of the optical density in the gels showed varying expression levels for several protein spots. Seventeen of the altered protein spots were identified, of which seven have previously not been reported for BALF. Many of these are nonplasma proteins involved in the inflammatory and oxidant-antioxidant processes. In conclusion, the bronchoalveolar lavage fluid protein content is altered in sarcoidosis patients, especially for proteins that are not derived from plasma. The described proteomics approach will in the future be used to asses overall changes in the protein content associated with sarcoidosis and may offer the possibility of identifying disease-specific proteins.
PTU-122 A Gmp Treg Expansion Protocol Restores Treg Suppressor Function In End-stage Liver Disease; Implications For Adoptive Transfer Therapy
Authors: N Safinia, T Vaikunthanathan, H Fraser, C Scotta, R Lechler, G Lombardi
Journal: Gut (2014)

<h3>Introduction</h3> Long-term survival in liver transplant recipients remains suboptimal because of the morbidity and mortality associated with the long-term use of immunosuppression (IS). However, IS weaning early post liver transplantation (LT) has largely been unsuccessful, supporting the need for active tolerance induction strategies. CD4<sup>+</sup>CD25<sup>+</sup>FOXP3+ (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance. Phase I trials in bone marrow transplantation have shown that <i>ex vivo</i> expanded Tregs have an excellent safety profile, which is encouraging for the broader application of these cells. The clinical trial, ThRIL, soon to be initiated at King’s College London, aims to investigate the therapeutic potential of Tregs in the setting of LT. We have devised a GMP compatible protocol that ensures the successful isolation and expansion of a functional and stable human Treg population in preparation for this trial. <h3>Methods</h3> Tregs were isolated from 150ml of blood from patients with end-stage liver disease by a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2 and rapamycin. <h3>Results</h3> A 580-fold expansion of pure Tregs was achieved (97.4% CD4<sup>+</sup>CD25<sup>+</sup> and 0.008% CD8<sup>+</sup> cells) and the cells maintained FoxP3 expression (99.6% of the CD4<sup>+</sup>CD25<sup>+</sup> cells express FoxP3). The populations of Tregs obtained were also stable and did not convert to Th17 cells when cultured in the presence of pro-inflammatory stimuli. This protocol further proved to be ideal for the expansion of Tregs from patients with liver disease in view of restoring the Tregs’ suppressive function (1:1 ratio – expanded Tregs 91.1% vs. freshly isolated Tregs 28.6% suppression, 1:10 ratio – 80.7% vs. 20.8% respectively). Based on these findings, we subsequently conducted an in-depth phenotypic characterisation of freshly isolated Tregs in order to delineate a population responsible for the apparent lack of suppressive function. An investigation into the possible mechanisms is currently ongoing. <h3>Conclusion</h3> The feasibility of Treg based therapy is now widely accepted, provided that tailor-made clinical grade procedures for isolation and ex-vivo cell handling are available. Our rapamycin-based protocol is ideal in this setting as it not only satisfies the rigours of GMP manufacturing standards, but also derives a population of Tregs that is stable and functionally superior compared to freshly isolated Tregs. <h3>Disclosure of Interest</h3> None Declared.
Cued Recall of Alcohol Advertising on Television and Underage Drinking Behavior
Authors: Susanne E. Tanski, Auden C. McClure, Zhigang Li, Kristina Jackson, Matthis Morgenstern, Zhongze Li, James D. Sargent
Journal: JAMA Pediatrics (2015)

<h3>Importance</h3> Alcohol is the most common drug among youth and a major contributor to morbidity and mortality worldwide. Billions of dollars are spent annually marketing alcohol. <h3>Objective</h3> To examine the reach of television alcohol advertising and its effect on drinking among underage youth. <h3>Design, Setting, and Participants</h3> Longitudinal telephone- and web-based surveys conducted in 2011 and 2013 involving 2541 US adolescents 15 to 23 years of age at baseline, with 1596 of these adolescents completing the follow-up survey. Cued recall of television advertising images for top beer and distilled spirits brands that aired nationally in 2010-2011 (n = 351). Images were digitally edited to remove branding, and the respondents were queried about 20 randomly selected images. An alcohol advertising receptivity score was derived (1 point each for having seen the ad and for liking it, and 2 points for correct brand identification). Fast-food ads that aired nationally in 2010-2011 (n = 535) were similarly queried to evaluate message specificity. <h3>Main Outcomes and Measures</h3> Among the underage youth at baseline, we determined (1) the onset of drinking among those who never drank, (2) the onset of binge drinking among those who were never binge drinkers, and (3) the onset of hazardous drinking among those with an Alcohol Use Disorders Identification Test consumption subscore of less than 4. Multivariate regressions were used to predict each outcome, controlling for covariates (demographics, drinking among friends and parents, and sensation seeking), weighting to the US population, and using multiple imputation to address loss to follow-up. <h3>Results</h3> Underage participants were only slightly less likely than participants of legal drinking age to have seen alcohol ads (the mean percentage of ads seen were 23.4%, 22.7%, and 25.6%, respectively, for youth 15-17, 18-20, and 21-23 years of age;<i>P</i> &lt; .005). The transition to binge and hazardous drinking occurred for 29% and 18% of youth 15 to 17 years of age and for 29% and 19% of youth 18 to 20 years years of age, respectively. Among underage participants, the alcohol advertising receptivity score independently predicted the onset of drinking (adjusted odds ratio [AOR], 1.69 [95% CI, 1.17-2.44]), the onset of binge drinking (AOR, 1.38 [95% CI, 1.08-1.77]), and the onset of hazardous drinking (AOR, 1.49 [95% CI, 1.19-1.86]). Fast-food advertising receptivity was not associated with any drinking outcome. <h3>Conclusions and Relevance</h3> Receptivity to television alcohol advertising predicted the transition to multiple drinking outcomes. The findings are consistent with the idea that marketing self-regulation has failed to keep television alcohol advertising from reaching large numbers of underage persons and affecting their drinking patterns.
A Small-Molecule Blocking Ribonucleotide Reductase Holoenzyme Formation Inhibits Cancer Cell Growth and Overcomes Drug Resistance
Authors: Bingsen Zhou, Leila Su, Shuya Hu, Weidong Hu, M.L. Richard Yip, Jun Wu, Shikha Gaur, D. Lynne Smith, Yate-Ching Yuan, Timothy W. Synold, David Horne, Yun Yen
Journal: Cancer Research (2013)

Abstract Ribonucleotide reductase (RNR) is an attractive target for anticancer agents given its central function in DNA synthesis, growth, metastasis, and drug resistance of cancer cells. The current clinically established RNR inhibitors have the shortcomings of short half-life, drug resistance, and iron chelation. Here, we report the development of a novel class of effective RNR inhibitors addressing these issues. A novel ligand-binding pocket on the RNR small subunit (RRM2) near the C-terminal tail was proposed by computer modeling and verified by site-directed mutagenesis and nuclear magnetic resonance (NMR) techniques. A compound targeting this pocket was identified by virtual screening of the National Cancer Institute (NCI) diverse small-molecule database. By lead optimization, we developed the novel RNR inhibitor COH29 that acted as a potent inhibitor of both recombinant and cellular human RNR enzymes. COH29 overcame hydroxyurea and gemcitabine resistance in cancer cells. It effectively inhibited proliferation of most cell lines in the NCI 60 human cancer panel, most notably ovarian cancer and leukemia, but exerted little effect on normal fibroblasts or endothelial cells. In mouse xenograft models of human cancer, COH29 treatment reduced tumor growth compared with vehicle. Site-directed mutagenesis, NMR, and surface plasmon resonance biosensor studies confirmed COH29 binding to the proposed ligand-binding pocket and offered evidence for assembly blockade of the RRM1-RRM2 quaternary structure. Our findings offer preclinical validation of COH29 as a promising new class of RNR inhibitors with a new mechanism of inhibition, with broad potential for improved treatment of human cancer. Cancer Res; 73(21); 6484–93. ©2013 AACR.
Impact of Short-Term Preoperative Radiotherapy on Health-Related Quality of Life and Sexual Functioning in Primary Rectal Cancer: Report of a Multicenter Randomized Trial
Authors: Corrie A.M. Marijnen, Cornelis J.H. van de Velde, Hein Putter, Mandy van den Brink, Cornelis P. Maas, Hendrik Martijn, Harm J. Rutten, Theo Wiggers, Elma Klein Kranenbarg, Jan-Willem H. Leer, Anne M. Stiggelbout
Journal: Journal of Clinical Oncology (2005)

Few prospective studies have been performed about the impact of preoperative radiotherapy (PRT) or total mesorectal excision (TME) on health-related quality of life (HRQL) and sexual functioning in patients with resectable rectal cancer. This report describes the HRQL and sexual functioning of 990 patients who underwent TME and were randomly assigned to short-term PRT (5 x 5 Gy).The Rotterdam Symptom Check List supplemented with additional items was used with questionnaires before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients without a recurrence the first 2 years were analyzed (n = 990).Few differences were found in HRQL between patients treated with or without PRT. Daily activities were significantly less for PRT patients 3 months postoperatively. Irradiated patients recovered slower from defecation problems than TME-only patients (P = .006). PRT had a negative effect on sexual functioning in males (P = .004) and females (P < .001). Irradiated males had more ejaculation disorders (P = .002), and erectile functioning deteriorated over time (P < .001). PRT had similar effects in patients who underwent a low anterior resection (LAR) versus an abdominoperineal resection (APR). Patients with an APR scored better on the physical (P = .004) and psychologic dimension (P = .007) than LAR patients, but worse on voiding (P = .0007).Short-term PRT leads to more sexual dysfunction, slower recovery of bowel function, and impaired daily activity postoperatively. However, this does not seriously affect HRQL. The comparison between LAR and APR patients demonstrates that the existence of a permanent stoma is not the only determinant of HRQL.