tbuckley/cabot-search huggingface dataset:
Abstract 3445: Specific inhibitors of nuclear export (SINE) for cancer therapy: from bench to bedside.
Authors: Asfar S. Azmi, Bin Bao, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad
Journal: Cancer Research (2013)

Abstract Nuclear protein transport is an evolutionary conserved mechanism that controls aberrant cell proliferation through balanced nuclear expression of tumor suppressor proteins (TSPs). In cancers, overexpression of exportin protein chromosome region maintenance 1 (CRM-1) disrupts this balance leading to nuclear exclusion of TSPs leading to the low efficacy of traditional anti-cancer drugs. Our recent screening of pancreatic, colon, triple negative breast cancer (TNBC) and non-Hodgkin's lymphoma (NHL) patient samples showed over-expression of CRM-1. These important finding suggests that therapeutic targeting of CRM-1 leading to restoration of TSPs in the nucleus is an attractive strategy against cancer. Earlier attempts to develop CRM-1 inhibitor were not successful as exemplified by the failure of the Leptomycin B in a single clinical trial due to severe off-target toxicity. Since then the field has not witnessed any serious attempts to develop newer classes of CRM-1 inhibitors that could be used clinically. We have developed specific inhibitors of nuclear export (SINE) that are highly specific, orally active drugs with excellent pharmacokinetic parameters. We tested SINEs as targeted inhibitors of CRM-1, in a panel of pancreatic, colon, prostate, breast, NHL cell lines. SINE showed cancer selectivity (IC50s in low nano molar range in cancer cells and &amp;gt;20 micro Molar in normal lymphocytes, fibroblasts and NIH-3T3 cells). SINE induces global re-alignment of important tumor suppressors such as IKB, FOXO, p53, p73 and p27. SINEs were ineffective in killing cancer cells that were transduced with cys528 mut-CRM-1 proteins (a binding site for SINE) confirming the drugs selectivity. In in vivo studies, the clinical grade SINE induced significant tumor growth inhibition in subcutaneous and orthotopic solid and disseminated NHL xenografts. Our new class of SINEs has excellent pharmacokinetic parameters and has passed advanced toxicity profiling. Based on our strong preclinical data, SINE has entered clinical trials for both solid tumors and hematological malignancies. Citation Format: Asfar S. Azmi, Bin Bao, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad. Specific inhibitors of nuclear export (SINE) for cancer therapy: from bench to bedside. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3445. doi:10.1158/1538-7445.AM2013-3445
Libraries Face Challenge of Providing Computer Access
Authors: Corinna Nelson
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Libraries Face Challenge of Providing Computer Access Get access Corinna Nelson Corinna Nelson Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 6, 15 March 1995, Pages 410–412, https://doi.org/10.1093/jnci/87.6.410 Published: 15 March 1995
PROTHESES COLIQUES: Etude rétrospective de 91 procédures
Authors: F Caillol, E Bories, C Pesenti, C Vivian Lopez, M Giovannini
Journal: Endoscopy (2008)

Introduction: Les prothèses coliques expansibles sont utilisées comme traitement des sténoses malignes coliques, des fistules coliques, ou pour calibration des sténoses bénignes coliques. Nous rapportons notre expérience de manière rétrospective sur le traitement endoscopique des sténoses coliques malignes et bénignes.
A Novel Approach to the Generation and Identification of Experimental Hepatic Metastases in a Murine Model
Authors: R Lafreniere, S A Rosenberg
Journal: JNCI Journal of the National Cancer Institute (1986)

A reproducible model for the selective generation of liver metastases has been developed. The spleen is exteriorized by means of a small subcostal incision and is directly injected with a 1-ml suspension of tumor cells. Tumor cells flow out of the splenic vein into the portal vein and lodge in the liver. Splenectomy is performed approximately 1 minute after tumor cell injection. The procedure is simple, requires a single operative procedure, and is applicable to a wide variety of tumors. Over a 6-month period, more than 3,000 such procedures with the use of 5 different tumors were performed in C57BL/6 mice, resulting in a 1.9% mortality. For reliable enumeration of the number of hepatic metastatic deposits, a suspension of india ink was injected iv, and the liver was removed and bleached with Fekete's solution. Tumor nodules appeared as discrete white nodules against the black background of normal liver parenchyma. This model provides a useful tool for the study of the experimental therapy of hepatic metastases in mice.
S68 Inhibition of p38 mitogen activated protein kinase (MAPK) prevents the development of experimental pulmonary hypertension
Authors: A. C. Church, R. Wadsworth, G. Bryson, D. J. Welsh, A. J. Peacock
Journal: Thorax (2011)

<h3>Introduction</h3> p38 MAPK has been linked to the pathobiology of pulmonary hypertension (PH) but its role has not been fully investigated. We have previously highlighted the importance of the p38 MAPK pathway in the proliferative response of pulmonary artery fibroblasts to hypoxia. In addition, the BMPR2 mutations seen in PH can lead to increased signalling through the p38 MAPK pathway. These findings suggest p38 MAPK may be an appropriate target for the treatment of PH. <h3>Methods</h3> We undertook an in vivo prevention study on male Sprague-Dawley rats that were exposed to hypobaric hypoxia (at 550 mm Hg=10% FiO2) for a period of 2 weeks. Five animals were dosed daily via an intraperitoneal route, with SB-203580, a p38 MAPK specific inhibitor, and a further five animals acted as controls. After 2 weeks the animals had right ventricular systolic pressure (RVSP) measured, degree of right ventricular hypertrophy (RVH) assessed and lung histology analysed for evidence of vascular remodelling. The lungs were stained with α-smooth muscle actin and the degree of distal muscularisation in vessels &lt;80 mm in diameter assessed. Results were analysed with appropriate statistical tests. <h3>Results</h3> There was a significant difference in the RVSP between groups (control 37.09 mm Hg±5.09 vs drug 20.59 mm Hg ±3.19; p=0.025). There was less RVH (control 0.38 vs drug 0.25;p=0.0032) in the drug treated group (see Abstract S68 figure 1) and the total RV weights were also less (control 147 mg vs drug 109 mg; p=0.018). There was no difference in haematocrit between groups. There was less pulmonary vascular remodelling as indicated by a reduction of fully muscularised and an increase in non-muscularised vessels observed in the drug treated group (p&lt;0.001). <h3>Conclusion</h3> We have shown in a chronic hypoxic model of PH that by inhibiting the p38 MAPK pathway in vivo the development of pulmonary hypertension can be prevented. This suggests that the p38 MAPK pathway could be a potential therapeutic target for PH. Further studies are warranted, in particular to see if inhibition can reverse established disease.
Brief Report: GTP-Binding Proteins As Oncogenes in Human Tumors
Authors: Frank McCormick
Journal: Environmental Health Perspectives (1991)

Ras oncogenes are the most commonly known oncogenes in human tumors; their prevalence in different types of tumors and their role in the development of these tumors have been discussed in recent reviews (1,2). We have investigated the biochemical mechanism that accounts for the activation of ras proto-oncogenes to become oncogenes. In normal cells, the ras p21 cycles between the active guanosine triphosphate (GTP)bound form and the inactive form, bound to guanosine diphosphate (GDP). The conversion of the GTPto the GDP-bound form is catalyzed by a cellular protein referred to as GAP (GTPase activating protein) (3). The mechanism by which the GTP-bound state is generated is not known; however, this mechanism must be much slower than the GAP-catalyzed reaction, so that most of the ras p21 in normal cells is in the GDP-bound state. In ras-transformed cells, the oncogenic mutant ras protein exists in its GTP-bound state constitutively. This is because GAP fails to catalyze hydrolysis of GTP bound to these proteins. Oncogenic mutants can therefore be thought of as mutants that escape from this aspect of GAP function. Two types of GAP cDNA have been cloned from human placenta (4). Figure 1 shows the structure of the proteins encoded by these cDNAs. Type I GAP is a 116,000 Da protein, with a hydrophobic amino terminus, two SH2 regions (src-homology region 2), one SH3 region, and a catalytic domain comprising the C-terminal one-third of the protein (5). All cells express type I GAP, whereas type II, which lacks the first 180 amino acids of type I GAP and is generated by an alternative splicing mechanism, has only been detected in human placenta and in certain human cell lines, such as MRC5 diploid fibroblasts. Interaction of GAP with ras p21 may have consequences additional to conversion of the GTP-bound to the GDP-bound form. This possibility was raised by the
Constipation Associated with a Lipoma
Authors: C Lamar Hardy, Gilbert Goliath
Journal: New England Journal of Medicine (2015)

A 13-year-old girl with a history of abdominal discomfort was admitted with an acute onset of bilious vomiting. During the preceding weeks, the patient had reported having constipation, nausea, vomiting, and abdominal and back pain of increasing intensity.
Recurrent Ventricular Fibrillation and Modes of Death in Survivors of Out-of-Hospital Ventricular Fibrillation
Authors: William A. Schaffer, Leonard A. Cobb
Journal: New England Journal of Medicine (1975)

We examined the causes of death in patients previously resuscitated from out-of-hospital ventricular fibrillation. In 51 months, 234 patients were sucessfully resuscitated, hospitalized and discharged home. During follow-up observation, 89 episodes of recurrent ventricular fibrillation or death (or both) occurred, 64 of which (72 per cent) were unexpected, out-of-hospital circulatory arrests. Ventricular fibrillation occurred in 77 per cent of the 44 episodes in which the electrocardiogram was observed. Ten patients survived one or more episodes of recurrent ventricular fibrillation. Median time to recurrent ciruclatory arrest was 20 weeks after the preceding episode. Prodromal symptoms were infrequent, and activity levels were generally low at the time of cardiac arrest. Recurrent ventricular fibrillation of sudden death (or both) occurred predominantly when the initial episode was not associated with acute myocardial infarction. Patients resuscitated from ventricular fibrillation are susceptible to early recurrence, probably reflecting continuing myocardial electrical instability.
Cardiac Sarcoma 14 Years after Treatment for Pleural Mesothelioma
Authors: Siyamek Neragi-Miandoab, Sidhu P. Gangadharan, David J. Sugarbaker
Journal: New England Journal of Medicine (2005)

Case 4-2005: Sodium Stibogluconate for Cutaneous Leishmaniasis to the editor: In Case 4-2005 (Feb.10 issue), 1 a discussant states that sodium stibogluconate (Pentostam, GlaxoSmithKline, United Kingdom) is available in the United States only from the Centers for Disease Control and Prevention (CDC).The U.S. military is another potential supplier of sodium stibogluconate.This drug has been used under an investigational-new-drug protocol at Walter Reed Army Medical Center (Washington, D.C.) since 1978 and is now also available at Brooke Army Medical Center (San Antonio, Tex.).Cutaneous leishmaniasis has been diagnosed in more than 800 soldiers and civilian contractors returning from Iraq or Afghanistan. 2,3Sodium stibogluconate may be a potential treatment option for these patients and is available to military health care beneficiaries and to those who acquire the infection while performing military duties. 3Providers with questions concerning the treatment or evaluation of leishmaniasis related to military service
THU0255 Marked increase in serum KL-6 and SP-D levels during 1st 4 weeks after tratment predicts poor prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis
Authors: S. Arai, K. Kurasawa, R. Maezawa, H. Okada, T. Owada, T. Fukuda
Journal: Annals of the Rheumatic Diseases (2013)

Background Interstitial pneumonia (IP) is a serious complication associated with polymyositis (PM) and dermatomyositis (DM). Predictive factors for poor prognosis have not been fully identified. KL-6 and surfactant protein D (SP-D) are biomarkers for existence and severity of IP. Clinical usefulness of these markers in IP in PM/DM has not been fully evaluated. Objectives To identify poor prognostic factors for IP in PM/PM. and to determine whether serum KL-6/SP-D levels predict patients with IP in PM/DM. Methods Consecutive 50 PM/DM (P: 17, DM 33) patients with active IP, 6 of whom were died of respiratory failure, were enrolled in this study. Active IP was defined as IP that was judged as requiring intensive immunotherapy for IP by physicians managing patients, based on worsening dyspnea and, expanding ground glass opacities in HR-CT or decreasing PaO2. Serum KL-6 and SP-D levels were measured before treatment for IP and every 2-4 weeks after starting therapy. To find correlation between KL-6/SP-D levels and clinical feature including prognosis, medical records were reviewed retrospectively. Results Serum KL-6 and SP-D levels were elevated in patients with active IP compared to those with inactive IP or without IP. Serum KL-6 and SP-D levels at the diagnosis of active IP were within normal range in 26% and 44% of patients with active IP, respectively. KL-6 and SP-D levels at the time of diagnosis failed to predict prognosis. Serum Kl-6 levels were increased up to 3 month after starting treatment and then decreased gradually to base lines, whereas SP-D levels were at peaks within 1st 4 weeks after the treatment and decreased rapidly to normal levels. In patients with poor prognosis showed in marked increased in KL-6/SP-D levels. Comparison of clinical features between patients with poor and good prognosis showed significant difference in Kl-6 levels at 1st 4 weeks and increase of KL-6 and SP-D levels during during 1st 4 weeks, increased AaDO2 levels before treatment and existence of alveolar opacities. Multivariate logistic regression analysis showed only increase in KL-6/SP-D levels during during 1st 4 weeks as a poor prognostic factor. Cut off levels determined by ROC analysis were 1.70 and 1.75 of increase ratio of KL-6 and SP-D levels at 2-4 weeks after treatment to those at 0 week, respectively. Increase of KL-6 during 1st 4 weeks over 800U/ml was a poor prognostic factor. Conclusions Increase in serum Kl-6/SP-D levels during 1st 4 weeks after starting therapy, but not their levels at any one time point, predicts poor prognosis. When marked increased of KL-6 and SP-D levels during the 1st 4 weeks, patients have risks of poor prognosis and additional therapy should be considered. Disclosure of Interest None Declared
Actions of sodium and potassium ions on baroreceptors of normotensive and spontaneously hypertensive rats.
Authors: W R Saum, S Ayachi, A M Brown
Journal: Circulation Research (1977)

Although mechanoreceptors are known to be sensitive to extracellular Na + and K + concentrations (INa + ] 0 and [K 4 1,,), the ionic sensitivity of baroreceptors as it relates to their function has not been reported.An in vitro aortic arch-aortic nerve preparation has been used to study this problem in normotensive (NTR) and spontaneously hypertensive (SHR) rats.The threshold of the response to pressure is increased and the sensitivity reduced by lowering [Na + J 0 ; an increase in |K*| 0 produces changes in the opposite direction.These changes in ionic environment have no effect upon the pressure-volume relationship of the isolated aortic arch segment so that the effects are upon the baroreceptors themselves.Differences in ionic sensitivity between SHR and NTR baroreceptors were not observed, but the number of receptors compared in this way was small.A proposed model based on conventional membrane electrophysiological theory describes the ionic effects observed in SHR and NTR baroreceptors.The increased threshold and decreased sensitivity of SHR baroreceptors can be accounted for by assuming that their membrane sodium to potassium permeability ratio is reduced and the distensibility of their aortas is not significantly reduced.A mechanism such as this might be involved in acute resetting of baroreceptors.The present results predict sodium-sensitive baroreceptor reflexes, and we have already reported that reductions of as little as 5% in [Na + |u bathing baroreceptors reflexly increase arterial blood pressure and urine output.CHANGES IN THE concentrations of sodium and potassium ions alter the functioning of mechanoreceptors such as the muscle spindle, 1 crayfish stretch receptor, 2 and Pacinian corpuscle. 3Information about the effects of alterations in the levels of extracellular Na + and K + on the functioning of cardiovascular baroreceptors should be of great interest because these mechanoreceptors not only regulate blood pressure but also participate in the regulation of body fluid volume. 4" 7 Surprisingly, such information is lacking, although Matsuura 8 reported that reducing the extracellular sodium in solutions perfusing baroreceptors in the common carotid artery decreased the electrotonic potential elicited by probing the vessel wall with a glass rod.In addition, the recent demonstration of a contribution of an electrogenic sodium pump to the threshold and sensitivity of aortic baroreceptors suggests that changes in salt concentrations should affect baroreceptor function. 9For these reasons, we examined the effects of alterations of the extracellular sodium and potassium concentrations ([Na + ] 0 and [K + ] o ) upon the pressure-discharge curves of individual arterial baroreceptors.Since abnormalities in salt metabolism have been implicated in hypertension, we compared the results between normotensive (NTR) and spontaneously hyperten-
Effect of exemestane on bone turnover markers and bone mineral density (BMD): 2 year results of the Dutch/Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.
Authors: JG van Nes, SE Papapoulos, JJ Braun, L Dirix, H Putter, RE Zwaan, BE Ballieux, I van Rongen, CJ van de Velde, C Seynaeve, JW Nortier
Journal: Cancer Research (2009)

Abstract Abstract #1154 Background Aromatase inhibitors (AIs) given to women with early breast cancer may adversely affect bone metabolism. We studied the effect of exemestane (E) on bone mineral density (BMD) and bone turnover and compared it to the effect of tamoxifen (T) treatment in a group of women participating in the Dutch and Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. In this trial, postmenopausal women with hormone sensitive early breast cancer (n=3168) were randomised between 5 years E or 2½-3 years T followed by 2½-2 years of E.&amp;#x2028; Methods In this subprotocol, 87 women were followed for two years. Patients with bone diseases were excluded. Total hip and lumbar spine BMD were assessed at baseline and after 1 and 2 years. The bone resorption marker cross-linked telopeptide of type-I collagen (CTX) and the bone formation marker N-terminal propeptide of type I collagen (PINP) were measured in fasting serum at baseline and after 3, 6, 12 and 24 months.&amp;#x2028; Results At baseline, there was no difference in total hip (E: 0.85g/cm2, T: 0.80g/cm2; p=0.642) and lumbar spine BMD (E: 0.99g/cm2, T: 1.02g/cm2; p=0.545) between both groups. After 2 years, there were no significant changes in total hip BMD (E: 0.02 g/cm2 95%CI -0.05;0.08, p=0.849; T: 0.03 g/cm2, 95%CI -0.02;0.09, p=0.466) and in spine BMD (E: -0.02 g/cm2 95%CI -0.11;0.06, p=0.834; T: 0.02 g/cm2 95%CI -0.05;0.10, p=0.747). At baseline, there was no difference in serum CTX (E: 0.34ng/mL, T: 0.29ng/mL; p=0.271) and P1NP (E: 57ng/L, T:58ng/L, p=0.973) between both groups. After 2 years of treatment, serum CTX increased, although not significantly in the E group (20%, 95%CI -6%;54%, p=0.223) while it decreased significantly in the T group (-40%, 95%CI -23%;-53%, p&amp;lt;0.001). At 24 months, the CTX was 0. 44ng/mL (E) and 0. 18ng/mL (T). Serum P1NP did not change in the E group (-2%, 95%CI -20%;19%, p=0.837) but decreased significantly in the T group (-48%, 95%CI -36%;-58%, p&amp;lt;0.001). At 24 months, the P1NP was 55ng/L (E) and 28ng (T).&amp;#x2028; Conclusion Although there was a trend for an increase in bone resorption with E treatment, this was not significant and was not associated with a decrease in BMD. The magnitude of the reported negative effect of aromatase inhibitors on bone metabolism in studies using T as comparator treatment may be overestimated by the effect of T on bone turnover. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1154.
Abstract 4009: Hypoxia potentiates Runx2-mediated increased Bcl-2 expression in prostate cancer resulting in apoptosis resistance
Authors: Gillian Browne, Heather McCook, Louise Ming, Janet L. Stein, Gary S. Stein, Jane B. Lian, Stephanie R. McKeown, Jenny Worthington
Journal: Cancer Research (2012)

Abstract Hypoxia is known to act as a selective pressure in the tumor microenvironment, often resulting in sub-populations of cells that have a propensity for more aggressive behaviour. More recently, Runx2 (an osteogenic transcription factor) has been associated with tumor growth, invasion and metastasis. Previous results in our laboratory have indicated that hypoxia selects for more invasive, apoptosis-resistant prostate cancer cells. Microarray analysis revealed that both Runx2 and Bcl-2 (an anti-apoptotic protein) were up-regulated in the hypoxia-selected cells (Butterworth et al, 2008). Bcl-2 is known to be up-regulated in various malignancies, and is associated with more aggressive disease and resistance to chemotherapy. Subsequent analysis of the Bcl-2 promoter revealed two binding sites for Runx2. In the current study we confirmed regulation of Bcl-2 by Runx2 though ChIP binding and reporter assays in LNCaP prostate cancer cells. Runx2 over-expressing LNCaP cells showed increased cell viability which was inhibited by Runx2 siRNA knockdown. A variety of assays demonstrated that Runx2 over-expressing cells were more resistant to apoptosis than controls. We further addressed the effect of hypoxia on Runx2 expression and the potential role Runx2 might play in the regulation of Bcl-2 expression and thus apoptosis in prostate cancer. When LNCaP cells were exposed to hypoxia, both Runx2 and Bcl-2 mRNA and protein levels were significantly increased over oxic controls. In a separate in vivo study, treatment of LNCaP tumors grown on the backs of immuno-compromised mice with the anti-androgen bicalutamide resulted in a profound decrease in tumor oxygenation during the first 14 days. Over the following 14 days, oxygen levels gradually increased. Further investigation of the excised tumors showed an increase in Runx2 mRNA levels from day 7, which was further confirmed by western and immunohistochemical analyses. In summary, this study shows that hypoxia promotes over-expression of Runx2 in prostate cancer cells. The cells exhibit a survival advantage through up-regulation of Bcl-2 leading to apoptosis resistance. These results, taken together with the in vivo data, suggest that Runx2 expression (either through microenvironmental pressures or ectopic expression) promotes progression to a more apoptosis-resistant and thus malignant phenotype, highlighting Runx2 as a potential therapeutic target in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4009. doi:1538-7445.AM2012-4009