tbuckley/cabot-search huggingface dataset:
Bmi-1 functions as a cooperative oncogene in Ewing's sarcoma.
Authors: Dorothea N. Douglas, Grace Peng, Long Hung, Srinivas Sai Somanchi, Timothy J. Triche, William A. May, Elizabeth R. Lawlor
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5638 

Background: The Ewing's sarcoma family of tumors (ESFT) comprises a group of highly aggressive bone and soft tissue tumors. All members of ESFT express chromosomal translocations that result in the creation of novel oncogenic fusion genes, most commonly EWS-FLI1. Although EWS-FLI1 functions as an aberrant transcription factor, the precise mechanisms underlying malignant transformation have yet to be elucidated. Importantly, it is evident from studies of primary cells that EWS-FLI1-mediated tumorigenesis requires the cooperation of other genetic lesions that function to inactivate innate tumor suppressor pathways. The identity of these cooperating events and the context of their expression are not yet known. The polycomb gene Bmi-1 , which is critical for the self-renewal of normal neural, neural crest and hematopoietic stem cells, has been shown to be highly expressed in many human cancers and to function as a cooperative oncogene in murine and human leukemogenesis. In this study we have investigated the potential role of Bmi-1 as a cooperative oncogene in the pathogenesis of ESFT. Results: We have found that ESFT cell lines and primary tumors express Bmi-1 and that short-interfering RNA (siRNA)-mediated knockdown of Bmi-1 significantly inhibits ESFT cell growth in vitro . In order to determine whether EWS-FLI1 modulates expression of Bmi-1 in ESFT we next evaluated cell lines and primary tumors by quantitative RT-PCR and discovered that a direct correlation exists between EWS-FLI1 and Bmi-1 expression levels. Interestingly, we also found that siRNA-mediated knockdown of cMyc (which is a direct transcriptional target of EWS-FLI1) in ESFT cells resulted in a concomitant down-regulation of Bmi-1 expression, suggesting that cMyc may be an upstream regulator of Bmi-1 in these tumors. Finally, to establish whether Bmi-1 and EWS-FLI1 co-operate in cellular transformation we evaluated the consequences of EWS-FLI1 expression in normal human fibroblasts with variable levels of Bmi-1 expression as a result of genetic modification. Whereas expression of EWS-FLI1 in control MRC5 cells resulted in growth arrest, co-expression of ectopic Bmi-1 in these cells promoted cell growth and survival. Summary: These data support the role of Bmi-1 as an oncogene in ESFT. Moreover, they suggest that EWS-FLI1 may indirectly deregulate expression of Bmi-1 through induction of cMyc. We hypothesize that high-level Bmi-1 expression may be a defining feature of the cell of origin of ESFT, functioning to repress Cdkn2a and thereby facilitate malignant transformation.
Fatal and mild primary dengue virus infections imported to Norway from Africa and south-east Asia, 2008-2010
Authors: K Vainio, S Noraas, M Holmberg, H Fremstad, M Wahlstrøm, G Ånestad, S Dudman
Journal: Eurosurveillance (2010)

Between 2008 and 2010, eight cases of viraemic dengue fever in travellers were diagnosed in Norway. They had returned from Eritrea, Thailand and Indonesia. All cases were primary dengue infections, seven non-complicated dengue fever and one dengue shock syndrome with a fatal outcome. Four patients were infected with dengue virus serotype 1, one with type 2 and three with type 3. Two cases from Thailand, the fatal case and the two imported from Eritrea were infected with type 1.
Abstract 4172: Short-Term Atorvastatin Treatment Reduces Vascular Oxidative Stress in Saphenous Vein Grafts by Improving eNOS Coupling and Reducing NADPH-Oxidase Activity in Patients Undergoing Elective CABG
Authors: Charalambos Antoniades, Costantinos Bakogiannis, Dimitris Tousoulis, Andreas Paschalis, Alexis S Antonopoulos, Michael Demosthenous, George Ekonomopoulos, Themistokles Psarros, Keith M Channon, Christodoulos Stefanadis
Journal: Circulation (2009)

Background: Statins improve survival of patients after coronary bypass surgery (CABG), but the exact mechanisms are unclear. We examined the effect of short-term treatment with high-dose atorvastatin, on vascular redox of saphenous vein grafts (SVG) used for CABG, and we explored the underlying mechanisms by using an ex-vivo SVG model.  Methods: Twenty-four pts undergoing CABG (not receiving statins due to low LDL) were randomized to receive atorvastatin 40mg/day or placebo for 3 days before operation, in a double-blind fashion. Vascular O2- was measured in SVG segments by lucigenin chemiluminescence in the presence of endothelial nitric oxide synthase (eNOS) inhibitor LNAME (100 μ M, to estimate eNOS coupling) or NADPH (100 μ M, to estimate NADPH-oxidase activity). To test the direct effect of atorvastatin on SVG redox state, SVG segments from 10 more pts were incubated with atorvastatin 0, 5 and 50 μ M ex-vivo, and vascular O2- was measured.  Results: Oral atorvastatin reduced O2- (A) and increased LNAME delta(O2-) (B, suggesting improved eNOS coupling), while LDL remained unchanged (p=NS). Ex-vivo atorvastatin incubation reduced O2- (C), improved eNOS coupling (D) and reduced NADPH-oxidase activity (from 41.4[26.4 –70.6] in control to 26.5[13.3– 62.9] in 5 μ M and 27.1[12.0 –30.6] RLU/Sec/mg in 50 μ M, p  Conclusions: Short-term preoperative treatment with atorvastatin, reduces vascular O2- generation in SVG by improving eNOS coupling and decreasing NADPH-oxidase activity, in patients with low LDL, undergoing CABG. This is the first study demonstrating a direct effect of atorvastatin on redox state of SVG used in CABG, and may have major clinical implications.
Rigosertib Blocks RAS Signaling By Acting As a Small Molecule RAS Mimetic That Binds to the RAS-Binding Domains of RAS Effector Proteins
Authors: E. Premkumar Reddy, Sai Krishna Divakar, Rodrigo Vasquez-Del Carpio, Kaushik Dutta, Stacey J Baker, Ramana Reddy, Aneel K Aggarwal
Journal: Blood (2014)
In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells
Authors: FC Zeigler, F de Sauvage, HR Widmer, GA Keller, C Donahue, RD Schreiber, B Malloy, P Hass, D Eaton, W Matthews
Journal: Blood (1994)
Skills and knowledge should be tested in postgraduate exams
Authors: B. Cook, A. Sarmah
Journal: BMJ (1995)

for trainees to acquire the necessary skills.It remains to be seen if the proficiency in resuscitation skills among those taking anaesthetic examinations is higher than that among candidates taking the examination for membership of the Royal College of Physicians.The resuscitation training officer has a valuable role in ensuring that these skills are retained.
Targeting the NQO1-redox Achilles heel of cancer using small molecule prooxidant redox cyclers.
Authors: Christopher Cabello, Georg Wondrak
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3339 

Constitutively elevated levels of cellular oxidative stress and dependence on mitogenic and anti-apoptotic reactive oxygen species (ROS)-signaling represent a specific vulnerability of malignant cells that can be selectively targeted by novel prooxidant redox chemotherapeutics. Here, we demonstrate that phenothiazinium-based redox cyclers (PRC-compounds) induce selective cancer cell apoptosis by NAD(P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds derived from methylene blue against human metastatic melanoma cell lines, apoptosis occurred with phosphatidylserine-externalization, loss of mitochondrial transmembrane potential, cytochrome C release, caspase-3 activation, and massive ROS production. Remarkably, PRC-apoptogenicity against G361 human metastatic melanoma cells was suppressed using the NQO1-inhibitor dicoumarol. The critical role of NQO1 in PRC-apoptogenicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT15) stably overexpressing active NQO1 displayed strongly enhanced PRC-sensitivity as compared to vector-control transfected cells with base line NQO1 activity. NQO1 is an antioxidant defense enzyme, and constitutive NQO1 overexpression leading to high specific enzymatic activity is associated with various human malignancies including melanoma, non-small-cell lung carcinoma, pancreas carcinoma, and breast and colon adenocarcinoma. The emerging role of overexpression of NQO1 in redox dysregulation of various human tumors resulting from Keap1 gene point mutations suggests feasibility of selecting NQO1-activated PRC lead compounds as tumor-selective bioreductive chemotherapeutics based on prior tumor genotyping. Moreover, a second class of quinone-based redox cyclers (QRC-compounds) has been identified that induces preferential cancer cell apoptosis by prooxidant mechanisms without dependence on NQO1-bioreductive activation. RT-PCR array expression analysis using the Human Stress and Toxicity PathwayFinder (Superarray) followed by immunoblot confirmation suggests that in human A375 melanoma cells, the redox cycler QRC-26 strongly upregulates heme oxygenase-1 (HO-1) and heat shock protein 70B’ (Hsp70B’), an Hsp70 subtype induced only under conditions of extreme cellular stress. Feasibility of therapeutic intervention using QRC-26 has been demonstrated in a human A375 melanoma mouse xenograft model. Future research will test the hypothesis that redox phenotyping and genotyping may guide the selection of PRC and QRC redox chemotherapeutics that efficiently target the NQO1-redox Achilles heel of the individual tumor. Supported in part by grants from NIH (R01CA122484; ES06694), ABRC (0721), and NSF (DGE-0114420).
Small numbers of patients with terminal cardiac failure may make considerable demands on services
Authors: J M Beattie, R G Murray, J. Brittle, T. Catanheira
Journal: BMJ (1995)

differing natural courses,' and their inclusion could require intolerable variations in manage- ment.The hospice environment may seem more dis- tressing for patients with diseases other than cancer; moreover, if such patients were treated in hospices, patients with cancer might have greater difficulties with body image and in accepting the inconsistency of more active management being given for non-malignant diseases.5Hospices are deliberately not generally equipped to deliver such management so that overmedicalisation of terminal care is avoided.Presently hospices see only about half of patients with cancer, which leaves little scope for the needs of a wider population (estimated at 150% extra bed days required for patients with diseases other than cancer6).Hospice-style input for non-malignant diseases remains equally important but requires appro- priate provision in addition to traditional hospices.Adequate community services could also meet much of this need.Hospices offer quality rather than quantity and should not be seen as an easy and cheaper option for providing care for patients with terminal disease as if they were a homogeneous group.
Abstract 18855: Outcomes after Coronary Artery Bypass Graft Surgery in Patients Treated with Thoracic Radiotherapy for Cancer
Authors: Jackson J Liang, Terence T Sio, John M Stulak, Ryan J Lennon, Abhiram Prasad, Robert C Miller, Gurpreet S Sandhu
Journal: Circulation (2014)

Introduction: Thoracic external beam radiation therapy (XRT) for cancer is associated with a multitude of long-term cardiotoxic side effects. Previous studies have suggested worse outcomes in XRT-treated cancer survivors who undergo revascularization with CABG, but sample sizes have been small. In addition, XRT after CABG is thought to portend decreased patency and survival. We aimed to examine outcomes after CABG in patients with XRT compared with to those without XRT. Methods: We identified all patients who were treated with both CABG (between 1999 and 2013) and curative thoracic XRT for cancer (between 1971 and 2013) (&gt;30 Gray). Baseline clinical characteristics and comorbidities at time of CABG, as well as long-term outcomes after CABG and XRT were compared with propensity matched control cohorts. Results: A total of 38 patients underwent CABG following XRT [Group 1] (mean age 67.9, 63% female) and 43 patients underwent XRT after CABG [Group 2] (mean age 69.3, 63% female). Compared with propensity-matched controls (Group 1: n=141; Group 2: n=167), baseline clinical and demographic characteristics between cases and controls were similar in both groups, except a lower incidence of triple vessel disease in XRT cases in Group 2 (64 vs 80%, p=0.02). For Group 1, there was no significant difference in all-cause survival in long-term follow-up after CABG (Fig. 1, p=0.72). Meanwhile, Group 2 cases had significantly higher all-cause mortality following XRT (Fig. 2, p&lt;0.001). Conclusions: Patients previously treated with thoracic XRT who subsequently undergo CABG for coronary artery disease have a similar overall mortality rate compared to patients without prior XRT. This suggests that CABG is an effective method of revascularization in these patients. The higher mortality rates in CABG patients who subsequently develop disease requiring thoracic XRT is likely due to oncologic rather than cardiovascular causes, but more data are necessary to evaluate this finding.
Abstract 13998: Mode of Delivery and Early Outcomes in Infants with Congenital Heart Disease
Authors: Luca Trento, Jay Pruetz, Ruey K Chang, Jon Detterich, Mark Sklansky
Journal: Circulation (2011)

Objectives: To evaluate the impact of mode of delivery (MOD) on postnatal outcome for neonates with congenital heart disease (CHD), and to assess the effect of prenatal diagnosis of CHD on perinata...
Study's design leaves cost effectiveness and "therapeutic impact" in doubt
Authors: P. J G Kirby, J. R Strang
Journal: BMJ (1995)

the true proportion of echocardiograms resulting in advice was 96/218 (44%).We find it difficult to accept that the authors could advise on the appropriateness of prescribing by general practitioners when guided only by patients' self reported symptoms.We believe that, in the absence of additional clinical information provided by the general practitioners, the authors were not in a position to advise on changes in treatment.Input for general practitioners when the study was being designed might have avoided this pitfall.Lastly, the poor uptake rate among general practitioners (93/550 (17%)) limits extrapolation of the results.
Chromatographic Studies on the Separation of the Virus from Chicken Tumor I. I. Effect of Salt Concentration on Adsorption, Elution, and Purification&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/xref&gt;
Authors: Vernon Riley
Journal: JNCI Journal of the National Cancer Institute (1950)

Journal Article Chromatographic Studies on the Separation of the Virus from Chicken Tumor I. I. Effect of Salt Concentration on Adsorption, Elution, and Purification Get access Vernon Riley Vernon Riley National Cancer Institute, National Institutes of Health, U. S. Public Health Service, Belhesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 11, Issue 1, August 1950, Pages 199–214, https://doi.org/10.1093/jnci/11.1.199 Published: 01 August 1950 Article history Received: 15 March 1950 Published: 01 August 1950
Increasing Benefit From Revascularization Is Associated With Increasing Amounts of Myocardial Hibernation
Authors: Gianni D'Egidio, Graham Nichol, Kathryn A. Williams, Ann Guo, Linda Garrard, Robert deKemp, Terrence D. Ruddy, Jean DaSilva, Dennis Humen, Karen Y. Gulenchyn, Michael Freeman, Normand Racine, Francois Benard, Paul Hendry, Rob S.B. Beanlands
Journal: JACC. Cardiovascular imaging (2009)
Abstract 15733: Inducible Postnatal Deletion Of COX-2 Accelerates Atherogenesis In Mice
Authors: Zhou Yu, Irene Crichton, Soon Yew Tang, Yiqun Hui, Ellen Pure, Garret A FitzGerald
Journal: Circulation (2011)

Background:  Nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard attributable to suppression of cyclooxygenase (COX)-2 derived prostacyclin (PGI 2 ). A predisposition to thrombogenesis, hypertension and heart failure - reflective of the human phenotype - can be recapitulated by disruption of this pathway in mice. However, although randomized trials of COX-2 inhibitors are consistent with risk transformation in humans and deletion of the PGI 2  receptor accelerates atherogenesis in mice, inhibition and conventional deletion of COX-2 have yielded conflicting results. Given the importance of COX-2 in development and the contrasting products of COX-2 formed by shifting cells prominent in the evolving plaque, we generated a mouse model in which timed, postnatal global deletion of COX-2 could be accomplished.   Method and results:  Inducible deletion of COX-2 (Ind.COX-2 KO) was achieved with Cre-ER TM  mice, resulting in ~95% suppression of peritoneal macrophage prostaglandin formation. In contrast to conventional COX-2 KOs, Ind.COX-2 KOs bypassed cardiorenal lesions during development. Atherogenesis was accelerated in both genders when Ind.COX-2 KO was crossed onto a hyperlipidemic ApoE KO background. COX-2 deletion promotes leukocyte infiltration, facilitates dedifferentiation of vascular smooth muscle cells from a “contractile” to a “synthetic” state as measured by loss of α-smooth muscle cell actin and upregulation of vascular cell adhesion molecule-1. While suppression of COX-2 derived PGI 2  can explain this phenotype, we addressed the possibility that rediversion of arachidonic acid (AA) to 5-lipoxygenase (LO) pathways might also contribute to this hazard. Disruption of 5-LO activating protein (FLAP) alone did not alter atherogenesis, but in Ind.COX-2/FLAP/ApoE triple KOs, the acceleration of atherogenesis due to COX-2 deletion was attenuated by concomitant FLAP deletion.   Conclusion:  Avoidance of the confounding effects of COX-2 disruption during development reveals the constraint exerted by COX-2 derived PGI 2  on atherogenesis. However, although disruption of FLAP has no direct effect on atherogenesis, rediversion to 5-LO products exacerbates the impact of PGI 2  suppression on atherogenesis in hyperlipidemic mice.
Inhibition Akt by tetracyclic triterpenoids induces cell cycle arrest and apoptosis in prostate cancer cells.
Authors: Aidee Constanza Estrada
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

628 

Akt are serine/threonine kinases controling cell metabolism, proliferation, and apoptosis. Akt activation is associated with aggressive behaviour of prostate cancer.    Akt1 and Akt2 are the major isoforms expressed in androgen-dependent LNCaP and androgen-independent PC-3 and DU 145 prostate cancer cells as measured by quantitative real-time PCR. Three structurally different Akt inhibitors were cytotoxic for prostate cancer cells indicating that the Akt pathway is indispensable for their viability. Oleogum resins from Boswellia species contain a complex mixture of triterpenoids with antitumor properties. In search for well-tolerated stable Akt inhibitors, we isolated several tetracyclic triterpenoids and purified them to chemical homogeneity. 3-Oxo-tirucallic acid, 3-α-acetoxy-tirucallic acid and 3-β-acetoxy-tirucallic acid potently inhibited the activities of human recombinant Akt1 and Akt2 in in vitro kinase assays, and Akt immunoprecipitated from PC-3 cells, but not the activity of IκB kinase. Interaction of Akt with the triterpenoids was quantified using surface plasmon resonance. The tetracyclic triterpenoids inhibited the phosphorylation of cellular Akt and glycogen synthase kinase-3β, whereas extracellular signal-regulated kinase 1/2 phosphorylation was increased. Further, the compounds inhibited nuclear accumulation of p65/relA, the androgen receptor, β-catenin, c-myc and the expression of cyclin D1, followed by hypophosphorylation of retinoblastoma protein. These events culminated in cell cycle arrest and induction of apoptosis. Selective down-regulation of Akt1, but not of Akt2 by siRNA similarly reduced the cell viability. In addition, the tetracyclic triterpenoids inhibited proliferation and induced apoptosis in tumors xenografted onto chick chorioallantoic membranes.    These results suggest that inhibition of Akt is sufficient to trigger apoptosis in prostate cancer cells. The isolated tetracyclic triterpenoids represent a new class of Akt inhibitors with anticancer properties in human prostate cancer cells.    This work was supported by the Deutsche Krebshilfe.
Alpha-fetoprotein derived growth inhibitory peptide (GIP) inhibits expression of cyclin E1
Authors: Casey Turk, Chung Wong, Joseph M. Gozgit, Michael Muehlemann, Margaret T. Reece, Gerald J. Mizejewski, Kathleen F. Arcaro
Journal: Cancer Research (2006)

4918  Alpha-fetoprotein (AFP) promotes both ontogenic growth and oncogenic progression of some tumor types, and has been shown to enhance cell proliferation via protein kinase A activity. In contrast, the alpha-fetoprotein derived Growth Inhibitory Peptide (GIP), a 34-amino acid fragment of the AFP molecule synthetically produced, suppresses growth of an array of tumor types in vitro and in vivo. The GIP site lies buried in a molecular cleft of naturally folded human alpha-fetoprotein, but it is partially exposed following introduction of fetal stress. It was previously demonstrated that treatment with low levels of GIP for eight days inhibited proliferation of MCF-7 cell cultures in what was noted as a cytostatic as opposed to a cytotoxic effect. The present study was initiated to determine whether cell cycle constituents required for G1-to-S phase transition were altered by treatment with GIP. MCF-7 breast cancer cultures were treated with various concentrations of GIP (10-5 to 10-14 M) for eight days after which cells were harvested and RNA or protein isolated. Analysis of gene expression with real time RT-PCR revealed that levels of Cyclin E1 were decreased as much as 5-fold after exposure to concentrations of GIP as low as 10-12 M. Concomitantly, mRNA levels of Rb1 were enhanced from 1.7 to 3.4 fold following GIP treatment. However, GIP had no effect on the mRNA expression of cdk2, cdk4, cdk6, Cyclin D1 or Cyclin B1. A decrease in protein levels of Cyclin E1 was detected with Western blot analysis after treatment with 10-9 M GIP as was a decrease in phosphorylated p27 suggesting that treatment of MCF-7 cells with physiologic levels of GIP may result in G1/S phase arrest.
Insurance against injury in clinical trials
Authors: J P Griffin
Journal: BMJ (1994)

... still no guidelines from Department of Health

Editor,--Early in 1993 the Department of Health, the Association of the British Pharmaceutical Industry, and a firm of solicitors representing the South West Regional Health Authority produced, after much discussion, an agreed form of indemnity for clinical studies. The department indicated that it would be issuing a guidance note for the benefit of health authorities, the note to …