tbuckley/cabot-search huggingface dataset:
Significant Impact of Protein Dispensability on the Instantaneous Rate of Protein Evolution
Authors: J. Zhang
Journal: Molecular Biology and Evolution (2005)

The neutral theory of molecular evolution predicts that important proteins evolve more slowly than unimportant ones. High-throughput gene-knockout experiments in model organisms have provided information on the dispensability, and therefore importance, of thousands of proteins in a genome. However, previous studies of the correlation between protein dispensability and evolutionary rate were equivocal, and it has been proposed that the observed correlation is due to the covariation with the level of gene expression or is limited to duplicate genes. We here analyzed the gene dispensability data of the yeast Saccharomyces cerevisiae and estimated protein evolutionary rates by comparing S. cerevisiae with nine species of varying degrees of divergence from S. cerevisiae. The correlation between gene dispensability and evolutionary rate, although low, is highly significant, even when the gene expression level is controlled for or when duplicate genes are excluded. Our results thus support the hypothesis of lower evolution rates for more important proteins, a widely used principle in the daily practice of molecular biology. When the evolutionary rate is estimated from closely related species, the ratio between the mean rate of nonessential proteins to that of essential proteins is 1.4. This ratio declines to 1.1 when the evolutionary rate is estimated from distantly related species, suggesting that the importance of a protein may change in evolution, so the dispensability data obtained from a model organism only predicts a short-term rate of protein evolution. A comparison of the fitness contributions of orthologous genes in yeast and nematode supports this conclusion.
Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma
Authors: Raphaël Maréchal, Jean-Baptiste Bachet, Annabelle Calomme, Pieter Demetter, Jean Robert Delpero, Magali Svrcek, Jérôme Cros, Armelle Bardier-Dupas, Francesco Puleo, Geneviève Monges, Pascal Hammel, Christophe Louvet, François Paye, Philippe Bachelier, Yves Patrice Le Treut, Jean-Christophe Vaillant, Alain Sauvanet, Thierry André, Isabelle Salmon, Jacques Devière, Jean-François Emile, Jean-Luc Van Laethem
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density. Experimental Design: Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated. Results: Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P &amp;lt; 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023). Conclusions: Shh and Gli1 are prognostic biomarkers for patients with resected PDAC. Clin Cancer Res; 21(5); 1215–24. ©2014 AACR.
Aberrant p16INK4A and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma
Authors: A V Biankin
Journal: Gut (2002)

<b>Background and aims:</b> Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor β/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT. <b>Methods:</b> Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16<sup>INK4A</sup>, p21<sup>CIP1</sup>, p27<sup>KIP1</sup>, cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the χ<sup>2</sup> and Fisher9s exact tests. <b>Results:</b> Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16<sup>INK4A</sup> expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p&lt;0.001). Similarly, loss of Smad4 expression was associated with IPMC: 3/8 (38%) versus adenoma/borderline IPMT 0/10 (p&lt;0.03). Loss of Smad4 expression within the IPMT was the best marker for the presence of invasive carcinoma (p&lt;0.001). <b>Conclusions:</b> These data indicate that loss of p16<sup>INK4A</sup> and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.
Analysis of H-2 determinants recognized during the induction of H-Y-immune cytotoxic T cells by monoclonal antibodies in vitro
Authors: M Brenan, A Mullbacher
Journal: The Journal of Experimental Medicine (1981)

Monoclonal antibodies directed to the D region of H-2(k) when present during in vitro culture inhibit the generation of CBA/H and C3H.H-2(o) H-Y-immune cytotoxic T cells . Monoclonal antibodies directed to the I-A(k) and I-E(k) region specifically inhibited induction of CBA/H H-Y-immune cytotoxic T cells only when they were present simultaneously in culture. These findings show T helper cell requirement for CBA/H H-Y-immune cytotoxic T cell induction, and suggest that two I region-coded restriction antigens for T helper cells are involved.
Endocrine Effects of Adjuvant Letrozole Compared With Tamoxifen in Hormone-Responsive Postmenopausal Patients With Early Breast Cancer: The HOBOE Trial
Authors: Emanuela Rossi, Alessandro Morabito, Francesca Di Rella, Giuseppe Esposito, Adriano Gravina, Vincenzo Labonia, Gabriella Landi, Francesco Nuzzo, Carmen Pacilio, Ermelinda De Maio, Massimo Di Maio, Maria Carmela Piccirillo, Gianfranco De Feo, Giuseppe D'Aiuto, Gerardo Botti, Paolo Chiodini, Ciro Gallo, Francesco Perrone, Andrea de Matteis
Journal: Journal of Clinical Oncology (2009)

PURPOSE We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. PATIENTS AND METHODS Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. CONCLUSION Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.
MEBROPHENHYDRAMINE ("MEBRYL") IN THE TREATMENT OF ALLERGIC CONDITIONS.
Authors: G. LESLIE
Journal: British Journal of Dermatology (1963)

Journal Article MEBROPHENHYDRAMINE (“MEBRYL”) IN THE TREATMENT OF ALLERGIC CONDITIONS. Get access G. LESLIE, M.D. (Glas.) G. LESLIE, M.D. (Glas.) The Department of Dermatology, Royal Infirmary, Glasgow Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 75, Issue 7, 1 July 1963, Pages 285–288, https://doi.org/10.1111/j.1365-2133.1963.tb15686.x Published: 01 July 1963
Inflamed Glomeruli—Specific Gene Activation that Uses Recombinant Adenovirus with the Cre/loxP System
Authors: TAKASHI YOKOO, TOYA OHASHI, YASUNORI UTSUNOMIYA, HIROAKI SHIBA, JIN SONG SHEN, YUTAKA HISADA, YOSHIKATSU ETO, TETSUYA KAWAMURA, TATSUO HOSOYA
Journal: Journal of the American Society of Nephrology (2001)

The authors previously reported that bone marrow-derived CD11b+CD18+ cells could be used as a vehicle to deliver foreign genes into inflamed glomeruli and that this vehicle cell (v-cell) could retard the progression of nephritis by delivering anti-inflammatory molecules. As a next step, the authors tried to establish a switching system by which v-cells are activated only at the inflamed glomeruli. A recombinant adenovirus (Ad) that expressed Cre recombinase under the control of the interleukin-1β (IL-1β) promoter (AxIL-1pr/Cre) was constructed and transfected into v-cells. After confirming that AxIL-1pr/Cre expresses Cre by lipopolysaccharide (LPS) treatment, AxIL-1pr/Cre was infected together with another Ad bearing a switching reporter unit in which the LacZ gene is activated under the control of the CAG promoter by the Cremediated excisional deletion of interposed stuffer DNA. Only a negligible number of double-infected (Cre/loxPCAG) cells expressed LacZ. This number, however, was significantly increased by LPS, which suggests that LPS-induced Cre effectively deletes the stuffer DNA, which allows for a complete CAG promoter. DBA/2j mice were then transplanted with Cre/loxPCAG cells via a tail vein and treated with anti—glomerular basement membrane (GBM) serum. To trace the transplanted cells, marker v-cells, infected with AxCANLacZ to constitutively express the LacZ gene, were also used. Although transplanted cells expressing LacZ collected in the spleen independent of anti-GBM treatment, they did not express the LacZ gene in the mice transplanted with Cre/loxPCAG cells. On the other hand, transplanted cells were recruited in the glomeruli and expressed the LacZ gene upon anti-GBM treatment. These results suggested that only the v-cells recruited in the glomeruli could be switched on and activate foreign genes.
The Disappearance of K <sup>42</sup> from the Nonuniformly Mixed Circulation Pool in Dogs
Authors: C. W. SHEPPARD, R. R. OVERMAN, W. S. WILDE, W. C. SANGREN
Journal: Circulation Research (1953)

The disappearance of injected labeled substances which disappear rapidly from the circulation is discussed theoretically and tested in experiments with injected K 42 in the dog. Comparing the inflow and outflow from a capillary bed, using semilogarithmic plots of label concentrations, events upstream are repeated downstream but displaced in time by the amount of the mean circulation time between the points of observation. Downward displacement occurs owing to the intervening loss of material, and smearing of the time relations is produced by the dispersing action of variable path lengths in the capillary labyrinth. For the circulation as a whole, the time relations consist of the sum of a periodic component and an aperiodic component. The periodic component is governed by the mixing relations in a virtual circulation whose architecture approximates that of the real circulation. Extrapolating the aperiodic component to zero time yields the volume of dilution of the injected material in the virtual circulation, providing that injection and sampling points are close together. When the points are separated, correction must be made for time delay and loss of label between. The initial slope is governed not only by the mean rate of exchange of injected substance with the tissues but also by the mean circulation time.
Phase III Trial Evaluating the Addition of Bevacizumab to Endocrine Therapy As First-Line Treatment for Advanced Breast Cancer: The Letrozole/Fulvestrant and Avastin (LEA) Study
Authors: Miguel Martín, Sibylle Loibl, Gunter von Minckwitz, Serafín Morales, Noelia Martinez, Angel Guerrero, Antonio Anton, Bahriye Aktas, Winfried Schoenegg, Montserrat Muñoz, José Ángel Garcia-Saenz, Miguel Gil, Manuel Ramos, Mireia Margeli, Eva Carrasco, Cornelia Liedtke, Grischa Wachsmann, Keyur Mehta, Juan R. De la Haba-Rodriguez
Journal: Journal of Clinical Oncology (2015)

Purpose To test whether combining bevacizumab, an anti–vascular endothelial growth factor treatment, with endocrine therapy (ET) could potentially delay the emergence of resistance to ET. Patients and Methods A multicenter, randomized, open-label, phase III, binational (Spain and Germany) study added bevacizumab (15 mg/kg every 3 weeks) to ET (ET-B; letrozole or fulvestrant) as first-line therapy in postmenopausal patients with human epidermal growth factor receptor 2 (HER2) –negative and hormone receptor–positive advanced breast cancer. We compared progression-free survival (PFS), overall survival (OS), overall response rate (ORR), response duration (RD), time to treatment failure (TTF), clinical benefit rate (CBR), and safety. Results From 380 patients recruited (2007 to 2011), 374 were analyzed by intent to-treat (184 patients on ET and 190 patients on ET-B). Median age was 65 years, 270 patients (72%) had Eastern Cooperative Oncology Group performance status of 0, 178 patients (48%) had visceral metastases, and 171 patients (46%) and 195 patients (52%) had received prior chemotherapy or ET, respectively. Median PFS was 14.4 months in the ET arm and 19.3 months in the ET-B arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.06; P = .126). ORR, CBR, and RD with ET versus ET-B were 22% versus 41% (P &lt; .001), 67% versus 77% (P = .041), and 13.3 months versus 17.6 months (P = .434), respectively. TTF and OS were comparable in both arms. Grade 3 to 4 hypertension, aminotransferase elevation, and proteinuria were significantly higher in the ET-B arm. Eight patients (4.2%) receiving ET-B died during study or within 30 days of end of treatment. Conclusion The addition of bevacizumab to ET in first-line treatment failed to produce a statistically significant increase in PFS or OS in women with HER2-negative/hormone receptor–positive advanced breast cancer.
EULAR evidence-based recommendations for the management of fibromyalgia syndrome
Authors: S F Carville, S Arendt-Nielsen, H Bliddal, F Blotman, J C Branco, D Buskila, J A P Da Silva, B Danneskiold-Samsøe, F Dincer, C Henriksson, K G Henriksson, E Kosek, K Longley, G M McCarthy, S Perrot, M Puszczewicz, P Sarzi-Puttini, A Silman, M Späth, E H Choy
Journal: Annals of the Rheumatic Diseases (2007)

Objective: To develop evidence-based recommendations for the management of fibromyalgia syndrome. Methods: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords “fibromyalgia”, “treatment or management” and “trial”. Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. Results: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and “other pharmacological” and exercise, cognitive behavioural therapy, education, dietary interventions and “other non-pharmacological”. In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. Conclusions: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.
Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor AZD2171 and Fractionated Radiotherapy in Mouse Models of Lung Cancer
Authors: Carolyn Cao, Jeffrey M. Albert, Ling Geng, Percy S. Ivy, Alan Sandler, David H. Johnson, Bo Lu
Journal: Cancer Research (2006)

Abstract The vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are being explored as targets for antiangiogenic cancer therapy. Radiotherapy also inhibits tumor growth and affects vasculature. We investigated the combination of the potent VEGFR tyrosine kinase inhibitor AZD2171 and ionizing radiation in cell culture and mouse models of lung cancer. We show that ionizing radiation induces expression of phosphorylated VEGFR-2 (Flk-1) in endothelial cells and that this phosphorylation is inhibited by AZD2171. Human umbilical vascular endothelial cells become more sensitive to radiation after treatment with AZD2171 as determined by clonogenic assay. Matrigel assay showed a decrease in in vitro endothelial tubule formation with AZD2171/radiation combination treatment. When similar combination was applied to the H460 lung cancer xenograft model in nude mice, loss of radiation-induced phosphorylated Flk-1 was observed in the combination treatment group, which also showed a large decrease in tumor vascular density by staining of the von Willebrand factor. H460 tumor growth delay was enhanced in the combination treatment group compared with the groups treated with AZD2171 or radiation alone. Additionally, after therapy, Ki67 index showed &amp;gt;4-fold reduction of tumor proliferation in the combination therapy group, which also showed increased intratumoral apoptotic index by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining. In conclusion, AZD2171 sensitizes lung tumor xenografts to radiation and inhibits angiogenesis both in vitro and in vivo. When used as a radiation enhancer, AZD2171 has the potential to improve tumor growth delay by inhibiting tumor proliferation and promoting apoptosis. Clinical trials are needed to determine the potential of this combination therapy in patients with locally advanced lung cancer. (Cancer Res 2006; 66(23): 11409-15)
Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction
Authors: K. C. Lord, S. K. Shenouda, E. McIlwain, D. Charalampidis, P. A. Lucchesi, K. J. Varner
Journal: Cardiovascular Research (2010)

Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Echocardiography and Millar pressure–volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased −dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction.
G<scp>ENETIC</scp>E<scp>FFECTS OF</scp>M<scp>ETHYLATION</scp>D<scp>IETS</scp>
Authors: Ignatia B. Van den Veyver
Journal: Annual Review of Nutrition (2002)

DNA methylation at cytosines in CpG dinucleotides can lead to changes in gene expression and function without altering the primary sequence of the DNA. Methylation can be affected by dietary levels of methyl-donor components, such as folic acid. This may be an important mechanism for environmentally induced changes in gene expression. Recent literature supports a role for DNA-methylation changes in a number of adult-onset disorders and during development. These changes may be significant for better understanding certain birth defects (e.g., neural tube defects) and the long-term consequences of early environmental influences on gene expression (metabolic programming). Optimal "methylation diets" should be investigated as part of the prevention and treatment of all these conditions, as well as in disorders such as Rett syndrome, whose primary defects may lie in DNA methylation-dependent gene regulation.
Comparative somatostatin receptor scintigraphy using In-111-DOTA-lanreotide and In-111-DOTA-Tyr3-octreotide versus F-18-FDG-PET for evaluation of somatostatin receptor-mediated radionuclide therapy
Authors: I. Virgolini, P. Patri, C. Novotny, T. Traub, M. Leimer, B. Füger, S.R. Li, P. Angelberger, M. Raderer, S. Wogritsch, A. Kurtaran, K. Kletter, R. Dudczak
Journal: Annals of Oncology (2001)