tbuckley/cabot-search huggingface dataset:
Combination of an Src Kinase Inhibitor with a Novel Pharmacological Antagonist of the Urokinase Receptor Diminishes <b> <i>in Vitro</i> </b> Colon Cancer Invasiveness
Authors: Douglas D. Boyd, Heng Wang, Hector Avila, Nila U. Parikh, Horst Kessler, Victor Magdolen, Gary E. Gallick
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The urokinase-type plasminogen activator receptor (u-PAR) contributes to colon cancer invasion and metastases. We have shown previously that u-PAR expression in colon cancer is driven by the Src tyrosine kinase. In the current study, we determined the ability of PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), a Src kinase inhibitor, to reduce u-PAR expression and colon cancer invasion. Experimental Design: Western blotting, Northern blotting, and u-PAR promoter-reporter assays were performed to determine whether PP2 represses u-PAR expression. In vitro invasion assays were used to determine whether this kinase inhibitor, with or without a novel u-PAR antagonist, diminished cultured colon cancer invasiveness. Results: A constitutively active c-Src increased in vitro invasiveness of SW480 cells, whereas HT-29 cells expressing antisense c-Src showed diminished invasiveness, validating c-Src as a target for low molecular weight compound(s). The Src inhibitor PP2 reduced u-PAR transcription in HT-29 cells over the concentration range that blocked Src kinase activity. PP2 also reduced u-PAR protein amounts in three other colon cancer cell lines with modest to high constitutive Src activity. Treatment of HT-29 cells and 2C8 cells (a SW480 clone expressing a constitutively active Src) with PP2 diminished their in vitro invasiveness. Furthermore, combination of the Src inhibitor with a novel u-PAR peptide antagonist (NI-5.12) proved superior to the individual agents in suppressing invasiveness. Conclusions: A c-Src kinase inhibitor represses u-PAR expression and, alone or in combination with a u-PAR antagonist, diminishes colon cancer invasiveness. Thus, concurrent targeting of c-Src expression and pharmacological blockade of the u-PAR may represent a novel means of controlling colon cancer spread.
Double-Blind, Placebo-Controlled, Multicenter, Randomized, Phase IIB Neoadjuvant Study of Letrozole-Lapatinib in Postmenopausal Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative, Operable Breast Cancer
Authors: Valentina Guarneri, Daniele Giulio Generali, Antonio Frassoldati, Fabrizio Artioli, Corrado Boni, Luigi Cavanna, Enrico Tagliafico, Antonino Maiorana, Alberto Bottini, Katia Cagossi, Giancarlo Bisagni, Federico Piacentini, Guido Ficarra, Stefania Bettelli, Enrica Roncaglia, Simona Nuzzo, Ramona Swaby, Catherine Ellis, Clare Holford, PierFranco Conte
Journal: Journal of Clinical Oncology (2014)

Purpose This is a randomized, double-blind, placebo-controlled study aimed to evaluate the clinical and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone receptor (HR) –positive/human epidermal growth factor receptor 2 (HER2) –negative operable breast cancer. Methods Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were randomly assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily or placebo. Surgery was performed within 2 weeks from the last study medication. Clinical response was assessed by ultrasonography. Pre- and post-treatment samples were evaluated for selected biomarkers. Fresh-frozen tissue samples were collected for genomic analyses. Results Numerically similar clinical response rates (partial + complete response) were observed (70% for letrozole-lapatinib and 63% for letrozole-placebo). Toxicities were generally mild and manageable. A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both arms. Overall, 34 patients (37%) had a mutation in PIK3CA exon 9 or 20. In the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation (objective response rate, 93% v 63% in PIK3CA wild type; P = .040). Conclusion The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and manageable toxicities. In unselected estrogen receptor–positive/HER2-negative patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate and similar effect on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer must now be independently confirmed.
The human <i>Tp53 Arg72Pro</i> polymorphism explains different functional prognosis in stroke
Authors: Jose C. Gomez-Sanchez, Maria Delgado-Esteban, Irene Rodriguez-Hernandez, Tomas Sobrino, Natalia Perez de la Ossa, Silvia Reverte, Juan P. Bolaños, Rogelio Gonzalez-Sarmiento, Jose Castillo, Angeles Almeida
Journal: The Journal of Experimental Medicine (2011)

The functional outcome after stroke is unpredictable; it is not accurately predicted by clinical pictures upon hospital admission. The presence of apoptotic neurons in the ischemic penumbra and perihematoma area may account for poor prognosis, but whether the highly variable stroke outcome reflects differences in genetic susceptibility to apoptosis is elusive. The p53 tumor suppressor protein, an important transcriptional regulator of apoptosis, naturally occurs in humans in two variants with single nucleotide polymorphisms resulting in Arg or Pro at residue 72. We show that poor functional outcome after either ischemic or hemorrhagic stroke was linked to the Arg/Arg genotype. This genotype was also associated with early neurological deterioration in ischemic stroke and with increased residual cavity volume in intracerebral hemorrhage. In primary cultured neurons, Arg72-p53, but not Pro72-p53, interacted directly with mitochondrial Bcl-xL and activated the intrinsic apoptotic pathway, increasing vulnerability to ischemia-induced apoptotic cell death. These results suggest that the Tp53 Arg/Arg genotype governs neuronal vulnerability to apoptosis and can be considered as a genetic marker predicting poor functional outcome after stroke.
No association between colon cancer and adenocarcinoma of the oesophagus in a population based cohort study in Sweden
Authors: J Lagergren, O Nyren
Journal: Gut (1999)

BACKGROUND Previous reports have indicated an association between Barrett’s metaplasia or adenocarcinoma of the oesophagus and colonic neoplasia, but the findings have been inconsistent. If true, such an association suggests common causal mechanisms. AIMS To test the hypothesis of an association between Barrett’s metaplasia or adenocarcinoma of the oesophagus and colonic neoplasia. METHODS A population based, retrospective cohort study was performed on all Swedish patients with colon cancer diagnosed between 1958 and 1992. 538 500 person years at risk were reviewed among the 118 030 patients in the cohort (average follow up 4.6 years, median 2.1 years). The standardised incidence ratio (SIR), the ratio of the observed to the expected number of incident oesophageal adenocarcinomas, was used as a measure of relative risk. The expected number was derived from the entire Swedish population. RESULTS Eleven oesophageal adenocarcinomas were found during follow up in the cohort, as against 9.5 expected (SIR=1.2; 95% confidence interval 0.6–2.1). Analysis by latency intervals after diagnosis of colon cancer showed no trend towards increasing or decreasing risk over time. There were no important sex differences in relative risk. CONCLUSIONS Results provide no support for a common link between colon cancer and oesophageal adenocarcinoma. Although the direct relation between colon cancer and Barrett’s oesophagus was not looked at, a search for common aetiological factors or genetic defects may not be fruitful. Screening for colonic neoplasia among patients with malignant or premalignant oesophageal mucosa, or vice versa, may not be warranted.
A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer
Authors: A. Schmittel, L. Fischer von Weikersthal, M. Sebastian, P. Martus, K. Schulze, P. Hortig, M. Reeb, E. Thiel, U. Keilholz
Journal: Annals of Oncology (2006)
Clinical Trials Data Collection: When Less Is More
Authors: Daniel J. Sargent, Stephen L. George
Journal: Journal of Clinical Oncology (2010)

The oncology clinical trials enterprise is clearly under duress.Despite the many documented successes in introducing new therapies to patients over the last 50 years, reform in virtually every area of the system is needed. 1 Harold Varmus, MD, in his introductory address as director of the US National Cancer Institute (NCI), indicated one of his first priorities is to fix the "dysfunctional" clinical trials system. 2 Many aspects of the process have appropriately come under close examination, including the substantial time and effort required to Editorials
Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest
Authors: Niklas Nielsen, Jørn Wetterslev, Tobias Cronberg, David Erlinge, Yvan Gasche, Christian Hassager, Janneke Horn, Jan Hovdenes, Jesper Kjaergaard, Michael Kuiper, Tommaso Pellis, Pascal Stammet, Michael Wanscher, Matt P. Wise, Anders Åneman, Nawaf Al-Subaie, Søren Boesgaard, John Bro-Jeppesen, Iole Brunetti, Jan Frederik Bugge, Christopher D. Hingston, Nicole P. Juffermans, Matty Koopmans, Lars Køber, Jørund Langørgen, Gisela Lilja, Jacob Eifer Møller, Malin Rundgren, Christian Rylander, Ondrej Smid, Christophe Werer, Per Winkel, Hans Friberg
Journal: New England Journal of Medicine (2013)

Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever.In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale.In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar.In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).
Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, NIH: A Short History
Authors: James R. Gillette
Journal: The Annual Review of Pharmacology and Toxicology (2000)

The Laboratory of Chemical Pharmacology (LCP) began in 1950 as the Section of Pharmacology within the National Heart Institute, the National Institutes of Health. Its first chief was Bernard B. Brodie, considered by many to be one of the fathers of modern pharmacology. Since its inception, LCP has made many significant contributions to the fields of pharmacology and toxicology. LCP was among the first to study (a) the effects of drugs on the turnover of serotonin and norepineprine in brain and other tissues, (b) the absorption of drugs from the gastrointestinal tract and their passage across the blood-brain barrier, (c) the oxidation and reduction of drugs and other foreign compounds by liver microsomal enzymes (later known as the cytochrome P450 enzymes) and inhibitors and inducers of these enzymes, (d) the formation of toxic chemically reactive metabolites of drugs and other foreign compounds, and (e) mechanisms of immunological responses. Approximately 300 scientists worked in LCP during its existence, and they and their collaborators published more than 1,300 papers. This is a short history of the people who worked in it and of their contributions to biomedical sciences.
Older individuals have increased oro-nasal breathing during sleep
Authors: M.R. Madronio, E. Di Somma, R. Stavrinou, J.P. Kirkness, E. Goldfinch, J.R. Wheatley, T.C. Amis
Journal: European Respiratory Journal (2004)

Breathing route during sleep has been studied very little, however, it has potential importance in the pathophysiology of sleep disordered breathing. Using overnight polysomnography, with separate nasal and oral thermocouple probes, data were obtained from 41 subjects (snorers and nonsnorers; 25 male and 16 female; aged 20–66 yrs). Awake, upright, inspiratory nasal resistance (Rn) was measured using posterior rhinomanometry. Each 30‐s sleep epoch (not affected by apnoeas/hypopnoeas) was scored for presence of nasal and/or oral breathing. Overnight, seven subjects breathed nasally, one subject oro-nasally and the remainder switched between nasal and oro-nasal breathing. Oral‐only breathing rarely occurred. Nasal breathing epochs were 55.79 (69.78) per cent of total sleep epochs (%TSE; median (interquartile range)), a value not significantly different to that for oro-nasal (TSE: 44.21 (68.66)%). Oro-nasal breathing was not related to snoring, sleep stage, posture, body mass index, height, weight, Rn (2.19 (1.77) cm H 2 O·L −1 ·sec −1 ) or sex, but was positively associated with age. Subjects ≥40 yrs were approximately six times more likely than younger subjects to spend &gt;50% of sleep epochs utilising oro-nasal breathing. Ageing is associated with an increasing occurrence of oro-nasal breathing during sleep.
Goblet and Clara cells of human distal airways: evidence for smoking induced changes in their numbers.
Authors: A B Lumsden, A McLean, D Lamb
Journal: Thorax (1984)

The goblet cell and Clara cell populations of human distal airway epithelium were examined. The bronchioles, terminal bronchioles, and respiratory bronchioles of 16 smokers and four non-smokers were studied by both light and electron microscopy in surgically resected specimens. A very significantly (p less than 0.001) greater number of goblet cells were found in the bronchioles of smokers compared than in those of non-smokers but no such difference was evident in terminal/respiratory bronchioles. Clara cell numbers in contrast were lower in the bronchioles (p less than 0.01) and terminal and respiratory bronchioles of smokers (p less than 0.01). Both of these alterations in cell frequency may adversely affect small airway function in smokers.
Effects of Chemopreventive and Antitelomerase Agents on the Spontaneous Immortalization of Breast Epithelial Cells
Authors: B.-S. Herbert, A. C. Wright, C. M. Passons, W. E. Wright, I. U. Ali, L. Kopelovich, J. W. Shay
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Activation of telomerase is an early event in the development of breast and other cancers that may lead to cell immortalization, a critical and rate-limiting step in cancer progression. Breast epithelial cells from women with Li–Fraumeni syndrome (LFS) immortalize spontaneously and reproducibly in culture. We, therefore, tested whether immortalization of these cells could be prevented by treating them with chemopreventive agents and by inhibiting telomerase activity. Methods: Noncancerous, preimmortal breast epithelial cells derived from a patient with LFS were treated for 3 months with nontoxic concentrations of the chemopreventive agents oltipraz, difluoromethylornithine, tamoxifen, and retinoic acid or with two different telomerase inhibitors. The frequency of spontaneous immortalization of LFS-derived cells was estimated by an approach based on fluctuation analyses. Statistical analyses were two-sided. Results: The frequency of spontaneous immortalization events of LFS-derived breast epithelial cells was reduced by long-term treatment with retinoic acid (P<.001) or tamoxifen (P<.05) compared with solvent-treated cells. The frequency of immortalization was also reduced by treating LFS-derived cells with an antitelomerase antisense oligonucleotide (P<.001) or by inducing the cells to express a dominant negative mutant of telomerase (P<.025) compared with cells treated with a control oligonucleotide or with empty vector, respectively. Conclusions: Treatment of preimmortal LFS breast epithelial cells with chemopreventive and antitelomerase agents decreased the frequency of spontaneous immortalization in vitro. These studies validate the application of a new cell culture model system to screen the effects of novel chemopreventive agents by use of cell immortalization as an end point. The results also suggest that the telomerase ribonucleoprotein complex may be an important molecular target for breast cancer prevention.
Pulmonary hypertension: a contraindication to the use of -adrenoceptor blocking agents
Authors: A. Peacock, K. Ross
Journal: Thorax (2010)

Supraventricular tachycardia (SVT) is a rare but important complication of pulmonary arterial hypertension. β-Adrenoceptor blocking agents are commonly used to treat SVT, but they are potentially dangerous in the context of pulmonary arterial hypertension. Their negative inotropic and chronotropic effects are poorly tolerated in this condition, where cardiac reserve is compromised by a reduced and fixed stroke volume, and their administration can result in significant cardiorespiratory compromise. This is not a new discovery, but it is nonetheless poorly recognised in day-to-day clinical practice.
To Tell the Truth, the Whole Truth, May Do Patients Harm: The Problem of the Nocebo Effect for Informed Consent
Authors: Rebecca Erwin Wells, Ted J. Kaptchuk
Journal: The American Journal of Bioethics (2012)

Abstract The principle of informed consent obligates physicians to explain possible side effects when prescribing medications. This disclosure may itself induce adverse effects through expectancy mechanisms known as nocebo effects, contradicting the principle of nonmaleficence. Rigorous research suggests that providing patients with a detailed enumeration of every possible adverse event—especially subjective self-appraised symptoms—can actually increase side effects. Describing one version of what might happen (clinical “facts”) may actually create outcomes that are different from what would have happened without this information (another version of “facts”). This essay argues that the perceived tension between balancing informed consent with nonmaleficence might be resolved by recognizing that adverse effects have no clear black or white “truth.” This essay suggests a pragmatic approach for providers to minimize nocebo responses while still maintaining patient autonomy through “contextualized informed consent,” which takes into account possible side effects, the patient being treated, and the particular diagnosis involved. Keywords: decision makinginformed consentprofessional ethicsprofessional–patient relationship Acknowledgments Rebecca Erwin Wells was supported by an institutional National Research Service Award number T32AT000051 from the National Center for Complementary & Alternative Medicine (NCCAM) at the National Institutes of Health (NIH). Dr. Wells worked on significant parts of this article with support from Beth Israel Deaconess Medical Center. Ted Kaptchuk was supported by grant number K24 AT004095 from the NCCAM at the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Complementary & Alternative Medicine or the National Institutes of Health.
Rare Mutations in <i>RINT1</i> Predispose Carriers to Breast and Lynch Syndrome–Spectrum Cancers
Authors: Daniel J. Park, Kayoko Tao, Florence Le Calvez-Kelm, Tu Nguyen-Dumont, Nivonirina Robinot, Fleur Hammet, Fabrice Odefrey, Helen Tsimiklis, Zhi L. Teo, Louise B. Thingholm, Erin L. Young, Catherine Voegele, Andrew Lonie, Bernard J. Pope, Terrell C. Roane, Russell Bell, Hao Hu, None Shankaracharya, Chad D. Huff, Jonathan Ellis, Jun Li, Igor V. Makunin, Esther M. John, Irene L. Andrulis, Mary B. Terry, Mary Daly, Saundra S. Buys, Carrie Snyder, Henry T. Lynch, Peter Devilee, Graham G. Giles, John L. Hopper, Bing-Jian Feng, Fabienne Lesueur, Sean V. Tavtigian, Melissa C. Southey, David E. Goldgar
Journal: Cancer Discovery (2014)

Abstract Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C&amp;gt;T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G&amp;gt;T (p.D403Y). On the basis of this finding, a population-based case–control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency &amp;lt; 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29–8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome–spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7–6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7–21; P = 0.0003). Significance: The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions. Cancer Discov; 4(7); 804–15. ©2014 AACR. See related commentary by Ngeow and Eng, p. 762 This article is highlighted in the In This Issue feature, p. 745