tbuckley/cabot-search huggingface dataset:
The Effect of Chemical Modification and Nanoparticle Formulation on Stability and Biodistribution of siRNA in Mice
Authors: Shan Gao, Frederik Dagnaes-Hansen, Ebbe Juel Bech Nielsen, Jesper Wengel, Flemming Besenbacher, Kenneth Alan Howard, Jørgen Kjems
Journal: Molecular Therapy (2009)

Instability and inadequate biodistribution of double-stranded RNA are major drawbacks to the clinical use of RNA interference. This work compares chemical modification and nanoparticle formulation as strategies to improve the systemic delivery of small interfering RNA (siRNA). Variable levels of chemical modified siRNA, either naked or within nanoparticle, were intravenously injected into mice to study temporal stability and biodistribution detected by direct radioactive labeling or by northern blotting. Naked siRNA showed rapid renal clearance, with circulatory half-life of <5 minutes that could be extended to >30 minutes by cholesterol conjugation. The integrity of the chemically stabilized siRNA was maintained in blood for at least 30 minutes, whereas, unmodified siRNA duplex was degraded within 1 minute. Intact chemically modified siRNA could also be detected in all analyzed organs at 30 minutes but disappeared at 24 hours, except for heavy locked nucleic acid (LNA)-modified and cholesterol-conjugated siRNA in the lungs. Chitosan, liposomal, or JetPEI formulation greatly improved the stability and biodistribution of siRNA. Interestingly, high siRNA accumulation of the chitosan/siRNA formulation within the kidney was observed 24 hours postadministration. This comparative study highlights improvements to siRNA stability and pharmacokinetics, key determinants for development of clinically relevant RNAi therapeutics.
Fine specificity of cytotoxic T lymphocytes primed in vivo either with virus or synthetic lipopeptide vaccine or primed in vitro with peptide.
Authors: H Schild, M Norda, K Deres, K Falk, O Rötzschke, K H Wiesmüller, G Jung, H G Rammensee
Journal: The Journal of Experimental Medicine (1991)

Standard synthetic peptide preparations contain numerous peptidic byproducts in small amounts, which may be efficiently recognized by cytotoxic T lymphocytes (CTL). Recognition patterns of such peptide mixtures by CTL may serve as a kind of fingerprint for CTL fine specificity. Three types of H-2Db-restricted CTL were compared in this way. CTL primed in vivo either with A/PR/8/34 influenza virus or with a synthetic lipopeptide vaccine prepared from influenza nucleoprotein (NP) peptide 365-380 showed identical fine specificity. Both recognize virus-infected cells. In contrast, CTL primed in vitro with NP 365-380 had a different fine specificity and they did not recognize virus-infected cells. Most significantly, the two in vivo primed CTL types efficiently recognized the natural viral nonapeptide NP 366-374 presented by virus-infected H-2b cells, whereas the in vitro primed CTL failed to do so.
Pharmacokinetic (Pk) Activity of Cabazitaxel (Cbz) in Patients (Pts) with Renal Impairment (Ri)
Authors: A. Azaro, J. Rodon, J. Machiels, S. Rottey, S. Damian, R. Baird, A. Nieuweboer, P. Clot, C. Wack, L. Shen, D. Bobilev, M. De Jonge
Journal: Annals of Oncology (2014)
Neurons Are Recruited to a Memory Trace Based on Relative Neuronal Excitability Immediately before Training
Authors: Adelaide P. Yiu, Valentina Mercaldo, Chen Yan, Blake Richards, Asim J. Rashid, Hwa-Lin Liz Hsiang, Jessica Pressey, Vivek Mahadevan, Matthew M. Tran, Steven A. Kushner, Melanie A. Woodin, Paul W. Frankland, Sheena A. Josselyn
Journal: Neuron (2014)
Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B
Authors: Jihong Chen, Feras M Ghazawi, Wafae Bakkar, Qiao Li
Journal: Molecular Cancer (2006)

Abstract Background In eukaryotic cells, the genomic DNA is packed with histones to form the nucleosome and chromatin structure. Reversible acetylation of the histone tails plays an important role in the control of specific gene expression. Mounting evidence has established that histone deacetylase inhibitors selectively induce cellular differentiation, growth arrest and apoptosis in variety of cancer cells, making them a promising class of anticancer drugs. However, the molecular mechanisms of the anti-cancer effects of these inhibitors have yet to be understood. Results Here, we report that a key determinant for the susceptibility of cancer cells to histone deacetylase inhibitors is their ability to maintain cellular Akt activity in response to the treatment. Also known as protein kinase B, Akt is an essential pro-survival factor in cell proliferation and is often deregulated during tumorigenesis. We show that histone deacetylase inhibitors, such as valproic acid and butyrate, impede Akt1 and Akt2 expression, which leads to Akt deactivation and apoptotic cell death. In addition, valproic acid and butyrate induce apoptosis through the caspase-dependent pathway. The activity of caspase-9 is robustly activated upon valproic acid or butyrate treatment. Constitutively active Akt is able to block the caspase activation and rescues cells from butyrate-induced apoptotic cell death. Conclusion Our study demonstrates that although the primary target of histone deacetylase inhibitors is transcription, it is the capacity of cells to maintain cellular survival networks that determines their fate of survival.
Characterization of MicroRNA Expression Levels and Their Biological Correlates in Human Cancer Cell Lines
Authors: Arti Gaur, David A. Jewell, Yu Liang, Dana Ridzon, Jason H. Moore, Caifu Chen, Victor R. Ambros, Mark A. Israel
Journal: Cancer Research (2007)

Abstract MicroRNAs are small noncoding RNAs that function by regulating target gene expression posttranscriptionally. They play a critical role in developmental and physiologic processes and are implicated in the pathogenesis of several human diseases including cancer. We examined the expression profiles of 241 human microRNAs in normal tissues and the NCI-60 panel of human tumor-derived cell lines. To quantify microRNA expression, we employed a highly sensitive technique that uses stem-loop primers for reverse transcription followed by real-time PCR. Most microRNAs were expressed at lower levels in tumor-derived cell lines compared with the corresponding normal tissue. Agglomerative hierarchical clustering analysis of microRNA expression revealed four groups among the NCI-60 cell lines consisting of hematologic, colon, central nervous system, and melanoma tumor–derived cell lines clustered in a manner that reflected their tissue of origin. We identified specific subsets of microRNAs that provide candidate molecular signatures characteristic of the tumor-derived cell lines belonging to these four clusters. We also identified specific microRNA expression patterns that correlated with the proliferation indices of the NCI-60 cell lines, and we developed evidence for the identification of specific microRNAs as candidate oncogenes and tumor suppressor genes in different tumor types. Our results provide evidence that microRNA expression patterns may mark specific biological characteristics of tumors and/or mediate biological activities important for the pathobiology of malignant tumors. These findings call attention to the potential of microRNAs to provide etiologic insights as well as to serve as both diagnostic markers and therapeutic targets for many different tumor types. [Cancer Res 2007;67(6):2456–68]
Acute Hemodynamic Responses to Inhaled Nitric Oxide in Patients With Limited Scleroderma and Isolated Pulmonary Hypertension
Authors: D.J. Williamson, C. Hayward, P. Rogers, L.L. Wallman, A.D. Sturgess, R. Penny, P.S. Macdonald
Journal: Circulation (1996)

Background Inhaled nitric oxide (NO) is a selective pulmonary vasodilator that reduces pulmonary vascular resistance (PVR) in patients with primary pulmonary hypertension. Their responses to inhaled NO predict their responses to other vasodilators, such as prostacyclin, and provide an estimate of the “fixed” component of their increased PVR. Some patients with limited cutaneous systemic sclerosis develop isolated pulmonary hypertension with a similar clinical course. Therefore, we have measured the acute hemodynamic response to inhaled NO in such patients. Methods and Results Seven patients were studied during inhalation of increasing concentrations of NO (0 to 80 ppm). Complete hemodynamic data were collected on five patients. They demonstrated a selective, dose-dependent, and rapidly reversible fall in PVR (34%) and mean pulmonary artery pressure (17%). There was a nonsignificant increase in cardiac index but no change in mean arterial pressure or systemic vascular resistance. The mean right atrial pressure fell (27%), but there was no change in pulmonary artery occlusion pressure. Of the seven patients, five responded to inhaled NO (≤40 ppm) with a decrease in total pulmonary resistance of at least 20%. Conclusions Inhaled NO is an effective and selective pulmonary vasodilator in a significant number of patients with pulmonary hypertension associated with limited cutaneous systemic sclerosis. It may be useful in determining the potentially reversible contribution to the increased PVR and should be considered for patients with acute pulmonary vascular crisis.
The Graft-Versus-Leukemia Effects of Allogeneic Cell Therapy
Authors: David L. Porter, MD, Joseph H. Antin, MD
Journal: Annual Review of Medicine (1999)

Until recently, the only cure for relapse after allogeneic bone marrow transplantation (BMT) has been a second BMT. Recently, infusions of leukocytes collected from the original transplant donor have been used to induce a direct graft-versus-leukemia (GVL) reaction in patients with relapsed disease. Adoptive immunotherapy with donor leukocyte infusions (DLI) results in complete remission for 60–80% of patients with relapsed chronic-phase CML; therapy is also effective for relapse of diseases other than CML, although response rates are lower. Adoptive immunotherapy induces remissions for the majority of patients with post-transplantation Epstein-Barr virus-related lymphomas and other viral-associated illnesses. The extraordinary success of DLI demonstrates that it is now possible to harness the GVL potential of the human immune system for clinical benefit. The necessary effector cells and target antigens required for GVL reactivity are poorly defined but are the subject of intensive investigation. Future trials will investigate strategies that retain and enhance the GVL effects while limiting toxicity from this therapy, and they may define methods of successful allogeneic adoptive immunotherapy outside the setting of allogeneic BMT.
Older patients with diabetes are often overtreated, say researchers
Authors: Jacqui Wise
Journal: BMJ (2015)

Older patients with diabetes whose treatment had resulted in very low blood pressure or haemoglobin A1c levels rarely had their medicines reduced or withdrawn, a US study published in JAMA Internal Medicine has found.1 The authors said that this represents a lost opportunity to reduce overtreatment among older people that can put them at risk of serious adverse events.

The retrospective cohort study included 211 667 diabetes patients with a mean age of 78 who were receiving treatment for blood pressure and blood glucose level control. More than half of the cohort received treatment that …
PRIVATE FEES AT HAMMERSMITH
Authors: D.J. Allison, P. Bourdillon, D.A.G. Galton, I.D.S. Gillies, A.W.G. Goolden, J.P. Lavender, R. Morrison, Jean Lumley, C.G. McKenzie, Celia Oakley, G.W. Poole, M.P. Singh, P. Stradling, L.H. Walter
Journal: The Lancet (1976)
Neutralizing Antibodies to HIV-1 in Seronegative Volunteers Immunized With Recombinant gp 120 From the MN Strain of HIV-1
Authors: Robert B. Belshe
Journal: JAMA (1994)

<h3>Objective.</h3> —To evaluate the safety and immunogenicity of the MN strain of recombinant gp 120 (MN rgp 120) as a vaccine prototype to prevent human immunodeficiency virus (HIV). <h3>Design.</h3> —Double-blind, randomized, placebo-controlled study with subjects vaccinated at 0, 4, 24, and 48 weeks and followed up through 64 weeks. <h3>Setting.</h3> —The AIDS Vaccine Evaluation Units in St Louis, Mo, Nashville, Tenn, and Rochester, NY, conducted the clinical study. Laboratory studies were conducted at Duke University, Raleigh, NC; data analysis was done by the Data Coordinating and Analysis Center at the EMMES Corporation, Potomac, Md. <h3>Participants.</h3> —Fifty-seven persons seronegative for HIV, at low risk for acquiring HIV infection, and 18 to 60 years of age. <h3>Interventions.</h3> —The MN rgp 120 vaccine was administered to 12 volunteers each in doses of 100 μg, 300 μg, or 600 μg, and 12 volunteers received a combination of 300 μg of MN rgp 120 vaccine and 300 μg of vaccine from rgp 120 of strain IIIB. Nine volunteers received alum adjuvant alone (control). <h3>Main Outcome Measures.</h3> —Safety was assessed by monitoring lymphocyte subsets, serum creatinine, and liver enzymes. Immunogenicity was measured by enzyme-linked immunosorbent assay using the immunogen and synthetic peptide corresponding to the variable region 3 domain of gp 120. Functional antibody assays included CD4 binding blocking; antibody-dependent, cell-mediated cytotoxicity; and neutralization of homologous and heterologous HIV strains. <h3>Results.</h3> —No severe adverse reactions occurred. In 33 of 48 volunteers, tw doses of vaccine induced antibodies that neutralized the homologous strain HIV-1/MN. Three doses of vaccine induced antibodies that neutralized MN (in 46 of 48 volunteers), SF-2 (in 45 of 48 volunteers), or IIIB strains of HIV-1 (in 30 of 48 volunteers). <h3>Conclusion.</h3> —The vaccines were safe and immunogenic. Multiple injections of vaccine broadened and increased the neutralizing antibody response. (<i>JAMA</i>. 1994;272:475-480)
Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer
Authors: A.M. Gonzalez-Angulo, A. Akcakanat, S. Liu, M.C. Green, J.L. Murray, H. Chen, S.L. Palla, K.B. Koenig, A.M. Brewster, V. Valero, N.K. Ibrahim, S. Moulder-Thompson, J.K. Litton, E. Tarco, J. Moore, P. Flores, D. Crawford, M.J. Dryden, W.F. Symmans, A. Sahin, S.H. Giordano, L. Pusztai, K.-A. Do, G.B. Mills, G.N. Hortobagyi, F. Meric-Bernstam
Journal: Annals of Oncology (2014)
Validation of current joint American Academy of Allergy, Asthma &amp; Immunology and American College of Allergy, Asthma and Immunology guidelines for antibody response to the 23-valent pneumococcal vaccine using a population of HIV-infected children
Authors: W KAMCHAISATIAN, W WANWATSUNTIKUL, J SLEASMAN, N TANGSINMANKONG
Journal: Journal of Allergy and Clinical Immunology (2006)
Nitric Oxide Inhibits Stretch-Induced MAPK Activation in Mesangial Cells Through RhoA Inactivation
Authors: Joan C Krepinsky, Alistair J Ingram, Damu Tang, Dongcheng Wu, Lieqi Liu, James W Scholey
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Glomerular capillary hypertension is an important determinant of glomerulosclerosis in rats with subtotal renal ablation. Dietary supplementation with L-arginine increases renal nitric oxide (NO) production and limits glomerular injury in this model, and early benefits are seen without altered glomerular capillary pressure. In an in vitro model of hemodynamically mediated signaling, the authors have reported that subjecting MC to cyclic stretch/relaxation activates the mitogen-activated protein kinase p42/44 (Erk) cascade and that NO and cyclic GMP abrogate stretch-induced Erk activation by inducing actin cytoskeletal disassembly. The actin cytoskeleton is regulated by the Rho family of GTPases, including RhoA; therefore, the authors examined the role of RhoA in stretch-induced Erk activation and as an NO target. In primary rat MC subjected to cyclic mechanical strain, RhoA activity was maximally increased (2.4-fold) after 1 min of stretch, and Erk activation temporally followed. The Rho-kinase inhibitor Y-27632 attenuated Erk activation in a dose-dependent manner and prevented stretch-induced actin stress fiber formation. The NO donors S-nitroso-N-acetylpenicillamine and cGMP both inhibited stretch-induced RhoA and Erk activation and stress fiber formation. Infection of MC with the RhoA mutant RhoA-Ala188, which is resistant to NO-dependent phosphorylation, abrogated the effects of NO and cGMP on stretch-induced Erk activation and stress fiber formation. The authors conclude that the early activation of RhoA is essential for stretch-induced actin stress fiber formation and Erk activation in MC, events which are prevented by NO and cGMP through their action on RhoA. Inhibition of RhoA may thus be a new approach to the prevention of hemodynamically mediated glomerular injury. E-mail: krepinj@mcmaster.ca
Heart rate following short‐term beta‐blocker titration predicts all‐cause mortality in elderly chronic heart failure patients: insights from the <scp>CIBIS‐ELD</scp> trial
Authors: Hans‐Dirk Düngen, Lindy Musial‐Bright, Simone Inkrot, Svetlana Apostolović, Frank Edelmann, Mitja Lainščak, Nikola Šekularac, Stefan Störk, Elvis Tahirovic, Verena Tscholl, Florian Krackhardt, Goran Loncar, Tobias D. Trippel, Götz Gelbrich
Journal: European Journal of Heart Failure (2014)
No effect of the oral neutral endopeptidase inhibitor candoxatril, on bronchomotor tone and histamine reactivity in asthma
Authors: RM Angus, MJ McCallum, JE Nally, NC Thomson
Journal: European Respiratory Journal (1994)

Neutral endopeptidase (NEP) is found in many tissues in man, including the lung. Metabolism by NEP is one of the main mechanisms for the clearance of atrial natriuretic peptide (ANP), a hormone that causes bronchodilation and reduces nonspecific bronchial reactivity in man. Candoxatril, an oral NEP inhibitor has been shown to elevate circulating ANP levels. We have sought to determine whether the administration of candoxatril will alter bronchomotor tone (forced expiratory volume in one second (FEV1)) and histamine reactivity. Ten male asthmatic patients with stable asthma were enrolled (mean (SD) age 32 (10) yrs; FEV1 92 (11)% predicted) in a randomized, double-blind, placebo-controlled study. On each study day, after baseline spirometry, patients received 200 mg of candoxatril or placebo. Spirometry was repeated at half hourly intervals. After 2 h a histamine inhalation test was performed. There was no significant difference in FEV1 values at baseline or at 2 h post-dosing between active and placebo study days, with mean (SEM) FEV1 at baseline and 2 h of 3.71 (0.29) l and 3.85 (0.29) l on the placebo day, and 3.89 (0.27) l and 4.05 (0.82) l on the active day, respectively. The geometric mean (range) provocative concentration of histamine producing a 20% fall in FEV1 (PC20) on the placebo day and active day did not differ significantly, being 1.17 (0.25-25.8) and 0.93 (0.13-32) mg.ml-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Phase I Study of Oral Gemcitabine Prodrug (LY2334737) Alone and in Combination with Erlotinib in Patients with Advanced Solid Tumors
Authors: Stijn L.W. Koolen, Petronella O. Witteveen, Robert S. Jansen, Marlies H.G. Langenberg, Roelien H. Kronemeijer, Annemarie Nol, Ignacio Garcia-Ribas, Sophie Callies, Karim A. Benhadji, Christopher A. Slapak, Jos H. Beijnen, Emile E. Voest, Jan H.M. Schellens
Journal: Clinical Cancer Research (2011)

Abstract Purpose: LY2334737 is an orally available prodrug of gemcitabine. The objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of daily administration of LY2334737 with or without erlotinib. Experimental Design: Patients with advanced or metastatic cancer were treated with escalating doses of LY2334737 monotherapy or in combination with continuous daily administration of 100 mg erlotinib. LY2334737 was given once daily for 14 days of a 21-day cycle. The study was extended with a bioequivalence trial to investigate a novel LY2334737 drug formulation. Results: A total of 65 patients were treated in this study. The MTD was 40 mg LY2334737. Fatigue was the most frequent DLT for LY2334737 monotherapy (4 patients) followed by elevated transaminase levels (2 patients), both observed at the 40- to 50-mg dose levels. Among the 10 patients in the combination arm, 2 had DLTs at the 40-mg dose level. These were fatigue and elevated liver enzyme levels. The most common adverse events were fatigue (n = 38), nausea (n = 27), vomiting (n = 24), diarrhea (n = 23), anorexia (n = 20), pyrexia (n = 18), and elevated transaminase levels (n = 14). The pharmacokinetics showed dose proportional increase in LY2334737 and gemcitabine exposure. The metabolite 2′,2′-difluorodeoxyuridine accumulated with an accumulation index of 4.3 (coefficient of variation: 20%). In one patient, complete response in prostate-specific antigen was observed for 4 cycles, and stable disease was achieved in 22 patients overall. Pharmacokinetic analysis showed that the 2 investigated LY2334737 drug formulations were bioequivalent. Conclusions: LY2334737 displays linear pharmacokinetics and the MTD is 40 mg with or without daily administration of 100 mg erlotinib. Signs of antitumor activity warrant further development. Clin Cancer Res; 17(18); 6071–82. ©2011 AACR.
Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies.
Authors: J R Boelaert, M de Locht, J Van Cutsem, V Kerrels, B Cantinieaux, A Verdonck, H W Van Landuyt, Y J Schneider
Journal: Journal of Clinical Investigation (1993)

This study investigates the pathophysiology of mucormycosis caused by Rhizopus, which has been reported in 46 dialysis patients, while treated with deferoxamine (DFO). This drug aggravates mucormycosis, which we experimentally induced in guinea pigs and which lead to a shortened animal survival (P < or = 0.01). The drug's effect on Rhizopus is not mediated through the polymorphonuclear cells. Fe.DFO, the iron chelate of DFO, abolishes the fungistatic effect of serum on Rhizopus and increases the in vitro growth of the fungus (P < or = 0.0001). This effect is present at Fe.DFO concentrations > or = 0.01 microM, at which fungal uptake of radioiron from 55Fe.DFO is observed. A 1,000-fold higher concentration of iron citrate is required to achieve a similar rate of radioiron uptake and of in vitro growth stimulation as observed with Fe.DFO. These in vitro effects of Fe.DFO (1 microM) in serum on radioiron uptake and on growth stimulation are more striking for Rhizopus than for Aspergillus fumigatus and are practically absent for Candida albicans. For these three fungal species, the rates of radioiron uptake from 55Fe.DFO and of growth stimulation in the presence of Fe.DFO in serum are directly related (r = 0.886). These results underscore the major role of Fe.DFO in the pathogenesis of DFO-related mucormycosis. Pharmacokinetic changes in uremia lead to a prolonged accumulation of Fe.DFO after DFO administration, which helps explain the increased sensitivity of dialysis patients to DFO-related mucormycosis.
Impact of Cancer on Work and Education Among Adolescent and Young Adult Cancer Survivors
Authors: Helen M. Parsons, Linda C. Harlan, Charles F. Lynch, Ann S. Hamilton, Xiao-Cheng Wu, Ikuko Kato, Stephen M. Schwartz, Ashley W. Smith, Gretchen Keel, Theresa H.M. Keegan
Journal: Journal of Clinical Oncology (2012)

To examine the impact of cancer on work and education in a sample of adolescent and young adult (AYA) patients with cancer.