tbuckley/cabot-search huggingface dataset:
Eukaryotic Translation Initiation Factor 4E–Induced Progression of Primary Human Mammary Epithelial Cells along the Cancer Pathway Is Associated with Targeted Translational Deregulation of Oncogenic Drivers and Inhibitors
Authors: Ola Larsson, Shunan Li, Olga A. Issaenko, Svetlana Avdulov, Mark Peterson, Karen Smith, Peter B. Bitterman, Vitaly A. Polunovsky
Journal: Cancer Research (2007)

Abstract Pathologic redirection of translational control by constitutive activation of eukaryotic translation initiation factor 4F (eIF4F), the cap-dependent translation initiation apparatus, is an obligatory step in oncogenesis; however, its mechanism remains undefined. Here, we simulate this pro-oncogenic state by overexpressing eIF4E, the rate-limiting component of eIF4F, in primary human mammary epithelial cells (HMECs) and examine the resultant changes in cell biology and gene expression profiles of total and polyribosome-bound mRNA genome wide. Overexpressed eIF4E rescues primary HMECs from telomere-independent growth arrest and disables checkpoints governing S-phase entry as well as apoptosis in HMECs immortalized by telomerase, imparting cells with proliferative and survival autonomy. Although the transcriptional response to increased eIF4E was modest, the translational response was large, selective, and bidirectional. In addition to translational activation of known and novel eIF4E-responsive oncogenic drivers regulating cell growth and survival, our data unveil previously unrecognized cellular defenses including translational activation of tumor suppressors, translational repression of transcripts enriched with miRNA target sites, and translational modulation of genes governing translation itself. These findings provide insight into the proneoplastic and compensatory mechanisms embedded in the oncogenic translational program. They support a model whereby deregulated eIF4E moves human epithelial cells along the cancer pathway by profoundly altering ribosomal recruitment to cancer-related transcripts, and eIF4E-modified cells counter these potentially oncogenic alterations with a compensatory translational mechanism that mitigates acquisition of malignancy. [Cancer Res 2007;67(14):6814–24]
A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma
Authors: W.K. Chia, W.-W. Wang, M. Teo, W.M. Tai, W.T. Lim, E.H. Tan, S.S. Leong, L. Sun, J.J. Chen, S. Gottschalk, H.C. Toh
Journal: Annals of Oncology (2011)
Effects of stellate stimulation and hypoxia on haemodynamics and coronary circulation
Authors: A. I. Obeid, H. Smulyan, R. H. Eich
Journal: Cardiovascular Research (1971)

The effects of left stellate ganglion stimulation on haemodynamics and coronary blood flow were studied in dogs, and compared with hypoxia produced by arterial anoxia. Both left stellate stimulation and hypoxia resulted in an increase in coronary blood flow and myocardial oxygen consumption, but the increment in coronary blood flow was much more pronounced during hypoxia. Coronary resistance was significantly reduced during hypoxia but not altered during left stellate stimulation. This suggests an inadequate coronary vasodilator response during left stellate stimulation, probably secondary to a vasoconstrictor effect of the sympathetic nerves. This vasoconstrictor effect interferes with maximum vasodilatory response to hypoxia that is induced by sympathetic stimulation.
Efficacy of High-Dose versus Standard-Dose Influenza Vaccine in Older Adults
Authors: Carlos A. DiazGranados, Andrew J. Dunning, Murray Kimmel, Daniel Kirby, John Treanor, Avi Collins, Richard Pollak, Janet Christoff, John Earl, Victoria Landolfi, Earl Martin, Sanjay Gurunathan, Richard Nathan, David P. Greenberg, Nadia G. Tornieporth, Michael D. Decker, H. Keipp Talbot
Journal: New England Journal of Medicine (2014)

As compared with a standard-dose vaccine, a high-dose, trivalent, inactivated influenza vaccine (IIV3-HD) improves antibody responses to influenza among adults 65 years of age or older. This study evaluated whether IIV3-HD also improves protection against laboratory-confirmed influenza illness.We conducted a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial to compare IIV3-HD (60 μg of hemagglutinin per strain) with standard-dose trivalent, inactivated influenza vaccine (IIV3-SD [15 μg of hemagglutinin per strain]) in adults 65 years of age or older. Assessments of relative efficacy, effectiveness, safety (serious adverse events), and immunogenicity (hemagglutination-inhibition [HAI] titers) were performed during the 2011-2012 (year 1) and the 2012-2013 (year 2) northern-hemisphere influenza seasons.A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada (15,991 were randomly assigned to receive IIV3-HD, and 15,998 to receive IIV3-SD). In the intention-to-treat analysis, 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol-defined influenza-like illness (relative efficacy, 24.2%; 95% confidence interval [CI], 9.7 to 36.5). At least one serious adverse event during the safety surveillance period was reported by 1323 (8.3%) of the participants in the IIV3-HD group, as compared with 1442 (9.0%) of the participants in the IIV3-SD group (relative risk, 0.92; 95% CI, 0.85 to 0.99). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥ 1:40) were significantly higher in the IIV3-HD group. Conclusions: Among persons 65 years of age or older, IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01427309.).
Changes in Breast Cancer Detection and Mammography Recall Rates After the Introduction of a Computer-Aided Detection System
Authors: David Gur, Jules H Sumkin, Howard E Rockette, Marie Ganott, Christiane Hakim, Lara Hardesty, William R Poller, Ratan Shah, Luisa Wallace
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Computer-aided mammography is rapidly gaining clinical acceptance, but few data demonstrate its actual benefit in the clinical environment. We assessed changes in mammography recall and cancer detection rates after the introduction of a computer-aided detection system into a clinical radiology practice in an academic setting. Methods: We used verified practice- and outcome-related databases to compute recall rates and cancer detection rates for 24 Mammography Quality Standards Act-certified academic radiologists in our practice who interpreted 115 571 screening mammograms with (n = 59 139) or without (n = 56 432) the use of a computer-aided detection system. All statistical tests were two-sided. Results: For the entire group of 24 radiologists, recall rates were similar for mammograms interpreted without and with computer-aided detection (11.39% versus 11.40%; percent difference = 0.09, 95% confidence interval [CI] = −11 to 11; P = .96) as were the breast cancer detection rates for mammograms interpreted without and with computer-aided detection (3.49% versus 3.55% per 1000 screening examinations; percent difference = 1.7, 95% CI = −11 to 19; P = .68). For the seven high-volume radiologists (i.e., those who interpreted more than 8000 screening mammograms each over a 3-year period), the recall rates were similar for mammograms interpreted without and with computer-aided detection (11.62% versus 11.05%; percent difference = −4.9, 95% CI = −21 to 4; P = .16), as were the breast cancer detection rates for mammograms interpreted without and with computer-aided detection (3.61% versus 3.49% per 1000 screening examinations; percent difference = −3.2, 95% CI = −15 to 9; P = .54). Conclusion: The introduction of computer-aided detection into this practice was not associated with statistically significant changes in recall and breast cancer detection rates, both for the entire group of radiologists and for the subset of radiologists who interpreted high volumes of mammograms.
Use of an Orthotopic Xenograft Model for Assessing the Effect of Epidermal Growth Factor Receptor Amplification on Glioblastoma Radiation Response
Authors: Jann N. Sarkaria, Brett L. Carlson, Mark A. Schroeder, Patrick Grogan, Paul D. Brown, Caterina Giannini, Karla V. Ballman, Gaspar J. Kitange, Abjahit Guha, Ajay Pandita, C. David James
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The influence of epidermal growth factor receptor (EGFR) amplification on glioblastoma patient prognosis following definitive radiotherapy has been extensively investigated in clinical studies, and yet the relationship between EGFR status and radiation response remains unclear. The intent of the current study was to address this relationship using several EGFR-amplified glioblastoma xenografts in an orthotopic athymic mouse model. Experimental Design: We examined the effect of radiation on the survival of nude mice with intracranial xenografts derived from 13 distinct patient tumors, 7 of which have amplified EGFR. Mice with established intracranial tumors were randomized to sham treatment or 12-Gy radiation in six fractions delivered over 12 days. Results: For six of the xenografts, radiation of mice with intracranial tumor significantly extended survival, and four of these xenografts had EGFR amplification. For seven other xenografts, radiation treatment did not significantly extend survival, and three of these, including GBM12, had EGFR amplification. Similar to EGFR, the tumor genetic status of p53 or PTEN did not show preferential association with radiation-sensitive or radiation-resistant xenografts whereas hyperphosphorylation of Akt on Ser473 was associated with increased radioresistance. To specifically investigate whether inhibition of EGFR kinase activity influences radiation response, we examined combined radiation and EGFR inhibitor treatment in mice with intracranial GBM12. The combination of oral erlotinib administered concurrently with radiation resulted only in additive survival benefit relative to either agent alone. Conclusions: Our results indicate that EGFR amplification, as a biomarker, is not singularly predictive of glioblastoma response to radiation therapy, nor does the inhibition of EGFR enhance the intrinsic radiation responsiveness of glioblastoma tumors. However, efficacious EGFR inhibitor and radiation monotherapy regimens can be used in combination to achieve additive antitumor effect against a subset of glioblastoma.
Margaret Eirlys Jefferson (née Hughes)
Journal: BMJ (2005)

Former paediatric research registrar and part time general practitioner (b Oswestry 1920; q University College Hospital, London, 1944; MRCP, DCH), died from pancreatic cancer on 22 December 2004.​2004.




Figure 1




Eirlys started paediatric training at the Queen Elizabeth Hospital, London. Marriage took her to Manchester, where she began pioneering research into retrolental fibroplasia; she was on the point of incriminating excess oxygen levels as the causative factor when her husband's move to Oxford took her there. In 1956 the family moved to Sheffield and Eirlys carried out much of the work required for the report on “Handicapped Children and Their Families” commissioned by the Carnegie Foundation. Her commitment to her family in an age when part time consultant appointments did not exist prevented her from continuing to employ her experience and expertise usefully. She leaves a husband, Antony; three daughters; and eight grandchildren.
Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide.
Authors: N K Jurkiewicz, M C Sanguinetti
Journal: Circulation Research (1993)

Class III antiarrhythmic agents act by selective prolongation of cardiac action potential duration (APD). Methanesulfonanilide class III agents (e.g., E-4031 and dofetilide) are extremely potent and lengthen action potentials in a "reverse" rate-dependent manner; i.e., effects are greater at low compared with high rates of stimulation. By using the whole-cell current-clamp technique in isolated guinea pig ventricular myocytes, APD was shortened by rapid pacing (244 +/- 16 msec at 30 pulses per minute, 166 +/- 8 msec at 240 pulses per minute; n = 8). Dofetilide (1 microM) prolonged APD more when cells were stimulated at the rate of 30 pulses per minute (44 +/- 10-msec increase) than at 240 pulses per minute (21 +/- 5-msec increase). We investigated the mechanism of APD prolongation using voltage-clamp techniques. Dofetilide selectively inhibited IKr (IC50, 31.5 nM), defined as the rapidly activating inward rectifying component of net delayed rectifier K+ current (IK), without effects on the larger but more slowly activating component of IK (IKs) or on the inward rectifier K+ current (IK1). To examine the rate-dependent effects of dofetilide on APD, trains of conditioning pulses to 0 mV (200-msec duration) were applied at either 30 or 240 pulses per minute to mimic the action potential experiments. Test pulses or ramps were given after the conditioning train to quantitate changes in IK1, IKr, or IKs. The magnitude of neither IK1 nor IKr was dependent on the rate of the preceding train of depolarizations. Sensitivity to block of IKr by dofetilide was rate independent.(ABSTRACT TRUNCATED AT 250 WORDS)
Antioxidants and Cancer Therapy: A Systematic Review
Authors: Elena J. Ladas, Judith S. Jacobson, Deborah D. Kennedy, Katherine Teel, Aaron Fleischauer, Kara M. Kelly
Journal: Journal of Clinical Oncology (2004)

Many patients with cancer take antioxidant nutritional supplements during cancer treatment to alleviate treatment toxicities and to improve long-term outcomes, but little is known about the efficacy and safety of antioxidant use during cancer treatment. We reviewed English-language manuscripts published in the biomedical literature, reporting the results of observational studies of antioxidant status and cancer outcomes and of intervention trials of antioxidants among patients receiving chemotherapy with or without radiation for various malignancies.We searched the Medline database and the bibliographies of the retrieved manuscripts, reviews, and books on antioxidants and cancer. The retrieved studies are grouped by study design, malignancy, and end points.More than 100 citations were retrieved; 52 met our criteria, 31 were observational studies, and 21 were intervention trials. The studies varied in study design, timing of observation/intervention, intervention protocol, malignancy, and anticancer regimen.These inconsistencies preclude a definitive conclusion as to the effect of chemotherapy on antioxidant status in patients undergoing anticancer therapy. However, our review suggests that total antioxidant status (measured by total radical antioxidant parameter) declines during cancer treatment. Adequately powered trials or observational studies among patients with a specific cancer diagnosis receiving a specific treatment regimen are needed to address patients' and physicians' concerns regarding these associations.
G PROTEIN βγ SUBUNITS
Authors: David E. Clapham, Eva J. Neer
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract Guanine nucleotide binding (G) proteins relay extracellular signals encoded in light, small molecules, peptides, and proteins to activate or inhibit intracellular enzymes and ion channels. The larger G proteins, made up of G αβγ heterotrimers, dissociate into G α and G βγ subunits that separately activate intracellular effector molecules. Only recently has the G βγ subunit been recognized as a signal transduction molecule in its own right; G βγ is now known to directly regulate as many different protein targets as the G α subunit. Recent X-ray crystallography of G α , G βγ , and G αβγ subunits will guide the investigation of structure-function relationships.
Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase–derived PGD2 biosynthesis
Authors: Satori Tokudome, Motoaki Sano, Ken Shinmura, Tomohiro Matsuhashi, Shintaro Morizane, Hidenori Moriyama, Kayoko Tamaki, Kentaro Hayashida, Hiroki Nakanishi, Noritada Yoshikawa, Noriaki Shimizu, Jin Endo, Takaharu Katayama, Mitsushige Murata, Shinsuke Yuasa, Ruri Kaneda, Kengo Tomita, Naomi Eguchi, Yoshihiro Urade, Koichiro Asano, Yasunori Utsunomiya, Takeshi Suzuki, Ryo Taguchi, Hirotoshi Tanaka, Keiichi Fukuda
Journal: Journal of Clinical Investigation (2009)

Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme responsible for PGD2 biosynthesis in the brain, is highly expressed in the myocardium, including in cardiomyocytes. However, the factors that control expression of the gene encoding L-PGDS and the pathophysiologic role of L-PGDS in cardiomyocytes are poorly understood. In the present study, we demonstrate that glucocorticoids, which act as repressors of prostaglandin biosynthesis in most cell types, upregulated the expression of L-PGDS together with cytosolic calcium-dependent phospholipase A2 and COX2 via the glucocorticoid receptor (GR) in rat cardiomyocytes. Accordingly, PGD2 was the most prominently induced prostaglandin in vivo in mouse hearts and in vitro in cultured rat cardiomyocytes after exposure to GR-selective agonists. In isolated Langendorff-perfused mouse hearts, dexamethasone alleviated ischemia/reperfusion injury. This cardioprotective effect was completely abrogated by either pharmacologic inhibition of COX2 or disruption of the gene encoding L-PGDS. In in vivo ischemia/reperfusion experiments, dexamethasone reduced infarct size in wild-type mice. This cardioprotective effect of dexamethasone was markedly reduced in L-PGDS–deficient mice. In cultured rat cardiomyocytes, PGD2 protected against cell death induced by anoxia/reoxygenation via the D-type prostanoid receptor and the ERK1/2-mediated pathway. Taken together, these results suggest what we believe to be a novel interaction between glucocorticoid-GR signaling and the cardiomyocyte survival pathway mediated by the arachidonic acid cascade.
Cardiac Magnetic Resonance Imaging Pericardial Late Gadolinium Enhancement and Elevated Inflammatory Markers Can Predict the Reversibility of Constrictive Pericarditis After Antiinflammatory Medical Therapy
Authors: DaLi Feng, James Glockner, Kyehun Kim, Matthew Martinez, Imran S. Syed, Philip Araoz, Jerome Breen, Raul E. Espinosa, Thoralf Sundt, Hartzell V. Schaff, Jae K. Oh
Journal: Circulation (2011)

Constrictive pericarditis (CP) is a disabling disease, and usually requires pericardiectomy to relieve heart failure. Reversible CP has been described, but there is no known method to predict the reversibility. Pericardial inflammation may be a marker for reversibility. As a pilot study, we assessed whether cardiac magnetic resonance imaging pericardial late gadolinium enhancement (LGE) and inflammatory biomarkers could predict the reversibility of CP after antiinflammatory therapy.Twenty-nine CP patients received antiinflammatory medications after cardiac magnetic resonance imaging. Fourteen patients had resolution of CP, whereas 15 patients had persistent CP after 13 months of follow-up. Baseline LGE pericardial thickness was greater in the group with reversible CP than in the persistent CP group (4 ± 1 versus 2 ± 1 mm, P = 0.001). Qualitative intensity of pericardial LGE was moderate or severe in 93% of the group with reversible CP and in 33% of the persistent CP group (P = 0.002). Cardiac magnetic resonance imaging LGE pericardial thickness ≥ 3 mm had 86% sensitivity and 80% specificity to predict CP reversibility. The group with reversible CP also had higher baseline C-reactive protein and erythrocyte sedimentation rate than the persistent CP group (59 ± 52 versus 12 ± 14 mg/L, P = 0.04 and 49 ± 25 versus 15 ± 16 mm/h, P = 0.04, respectively). Antiinflammatory therapy was associated with a reduction in C-reactive protein, erythrocyte sedimentation rate, and pericardial LGE in the group with reversible CP but not in the persistent CP group.Reversible CP was associated with pericardial and systemic inflammation. Antiinflammatory therapy was associated with a reduction in pericardial and systemic inflammation and LGE pericardial thickness, with resolution of CP physiology and symptoms. Further studies in a larger number of patients are needed.
JITC launches a new section: commentary and editorials
Authors: Christian M. Capitini, Pedro Romero
Journal: Journal for ImmunoTherapy of Cancer (2015)

### Background We are pleased to announce the launch of a new section in the Journal for ImmunoTherapy of Cancer (JITC), the Commentary/Editorials section edited by Christian Capitini, MD of the University of Wisconsin. With all of the changes occurring in the field of immunotherapy, we felt having
Sodium-coupled Taurocholate Transport in the Proximal Convolution of the Rat Kidney In Vivo and In Vitro
Authors: Frederick A. Wilson, Gerhard Burckhardt, Heini Murer, Gerhard Rumrich, Karl J. Ullrich
Journal: Journal of Clinical Investigation (1981)

Using the standing droplet technique in the renal proximal convolution and simultaneous microperfusion of the peritubular capillaries, the zero net flux transtubular concentration difference of taurocholate (ΔCTC−) at 45 s was determined as a measure of active bile acid reabsorption in vivo. Starting with 0.1 mmol/liter taurocholate in both perfusates the control ΔCTC− of 0.042 mmol/liter fell to 0.006 mmol/liter (P < 0.001) when the Na+ concentration in the perfusates was reduced to zero. Removal of bicarbonate from the perfusates to alter pH had no influence on ΔCTC−. When glycocholate was added to the perfusates ΔCTC− was decreased, while probenecid increased ΔCTC−.
Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy
Authors: Gema Mateo, M. Angeles Montalbán, Maria-Belén Vidriales, Juan J. Lahuerta, Maria V. Mateos, Norma Gutiérrez, Laura Rosiñol, Laura Montejano, Joan Bladé, Rafael Martínez, Javier de la Rubia, Joaquín Diaz-Mediavilla, Anna Sureda, José M. Ribera, José M. Ojanguren, Felipe de Arriba, Luis Palomera, Maria J. Terol, Alberto Orfao, Jesús F. San Miguel
Journal: Journal of Clinical Oncology (2008)

To analyze the prognostic impact of immunophenotyping in patients with multiple myeloma (MM).We have prospectively analyzed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM 2000 protocol.Our results show that expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and del(17p), while CD117-negative patients were associated with t(4;14) and del(13q). Simultaneous assessment of CD28 and CD117 antigens allowed stratification of patients with MM into three risk categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive), with PFS rates of 30, 37, and 45 months, respectively (P = .01), and OS rates of 45, 68, and not reached, respectively (P = .0001).To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression.