tbuckley/cabot-search huggingface dataset:
Abstract S2-01: Theranostic multiparametric tests improve residual risk assessment in early luminal breast cancer
Authors: John MS Bartlett, Vicky S Sabine, Syed Haider, Camilla Drake, Cheryl Crozier, Cindy Q Yao, Cassandra L Brookes, Cornelis JH van de Velde, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Caroline Seynaeve, Daniel W Rea, Paul C Boutros
Journal: Cancer Research (2015)

Abstract Background: Despite rapidly expanding availability of multiparametric tests which inform residual risk following adjuvant therapy for early breast cancer current approaches provide minimal information on the appropriate targeted therapy to be selected for patients at high risk of recurrence. We hypothesised that inclusion of key signalling nodes from driver molecular pathways in early breast cancer in residual risk signatures would both improve risk stratification and identify candidate theranostic targets for the next generation of clinical trials. Methods: RNA was extracted from FFPE luminal breast cancers from the TEAM pathology study (Exemestane versus Tamoxifen-Exemestane). Gene expression analyses were performed for 29 genes mapped across key signalling nodes within the PIK3CA pathway. mRNA assessment for IHC4 (ER, PgR, HER2 and Ki67) was included in the model. Quantitative gene expression was performed using the Nanostring platform. Novel signatures were trained in a randomly selected sub-set of the TEAM pathology cohort (n=˜1700) and validated using the remaining 50% of patients (n=˜1700). Results presented represent those from the validation cohort. Results: The IHC4-protein and IHC4-mRNA risk scores were highly correlated (Rho=0.72, p=4.12x10-265), suggesting the mRNA abundance-based classifier is able to serve as a good substitute for the protein-based model. A gene signature including IHC4 markers assessed by mRNA performed significantly better (AUC 0.70 vs 0.66) than conventional IHC4. A gene signature including 4 signalling modules from the PIK3CA pathway significantly outperformed both IHC4 and the 4 gene (ER, PgR, HER2, Ki67) classifier (AUC 0.75; p = 3.23x10-7 vs IHC4 and 1.39x10-3 vs "IHC4mRNA"). Conclusions: Inclusion of PIK3CA signalling modules identified key genes/nodes which are linked to early relapse in luminal breast cancer and provided a significantly improvement in risk classification when compared to a currently validated multiparameter test. Citation Format: John MS Bartlett, Vicky S Sabine, Syed Haider, Camilla Drake, Cheryl Crozier, Cindy Q Yao, Cassandra L Brookes, Cornelis JH van de Velde, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Y Dirix, Caroline Seynaeve, Daniel W Rea, Paul C Boutros. Theranostic multiparametric tests improve residual risk assessment in early luminal breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-01.
123. Adenovirus Type 11 Based Vectors as a Platform for Treatment of Metastatic and Hematopoietic Disease
Authors: Daniel Stone, Andre Lieber
Journal: Molecular Therapy (2004)

Adenovirus (Ad) vectors derived from group C serotype Ad5 have shown great promise for treatment of disease based on their ability to efficiently infect multiple therapeutic target cell populations. Despite this ability these vector systems do not efficiently infect all potential disease target cell types, due to a lack of primary attachment receptors on target cells, and are hampered in vivo by native virus neutralizing immune responses and acute vector-mediated toxicity. In an attempt to circumvent these limitations to Ad-mediated gene therapy we have developed a vector system based on group B serotype Ad11 whereby first generation (E1 deleted) vector genomes can be generated by E.coli recombination or by co-transfection of 2 shuttle plasmids into the cell line 293-Ad11E1B55K. Vector preparations of > 1012 particles/ml can be generated with the optimum cell harvest time being 72 hours after infection. Competition experiments using recombinant Ad11p fiber knob to block binding of the vector Ad11-CMV-GFP to CHO cells expressing the previously identified adenovirus receptors CAR and CD46 demonstrated that Ad11 vectors are able to infect cells through a CAR-independent fiber knob/CD46 mediated pathway. Analysis of serum samples taken from normal US or normal and cervical cancer positive Senegalese volunteers demonstrated that virus directed neutralizing antibodies (VNAbs) against Ad11 were present in less than 10% of samples whilst VNAbs against Ad5 were present in more than 30% of samples. Transformation assays in baby rat kidney (BRK) cells transfected with wild type or E1 deleted genomes from Ad5 or Ad11 showed no transformed foci in E1 deleted genome transfected cells of either serotype whilst wild type Ad5 showed more foci than wild type Ad11. Transduction studies using Ad5 and Ad11 vectors expressing the reporter gene GFP from the CMV promoter were also carried out. A panel of human tumor cell lines derived from cervix, lung, liver, breast, prostate, colon, ovary, blood and brain demonstrated transduction profiles for Ad5 and Ad11 derived vectors that correlated with levels of CAR and CD46 expression. Primary human cord blood derived CD34+ve cells and peripheral blood derived dendritic cells were readily infectable with Ad11 derived vectors in contrast to vectors based on Ad5. Additionally we previously developed an Ad5 based system (Ad.IR) in which tumor specific replication of E1 deleted Ad DNA upon infection mediates expression of a toxic protein. Replication of Ad11 vector DNA in a panel of tumor cells demonstrated the suitability of Ad11 based vectors for application in an Ad.IR system. In summary we have developed E1 deleted Ad11 vectors that can utilize CD46 for cell infection, have a low prevalence to neutralization by human serum and are non-transforming. These vectors provide an excellent platform for the treatment of diseases in which Ad5 based vectors have shown limitations including treatment of metastatic and hematopoietic disease.
Effect of 127 Mutations at 72 Positions on the Surface of Adeno-Associated Virus Type-2
Authors: Michael Lochrie, Gwen Tatsuno, Jennifer Wellman, Shang-zhen Zhou, Richard Surosky, Glenn Pierce, Peter Colosi
Journal: Molecular Therapy (2004)

Our goal is to identify mutations on the external surface of AAV-2 capsid that reduce neutralization by antibodies, but have minimal effects on biological properties. 127 mutations were made at 72 positions (55 % of surface area) deemed most likely to be accessible to antibody binding based on manual docking of IgG and AAV-2 structures. Single alanine substitutions (57), single non-alanine substitutions (41), multiple mutations (27), and insertions (2) were made. Mutant rAAV-2 lacZ was generated by triple transfection of 293 cells. Freeze-thaw lysates of the transfected cells were prepared and assayed for total capsid synthesis (Western blotting), DNA packaging (Q-PCR), heparin-binding (ceramic beads), and in vitro transduction (Hep G2 cells/etoposide). CsCl gradient-purified viruses were made for antibody binding and in vitro neutralization assays.
ELECTROCARDIOGRAPHIC ALTERATIONS RESEMBLING THOSE PRODUCED BY MYOCARDIAL INFARCTION OBSERVED DURING A SPONTANEOUS ATTACK OF ANGINA PECTORIS
Authors: F S RANDLES, N F FRADKIN
Journal: Annals of Internal Medicine (1948)

Case Reports1 March 1948ELECTROCARDIOGRAPHIC ALTERATIONS RESEMBLING THOSE PRODUCED BY MYOCARDIAL INFARCTION OBSERVED DURING A SPONTANEOUS ATTACK OF ANGINA PECTORISF. STANLEY RANDLES, M.D., NATHAN F. FRADKIN, M.D.F. STANLEY RANDLES, M.D., NATHAN F. FRADKIN, M.D.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-28-3-671 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptOccasionally opportunities have been afforded for securing electrocardiograms of patients with angina pectoris during a spontaneous paroxysm. Thesehave shown distinct changes resembling those found after thrombosis of a large coronary artery.1 We should like to place on record our electrocardiographic findings in a patient observed before, during, and after a spontaneous attack of angina pectoris.CASE REPORTMr. F. Van V., aged 46, was seen in the office by one of us (F. S. R.) on January 3, 1944, complaining of substernal distress on exertion. A brief history was obtained, an electrocardiogram was taken, and an appointment was made...Bibliography1. WILSONJOHNSTON FNFD: The occurrence in angina pectoris of electrocardiographic changes similar in magnitude and in kind to those produced by myocardial infarction, Am. Heart Jr., 1941, xxii, 64-74. CrossrefGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Albany, New York*Received for publication June 18, 1946.From the Department of Internal Medicine, Albany Medical College and the Albany Hospital, Albany, New York. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited BySignificance of Transient Electrocardiographic Q Waves in Coronary Artery DiseaseVariant Angina-Correlation of Clinical, Electrocardiographic and Angiographic Features: Results of Medical and Surgical ManagementAngina Pectoris at Rest with Preservation of Exercise CapacityChest PainAdams-Stokes syndrome during angina pectoris associated with coronary artery diseaseSelected electrocardiographic changes during acute renal failure and hemodialysisAngina pectoris I. A variant form of angina pectorisTransient electrocardiographic changes simulating acute myocardial infarctionTHE ELECTROCARDIOGRAPHIC DIAGNOSIS OF ACUTE MYOCARDIAL ISCHEMIA*†GORDON B. MYERS, M.D., F.A.C.P., FREDERICK N. TALMERS, M.D.The anoxemia testTransient electrocardiographic changes identical with those of acute myocardial infarction accompanying attacks of angina pectorisAn Exercise Test for Coronary InsufficiencySubendocardial myocardial infarction with special reference to the electrocardiographic changes 1 March 1948Volume 28, Issue 3Page: 671-676KeywordsAnginaElectrocardiographyElectrode recordingHospital medicineIn vitro fertilizationMyocardial infarctionThrombosisTongue Issue Published: 1 March 1948 PDF DownloadLoading ...
Abstract 15196: Autophagy Regulates Vascular Smooth Muscle Cell Phenotypic Switching: Translational Implications for Aneurysm Formation
Authors: Azza Ramadan, Krishna Singh, Adrian Quan, Yi Pan, Mehroz Ehsan, Fina Lovren, Hwee Teoh, Mark Wheatcroft, Subodh Verma
Journal: Circulation (2013)

Background: In response to diverse inflammatory and hemodynamic stressors, vascular smooth muscle cells (SMCs) undergo a phenotypic switch from a quiescent/contractile state to a proliferative/synt...
Abstract 14857: Changes in Lp-PLA2 Activity in Secondary Prevention Predict Coronary Events and Treatment Effect by Pravastatin in the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Trial
Authors: Harvey D. White, John Simes, Elizabeth Barnes, Stefan Blankenberg, Ian Marschner, Malcolm West, Tanja Zeller, David M. Colquhoun, Paul Nestel, Anthony C. Keech, David R. Sullivan, Andrew Tonkin, Lipid Study Investigators
Journal: Circulation (2011)

Background Elevated levels of the pro-inflammatory enzyme, lipoprotein-associated phospholipase 2 (Lp-PLA2) are associated with increased cardiovascular risk in healthy individuals, but have not be...
Restoration of synaptic function in sight for degenerative retinal disease
Authors: Timm Schubert, Bernd Wissinger
Journal: Journal of Clinical Investigation (2015)

Synaptic disorganization is a prominent feature of many neurological diseases of the CNS, including Parkinson's disease, intellectual development disorders, and autism. Although synaptic plasticity is critical for learning and memory, it is unclear whether this innate property helps restore synaptic function in disease once the primary cause of disease is abrogated. An answer to this question may come from a recent investigation in X-linked retinoschisis, a currently untreatable retinopathy. In this issue of the JCI, Ou, Vijayasarathy, and colleagues showed progressive disorganization of key functional elements of the synapse between photoreceptors and ON-bipolar cells in a retinoschisin-deficient mouse model. Moreover, they demonstrated that adeno-associated virus–mediated (AAV-mediated) delivery of the retinoschisin gene restores structure and function to the photoreceptor to ON–bipolar cell synapse in mouse models, even in adults at advanced stages of the disease. The results of this study hold promise that AAV-based supplemental gene therapy will benefit patients with X-linked retinoschisis in a forthcoming clinical trial.
Effects of Differently Activated Rodent Macrophages on Sensory Neurons: Implications for Arthritis Pain
Authors: Julia Massier, Annett Eitner, Gisela Segond von Banchet, Hans‐Georg Schaible
Journal: Arthritis & Rheumatology (2015)

In arthritis, macrophages invade the affected joint. Experimental arthritis models have shown that macrophages also invade the dorsal root ganglia (DRGs) of the inflamed segments in which the perikarya of sensory neurons are located. It is unclear whether this macrophage invasion contributes to arthritis pain and/or furthers neuronal damage. The present study was undertaken to investigate how differently activated macrophages affect DRG neurons.We determined the phenotype of macrophages in the DRGs of rats with antigen-induced arthritis (AIA). In a DRG neuron-macrophage coculture system, we investigated whether differently activated macrophages (stimulated with either lipopolysaccharide [LPS]/interferon-γ [IFNγ], tumor necrosis factor [TNF], or interleukin-4) damage DRG neurons and/or stimulate them to release the mediator calcitonin gene-related peptide (CGRP), which promotes pain and neurogenic inflammation.Macrophages in the DRGs of rats with AIA showed the phenotype of TNF-stimulated macrophages but did not express inducible nitric oxide synthase, which was found in cultured macrophages only after LPS/IFNγ activation. In neuron-macrophage cocultures, activation of macrophages stimulated DRG neurons to release CGRP within 1 hour, indicating neuronal activation by macrophages. Only 48-hour activation of macrophages with LPS/IFNγ increased the neuronal cell death rate in culture, provided that the macrophages were in direct contact with DRG neurons. This effect was dependent on nitric oxide.Macrophages have the potential to stimulate sensory neurons in the DRGs, and this may contribute to arthritis pain. If they are classically activated, such as after LPS/IFNγ stimulation, this may also further neuronal cell death. This is not the case in AIA but may occur in models involving damage of sensory neurons.
Tiotropium respimat versus HandiHaler to improve sleeping oxygen saturation and sleep quality in COPD
Authors: Izolde Bouloukaki, Katerina Giannadaki, Charalampos Mermigkis, Stylianos Michelakis, Eleni Mauroudi, Violeta Moniaki, Nikolaos Siafakas, Sophia Schiza
Journal: European Respiratory Journal (2014)

Introduction:  Sleep can be associated with clinically important adverse effects in patients with chronic obstructive pulmonary disease (COPD), such as disordered gas exchange and poor sleep quality. There is a shortage of data of the efficacy of long-acting inhaled anticholinergic agents in improving these adverse effects. We aimed to compare the effect of Tiotropium Respimat Soft Mist Inhaler versus HandiHaler on sleeping arterial oxygen saturation (SaO 2 ) and sleep quality in patients with COPD, 6 months after treatment initiation.   Methods:  In a randomized, parallel-group trial involving patients with mild to moderate COPD, we compared 6 month treatment with tiotropium Respimat to HandiHaler on sleeping SaO 2  and sleep quality. Overnight polysomnography and pulmonary function testing was performed at baseline and 6 month after treatment.   Results:  A total of 361 patients with newly diagnosed COPD, for whom inhaled anticholinergic therapy had been recommended, were randomised and 200 patients completed the 6 month trial. At the end of treatment both groups showed significant improvements in minimum SaO 2  and percentage of sleep spent below 90% of SaO 2  (TST90) compared to baseline. However, the patients who received Respimat had significantly better TST90 than did the patients receiving handihaler. Sleep disturbance was highly variable in these patients, but duration of sleep stages were significant better in the Respimat group.   Conclusion:  Sleeping SaO 2  can be improved with tiotropium delivered either by the HandiHaler, or via Respimat device. However, the patients who received tiotropium respimat had significantly improved TST90 as well as sleep architecture parameters.
Abstract 9749: In Vivo Results of Cobra Pzf ™ Stented Rabbit Iliac Arteries
Authors: Luc Maillard, Delphine Corseaux, Alexandre Altié, Alexandre Ung, Joël Courageot, Emmanuel Teiger, Eric Van Belle
Journal: Circulation (2014)

Introduction: The CeloNova Cobra PzF™ coronary stent is a new stent design, balloon expandable cobalt chromium alloy that is pre-mounted on a custom rapid exchange balloon delivery catheter. The alloy stent is surface treated with a nano-layer Polyzene®-F (PzF). In vitro studies have indicated that the PzF surface treatment is a nonthrombogenic and has pro-endothelialization properties. Methods: Only 3.0 mm diameter x 15 mm length stents were used, 32 external right iliac rabbit arteries were harvested at 7 days for electron microscopy analysis, half cylinder for thrombus area formation and the other half cylinder for reendothelialization. Then, a time course of reendothelialization was performed with 10 additional animals. Five animals were examined at day 3 and 5 animals at day 5. Each animal received in one leg a Cobra PzF stent and on the opposite leg a control stent randomly assigned. The 2 half cylinders were examined for reendothelialization. Results: Thrombotic occlusion was a rare event in this experiment (3/52, 5.76%) of the stented vessels. The 3 occluded stents were observed in control Cobra BMS group (3/27, 11.11%) versus 0 (0/25, 0%) in the Cobra PzF™ group (p = 0.04). At day 7, almost a complete coverage of endothelial cells was observed in both group. 99.86 +/- 0.09 % in the Cobra BMS group versus 99.54 +/- 0.25% in the Cobra PzF™ group, (p = NS). The only defects of reendothelialization were observed on pieces of struts of stents in front of take off of large side branches in both group. No thrombus area was observed in both group at day 7, 0% versus 0%, (p = NS). At day 3, more than half area of the examined pieces was reendotheliazed in both group, 54.25 +/- 4.4 % in the Cobra PzF™ group versus 53.78 +/- 4.4 % in the Cobra BMS group (p = NS), and reached 78.30 +/- 3.7 % in the Cobra PzF™ group versus 79.03 +/- 4.% in the Cobra BMS group (p = NS). All stents were well expanded against the arterial wall and no struts were malapposed with no difference between groups. Conclusions: There is a significant reduction of stent occlusion in the Cobra PzF™ group as compared to the same stent without PzF modified surface, with a complete and rapid reendothelialization in both group at day 7 that proves the benefit both of this new thin struts deign and the modified PzF surface.
When Military Parents Are Sent to War, Children Left Behind Need Ample Support
Authors: Lynne Lamberg
Journal: JAMA (2004)

WHEN ONE US SOLDIER—A single mother of twins— was deployed to Iraq for a year, she sent one twin to live with her own parents and the other to her former husband’s parents. Although military family life is only rarely disrupted to this extent, even two-parent families find that the deployment of one parent often prompts the other to move nearer to relatives, forcing children to change schools and leave friends. “Soldiers’ children once worried only about their parents’ being in an unsafe place,” said Jean Silvernail, EdD, who directs services for the military child in transition and deployment in the Department of Defense (DoD) educational opportunities directorate. “Now, with threats of terrorism at home,” she said, “they also worry about having been left in an unsafe place.” The number of children whose parents are serving in Iraq or Afghanistan is hard to estimate, Silvernail said, because troops rotate frequently. About 1.5 million school-age children have military parents who are on active duty. About 49 000 US military families include two parents on active duty.
Activation of downstream EGFR signaling provides gefitinib-resistance in cells carrying EGFR mutation
Authors: Akiko Uchida
Journal: Cancer Research (2007)

Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor (EGFR) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild-type (WT) or mutant (L858R) EGFR, and then expressed oncogenic K-Ras12V mutant in the latter transfectant. Although 293T cells expressing wild-type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non-transfected cells, the cells expressing the EGFR-L858R were exquisitely sensitive. Consistently, phospho-Akt levels were decreased in response to gefitinib in cells expressing EGFR-L858R but not in cells with EGFR-WT. In contrast, 293T cells expressing both EGFR-L858R and oncogenic K-Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K-Ras12V in the gefitinib-sensitive pulmonary adenocarcinoma cell line PC-9, which harbors an in-frame deletion in the EGFR gene. The activated K-Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho-Akt, as well as phospho-Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation.
The delay time in sickle cell disease after 40 years: A paradigm assessed
Authors: Frank A. Ferrone
Journal: American Journal of Hematology (2015)

Sickle hemoglobin polymerization commences with a striking latency period, called a "delay time" followed by abrupt polymer formation. The delay time is exceedingly concentration dependent. This discovery (40 years ago) led to the "kinetic hypothesis," that is, that the pathophysiology was related to the relationship between the delay time and the capillary transit. The delay time is well described by a double-nucleation mechanism of polymer formation. In macroscopic volumes, the delay time is highly reproducible, but in small volumes such as erythrocytes, under certain conditions, the intrinsic delay time can be augmented by a stochastic delay owing to random waiting times for the first nucleus to form. This lengthens the average delay and adds further protection from vaso-occlusion. When oxygen removal is not sudden, the growth of polymers after the delay time is limited by the rate of oxygen removal, further lengthening the time before occlusion may occur. This is important if some polymers have remained in the cell after pulmonary transit as their presence otherwise would obliterate any delay. The difficulty of deforming a cell once polymerized rationalizes the "two-step" model of vaso-occlusion in which a postcapillary adhesion event is followed by a sickling logjam. The delay time that is required is therefore generalized to be the delay time for an erythrocyte to move beyond regions in the venuoles where adherent cells have reduced the available lumen. The measurements of delay times correlate well with the severity of sickling syndromes. They also correlate with the improvements owing to the administration of hydroxyurea.