tbuckley/cabot-search huggingface dataset:
Delocalization and Destabilization of the Arf Tumor Suppressor by the Leukemia-Associated NPM Mutant
Authors: Emanuela Colombo, Paola Martinelli, Raffaella Zamponi, Danielle C. Shing, Paola Bonetti, Lucilla Luzi, Sara Volorio, Loris Bernard, Giancarlo Pruneri, Myriam Alcalay, Pier Giuseppe Pelicci
Journal: Cancer Research (2006)

Abstract One third of acute myeloid leukemias (AMLs) are characterized by the aberrant cytoplasmic localization of nucleophosmin (NPM) due to mutations within its putative nucleolar localization signal. NPM mutations are mutually exclusive with major AML-associated chromosome rearrangements and are frequently associated with a normal karyotype, suggesting that they are critical during leukemogenesis. The underlying molecular mechanisms are, however, unknown. NPM is a nucleocytoplasmic shuttling protein that has been implicated in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression, and stress response. It has been recently shown that NPM is required for the stabilization and proper nucleolar localization of the tumor suppressor p19Arf. We report here that the AML-associated NPM mutant localizes mainly in the cytoplasm due to an alteration of its nucleus-cytoplasmic shuttling equilibrium, forms a direct complex with p19Arf, but is unable to protect it from degradation. Consequently, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Furthermore, we show that expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest. Inactivation of p19Arf, a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM. (Cancer Res 2006; 66(6): 3044-50)
Echocardiographic findings in atrial flutter.
Authors: S Zoneraich, O Zoneraich, J J Rhee
Journal: Circulation (1975)

Echocardiographic studies were performed in 22 patients with atrial fibrillation and atrial flutter. In atrial flutter, the echocardiograms consistently demonstrated regular undulatory waves of the posterior left atrial wall and upper left interventricular septum coinciding with each flutter wave of the electrocardiogram. The mitral valve was slightly reopened by each flutter wave occurring after diastolic mitral closure. The phonocardiogram simultaneously recorded with the echocardiogram showed only occasional atrial sounds. Coarse atrial fibrillation produced undulatory low frequency motion of both leaflets of the mitral valve during diastole. Atrial fibrillation with fine fibrillatory waves failed to show any significant and constant undulations of the left atrial wall and upper left interventricular septum. Echocardiographic evaluation of patients with atrial flutter could have diagnostic implications in doubtful cases with nondiagnostic electrocardiograms.
A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased<i>Akkermansia</i>spp. population in the gut microbiota of mice
Authors: Fernando F Anhê, Denis Roy, Geneviève Pilon, Stéphanie Dudonné, Sébastien Matamoros, Thibault V Varin, Carole Garofalo, Quentin Moine, Yves Desjardins, Emile Levy, André Marette
Journal: Gut (2014)

<h3>Objective</h3> The increasing prevalence of obesity and type 2 diabetes (T2D) demonstrates the failure of conventional treatments to curb these diseases. The gut microbiota has been put forward as a key player in the pathophysiology of diet-induced T2D. Importantly, cranberry (<i>Vaccinium macrocarpon</i> Aiton) is associated with a number of beneficial health effects. We aimed to investigate the metabolic impact of a cranberry extract (CE) on high fat/high sucrose (HFHS)-fed mice and to determine whether its consequent antidiabetic effects are related to modulations in the gut microbiota. <h3>Design</h3> C57BL/6J mice were fed either a chow or a HFHS diet. HFHS-fed mice were gavaged daily either with vehicle (water) or CE (200 mg/kg) for 8 weeks. The composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. <h3>Results</h3> CE treatment was found to reduce HFHS-induced weight gain and visceral obesity. CE treatment also decreased liver weight and triglyceride accumulation in association with blunted hepatic oxidative stress and inflammation. CE administration improved insulin sensitivity, as revealed by improved insulin tolerance, lower homeostasis model assessment of insulin resistance and decreased glucose-induced hyperinsulinaemia during an oral glucose tolerance test. CE treatment was found to lower intestinal triglyceride content and to alleviate intestinal inflammation and oxidative stress. Interestingly, CE treatment markedly increased the proportion of the mucin-degrading bacterium <i>Akkermansia</i> in our metagenomic samples. <h3>Conclusions</h3> CE exerts beneficial metabolic effects through improving HFHS diet-induced features of the metabolic syndrome, which is associated with a proportional increase in <i>Akkermansia</i> spp. population.
HER-2 Gene Amplification, HER-2 and Epidermal Growth Factor Receptor mRNA and Protein Expression, and Lapatinib Efficacy in Women with Metastatic Breast Cancer
Authors: Michael F. Press, Richard S. Finn, David Cameron, Angelo Di Leo, Charles E. Geyer, Ivonne E. Villalobos, Angela Santiago, Roberta Guzman, Armen Gasparyan, Yanling Ma, Kathy Danenberg, Anne Marie Martin, Lisa Williams, Cristina Oliva, Steven Stein, Robert Gagnon, Michael Arbushites, Maria T. Koehler
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. Experimental Design: In available breast cancer tissue from EGF30001 (paclitaxel ± lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine ± lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory. Results: The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P &amp;lt; 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P &amp;lt; 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P &amp;lt; 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among “HER-2-negative” breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory. Conclusions: Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.
gammadelta T lymphocytes in the peripheral blood of patients with tuberculosis with and without HIV co-infection
Authors: A C C Carvalho
Journal: Thorax (2002)

Background: Several recent studies suggest that γδ T lymphocytes play an important role in immunity against <i>Mycobacterium tuberculosis.</i> However, the dynamics of these cells in the peripheral blood of patients with tuberculosis (TB) with and without HIV infection is not fully understood. A study was undertaken to evaluate the profile of the γδ T cell population in patients at the time the diagnosis of TB was established. Methods: A cross sectional study was performed in consecutive TB patients from the Department of Infectious Diseases, Spedali Civili, Brescia. CD4+, CD8+ and Vδ1 and Vδ2 T cell counts were analysed. Lymphocyte surface membrane expression was evaluated with the FITC-TCRγδ, -Vδ1, -Vδ2 and PE-Vδ1 monoclonal antibodies. Blood donors and HIV seropositive asymptomatic individuals acted as controls. Results: Seventy four TB patients were evaluated, 20 of whom (27%) were co-infected with HIV. HIV seronegative TB patients (n=54) had total γδ T cells and Vδ1 subsets comparable to those in blood donors (n=39). However, the percentage with the Vδ2 subset was significantly lower in patients with TB than in controls (median 1.5 <i>v</i> 2.1; p=0.05). Responsiveness to PPD was not associated with predominance of a specific γδ T cell subset. HIV seropositive individuals had a decreased percentage of circulating Vδ2 cells at a level similar to that in HIV seronegative TB patients, regardless of the presence of active TB. Conclusions: HIV seronegative TB patients and HIV infected individuals (with or without active TB) have a reduced number of circulating Vδ2 T cells compared with healthy individuals. Whether TB and HIV infection share a common mechanism causing Vδ2 T cell depletion still needs to be established.
Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials
Authors: Katayoun Vahedi, Jeannette Hofmeijer, Eric Juettler, Eric Vicaut, Bernard George, Ale Algra, G Johan Amelink, Peter Schmiedeck, Stefan Schwab, Peter M Rothwell, Marie-Germaine Bousser, H Bart van der Worp, Werner Hacke
Journal: The Lancet Neurology (2007)
Quality of Care
Authors: Holly L. Howe
Journal: JAMA (1992)

<h3>To the Editor.</h3> —The stated objective for the study by Hand et al<sup>1</sup>was to determine the degree of compliance with clinical standards among hospitals and to account for compliance variations among them. However, the authors had a significant bias in their sample selection that may have resulted in erroneous conclusions. All hospitals selected for the sampling frame had tumor registries and, in all probability, had a cancer program certified by the American College of Surgeons. Less than half of the 208 Illinois hospitals treating cancer patients in 1988 had this certification. The authors noted, as was noted in the Editorial,<sup>2</sup>that the hospitals selected treat the vast majority of breast cancer patients in Illinois, but this is irrelevant in a study examining hospitals as the unit of analysis. The study design would have been improved if all Illinois hospitals had a chance to be included in the
The Fate and Toxicity of Raman-Active Silica-Gold Nanoparticles in Mice
Authors: Avnesh S. Thakor, Richard Luong, Ramasamy Paulmurugan, Frank I. Lin, Paul Kempen, Cristina Zavaleta, Pauline Chu, Tarik F. Massoud, Robert Sinclair, Sanjiv S. Gambhir
Journal: Science Translational Medicine (2011)

Gold-core nanoparticles designed for imaging by Raman spectroscopy in patients are generally nontoxic in mice, causing only temporary liver inflammation when given intravenously.
Underestimation of true pulmonary blood volume by the pulmonary artery wedge injection technique in cardiac patients
Authors: B. F. SCHREINER, D. J. FARNHAM, D. C. LOGAN
Journal: Cardiovascular Research (1978)

Pulmonary blood volume measurements were made comparing pulmonary artery with pulmonary artery wedge and left atrial dye dilution curves in 32 patients with cardiac disease. Mean transit times across the lungs were underestimated by the PAW curve technique. Hence calculated PBV by the right heart injections alone underestimates true PBV.
Differences between asthmatics and nonasthmatics hospitalised with influenza A infection
Authors: Pierre Ernst, Amnon Ariel, Samy Suissa
Journal: European Respiratory Journal (2013)

iral respiratory infections are the major cause of asthma exacerbations [1], while subjects with asthma are more likely to suffer significant morbidity when infected [2].The severity and duration of respiratory insult depend on complex viral-host interactions.Abnormalities of the innate and adaptive immune response have been demonstrated in humans and in animal models of asthma [3].These phenomena may explain the increased vulnerability of asthmatics to viral respiratory infections.
Histone Deacetylases Are Required for Androgen Receptor Function in Hormone-Sensitive and Castrate-Resistant Prostate Cancer
Authors: Derek S. Welsbie, Jin Xu, Yu Chen, Laetitia Borsu, Howard I. Scher, Neal Rosen, Charles L. Sawyers
Journal: Cancer Research (2009)

Transcriptional activity of the androgen receptor (AR) is crucial for growth and survival of prostate cancer even upon development of resistance to androgen ablation and antiandrogen therapies. Therefore, novel therapies that can suppress AR transcriptional activity when conventional hormone therapies fail are needed. Here, we show that histone deacetylase (HDAC) inhibitors, including SAHA (vorinostat) and LBH589, which are currently being tested in clinic, could be such a therapy. HDAC inhibitors block the AR-mediated transcriptional activation of many genes, including the TMPRSS2 gene involved in fusion with ETS family members in a majority of prostate cancers. Genetic knockdown of either HDAC1 or HDAC3 can also suppress expression of AR-regulated genes, recapitulating the effect of HDAC inhibitor treatment. Whereas HDAC inhibitor treatment can lower androgen receptor protein levels in prostate cancer cells, we show that independent of AR protein levels, HDAC inhibitors block AR activity through inhibiting the assembly of coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in castration-resistant prostate cancer models and, therefore, merit clinical investigation in this setting. The HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition.
5-Aza-2′-Deoxycytidine Delays Androgen-Independent Disease and Improves Survival in the Transgenic Adenocarcinoma of the Mouse Prostate Mouse Model of Prostate Cancer
Authors: Christoph S. Zorn, Kirk J. Wojno, Michael T. McCabe, Rainer Kuefer, Juergen E. Gschwend, Mark L. Day
Journal: Clinical Cancer Research (2007)

Abstract Purpose: We have previously shown that 5-aza-2′-deoxycytidine (5-aza) is an effective chemopreventive agent capable of preventing early disease progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The purpose of this study was to determine the effect of 5-aza on preexisting TRAMP prostate cancers and prevention of androgen-independent prostate cancer. Experimental Design: TRAMP mice with established prostate cancers were treated with 5-aza, castration, castration + 5-aza, or vehicle control (PBS). One cohort of 22 mice per treatment was euthanized after 10 weeks of treatment, whereas a second cohort of 14 mice per group was followed until death to determine survival. Histologic sections of prostate, pelvic lymph nodes, lung, and liver were blinded and analyzed by a certified genitourinary pathologist (K.J.W.). Results: Combined treatment (castration + 5-aza) provided significant survival benefits over either single treatment (combined versus castration P = 0.029, combined versus 5-aza P = 0.036). At 24 weeks of age, 86% of mice within the PBS cohort exhibited histologic evidence of prostate cancer, whereas only 47% of the combined cohort exhibited malignant disease (P &amp;lt; 0.0001). Additionally, whereas 43% of the PBS treatment group exhibited lymph node metastases, these were only observed in 21% of the combined treatment mice. Conclusions: This is the first study to examine the effect of 5-aza and combined castration + 5-aza on preexisting prostate cancer in an animal model. Based on these preclinical findings, we suggest that 5-aza treatment may prolong the time to an androgen-independent status and thus survival in a hormone-deprived setting in prostate cancer.
Comparison of Outcomes Following Thrombolytic Therapy Among Patients With Prior Stroke and Diabetes in the Virtual International Stroke Trials Archive (VISTA)
Authors: Nishant Kumar Mishra, Stephen M. Davis, Markku Kaste, Kennedy R. Lees
Journal: Diabetes Care (2010)

OBJECTIVE The use of alteplase in patients who have had a prior stroke and concomitant diabetes is not approved in Europe. To examine the influence of diabetes and prior stroke on outcomes, we compared data on thrombolysed patients with nonthrombolysed comparators. RESEARCH DESIGN AND METHODS We selected patients with ischemic stroke on whom we had data on age, pretreatment baseline National Institutes of Health Stroke Scale (b-NIHSS), and 90-day outcome measures (functional modified Rankin score [mRS]) and neurological measures [NIHSS]) in the Virtual International Stroke Trials Archive. We compared outcomes between thrombolysed patients and nonthrombolysed comparators in those with and without diabetes, those who have had a prior stroke, or both and report findings using the Cochran-Mantel-Haenszel (CMH) test and proportional odds logistic regression analyses. We report an age-adjusted and b-NIHSS–adjusted CMH P value and odds ratio (OR). RESULTS Rankin data were available for 5,817 patients: 1,585 thrombolysed patients and 4,232 nonthrombolysed comparators. A total 1,334 (24.1%) patients had diabetes, 1,898 (33.7%) patients have had a prior stroke, and 491 (8%) patients had both. Diabetes and nondiabetes had equal b-NIHSS (median 13; P = 0.3), but patients who have had a prior stroke had higher b-NIHSS than patients who have not had a prior stroke (median 13 vs. 12; P &amp;lt; 0.0001). Functional outcomes were better for thrombolysed patients versus nonthrombolysed comparators among both nondiabetic (P &amp;lt; 0.0001; OR 1.4 [95% CI 1.3–1.6]) and diabetic (P = 0.1; 1.3 [1.05–1.6 ]) subjects. Similarly, outcomes were better for thrombolysed patients versus nonthrombolysed comparators among who have not had a prior stroke (P &amp;lt; 0.0001; 1.4 [1.2–1.6 ]) and those who have (P = 0.02; 1.3 [1.04–1.6 ]). There was no interaction of diabetes and prior stroke with treatment (P = 0.8). Neurological outcomes were consistent with the mRS. CONCLUSIONS Outcomes from thrombolysis are better among patients with diabetes and/or those who have had a prior stroke than in control subjects. Withholding thrombolytic treatment from otherwise-eligible patients may not be justified.
Suppression of IgE antibody production in SJL mice. III. Characterization of a suppressor substance extracted from normal SJL spleen cells.
Authors: N Watanabe, Z Ovary
Journal: The Journal of Experimental Medicine (1977)

SJL mice were immunized with 1 microng dinitrophenylated keyhole limpet hemocyanin in 1 mg Al(OH)3. The mice were infected 21 days later with 750 third stage larvae of Nippostrongylus brasiliensis. On day 35, 14 days after infection, they were injected with 1 microng DNP-N, brasiliensis extract (Nb) in 1 mg Al(OH)3. In order to obtain high titer and persistent anti-DNP IgE antibody the mice were irradiated (540 R) 1 day after injection of DNP-Nb. Suppression of anti-DNP IgE antibody production was induced by spleen cells from normal SJL mice. Suppression of IgE antibody response is also obtained by an extract from normal SJL spleen cells. The suppressor substance from normal SJL spleen cell extract is a heat-labile protein, and is not absorbed by anti-mouse immunoglobulin. The mol wt of this substance is larger than 300,000 daltons as determined by gel filtration on Sephadex G-200, but after ultracentifugation, the supernate still has suppressive activity on IgE antibody production.
Production and biological role of hepatocyte and myeloid cell-derived interleukin-1 receptor antagonist in a model of systemic inflammation
Authors: C Lamacchia, G Palmer, E Rodriguez, D Talabot-Ayer, C Gabay
Journal: Annals of the Rheumatic Diseases (2010)

Background Interleukin-1 receptor antagonist (IL1Ra) is a specifi c IL1 inhibitor that possesses anti-infl ammatory activities in experimental models and in patients.Interestingly, administration of IL1Ra, particularly in animal models, can ameliorate the physiological consequences of septic shock.The contribution of the IL1/IL1Ra balance during endotoxaemia was confi rmed by the high susceptibility of IL1Ra defi cient mice to a lethal dose of lipopolysaccharide (LPS).Previous in vitro data demonstrated that both hepatocytes and myeloid cells produce IL1Ra in large amounts in response to LPS.Objectives The aim of this study was to determine the role of hepatocyte-and myeloid cell-derived IL1Ra in the production of circulating IL1Ra and in the control of survival in response to endotoxin in vivo.Methods Conditional knockout mice in which IL1Ra production has been specifi cally targeted in hepatocytes (IL1RadeltaH), myeloid cells (IL1RadeltaM) or in both cellular sources (IL1RadeltaH+M) were generated in a pure C57BL/6 genetic background by using the LoxP/Cre-recombinase system.Systemic infl ammation was induced by intraperitoneal (ip) injection of 10 mg/kg LPS in IL1RadeltaH, IL1RadeltaM, IL1RadeltaH+M and control mice.IL1Ra was quantifi ed by ELISA in different organs and sera 4 or 18 h after injection.LPS (10 mg/kg) was also injected ip in the different conditional IL1Ra knockout mouse lines as well as in constitutively IL1Ra knockout (IL1Ra-/-) and control mice for a survival test. ResultsThe levels of circulating IL1Ra were decreased by 15% and 57% in IL1RadeltaH and IL1RadeltaM mice, respectively, 4 h after LPS administration compared with control mice.IL1Ra levels were very low in the circulation of IL1RadeltaH+M mice (decreased by 92% and 75% 4 h and 18 h after LPS injection, respectively).In addition, IL1Ra levels were decreased by 56%, 20% and 76% in the livers of IL1RadeltaH, IL1RadeltaM on August 18,
Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors
Authors: M.P. Morelli, T. Cascone, T. Troiani, F. De Vita, M. Orditura, G. Laus, S.G. Eckhardt, S. Pepe, G. Tortora, F. Ciardiello
Journal: Annals of Oncology (2005)