tbuckley/cabot-search huggingface dataset:
Yeast Mutants As a Model System for Identification of Determinants of Chemosensitivity
Authors: Paola Perego, Gretchen S. Jimenez, Laura Gatti, Stephen B. Howell, Franco Zunino
Journal: Pharmacological Reviews (2000)

The fission yeast Schizosaccharomyces pombe and the budding yeast Saccharomyces cerevisiae have become valuable tools for the study of basic cellular functions of eukaryotic cells, including DNA repair mechanisms and cell cycle control. Since the major signaling pathways and cellular processes involved in cellular response to cytotoxic agents are conserved between yeasts and mammalian cells, these simple eukaryotic systems could be excellent models for the identification of molecular/cellular mechanisms of sensitivity to antitumor drugs. We describe relevant biological features of yeast cells and potential applications derived by their genetic manipulation. In particular, we have outlined the role of genes involved in repair processes and in checkpoint control, with specific reference to genes regulating radiation-sensitivity. Specific examples are provided concerning the use of both yeasts in understanding the mechanism of action of platinum compounds and topoisomerase inhibitors. The availability of the genomic sequence of these organisms as well as of new technologies (microarrays, proteomics) is expected to allow the identification of potential drug targets, since the drug discovery process is moving toward a genomic orientation. Among eukaryotic organisms, yeasts are suitable for easy genetic manipulations, and specific genetic alterations are exploitable for assessing the effects of chemotherapeutic agents with different mechanism of action. Although still at an early stage, this fast-moving field shows promise as a novel and potentially useful method for development of target-specific therapeutic approaches.
Penetration of Endothelial Cell Coated Multicellular Tumor Spheroids by Iron Oxide Nanoparticles
Authors: Don N. Ho, Nathan Kohler, Aruna Sigdel, Raghu Kalluri, Jeffrey R. Morgan, Chenjie Xu, Shouheng Sun
Journal: Theranostics (2012)

Iron oxide nanoparticles are a useful diagnostic contrast agent and have great potential for therapeutic applications.Multiple emerging diagnostic and therapeutic applications and the numerous versatile parameters of the nanoparticle platform require a robust biological model for characterization and assessment.Here we investigate the use of iron oxide nanoparticles that target tumor vasculature, via the tumstatin peptide, in a novel three-dimensional tissue culture model.The developed tissue culture model more closely mimics the in vivo environment with a leaky endothelium coating around a glioma tumor mass.Tumstatin-iron oxide nanoparticles showed penetration and selective targeting to endothelial cell coating on the tumor in the three-dimensional model, and had approximately 2 times greater uptake in vitro and 2.7 times tumor neo-vascularization inhibition.Tumstatin provides targeting and therapeutic capabilities to the iron oxide nanoparticle diagnostic contrast agent platform.And the novel endothelial cell-coated tumor model provides an in vitro microtissue environment to evaluate nanoparticles without moving into costly and time-consuming animal models.
The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer
Authors: Emily E. Bosco, Ying Wang, Huan Xu, Jack T. Zilfou, Karen E. Knudsen, Bruce J. Aronow, Scott W. Lowe, Erik S. Knudsen
Journal: Journal of Clinical Investigation (2006)

The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates G1/S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. Here the specific impact of RB deficiency on E2F-regulated gene expression, tumorigenic proliferation, and the response to 2 distinct lines of therapy was investigated in breast cancer cells. RB knockdown resulted in RB/E2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the RB deficiency compromised the short-term cell-cycle inhibition following cisplatin, ionizing radiation, and antiestrogen therapy. In the context of DNA-damaging agents, this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of antiestrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of aberrations in RB function were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.
Palmoplantar psoriasis is associated with greater impairment of health-related quality of life compared with moderate to severe plaque psoriasis
Authors: Jina Chung, Kristina Callis Duffin, Junko Takeshita, Daniel B. Shin, Gerald G. Krueger, Andrew D. Robertson, Andrea B. Troxel, Abby S. Van Voorhees, Emily Edson-Heredia, Joel M. Gelfand
Journal: Journal of the American Academy of Dermatology (2014)
Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205
Authors: Madhav V. Dhodapkar, Mario Sznol, Biwei Zhao, Ding Wang, Richard D. Carvajal, Mary L. Keohan, Ellen Chuang, Rachel E. Sanborn, Jose Lutzky, John Powderly, Harriet Kluger, Sheela Tejwani, Jennifer Green, Venky Ramakrishna, Andrea Crocker, Laura Vitale, Michael Yellin, Thomas Davis, Tibor Keler
Journal: Science Translational Medicine (2014)

Dendritic cell targeting safely leads to integrated humoral and cellular immunity when combined with TLR agonists in cancer patients.
New Strategies in Barrett's Esophagus: Integrating Clonal Evolutionary Theory with Clinical Management
Authors: Brian J. Reid, Rumen Kostadinov, Carlo C. Maley
Journal: Clinical Cancer Research (2011)

Abstract Barrett's esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades, the prevailing clinical paradigm has been that Barrett's esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma. However, no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5% to 10% of individuals with Barrett's esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett's metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge for investigators of Barrett's esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespan and quality of life of individuals with this condition. Clin Cancer Res; 17(11); 3512–9. ©2011 AACR.
Outcomes associated with routine systemic antifungal therapy in critically ill patients with Candida colonization
Authors: David Ferreira, Frederic Grenouillet, Gilles Blasco, Emmanuel Samain, Thierry Hénon, Alain Dussaucy, Laurence Millon, Mariette Mercier, Sebastien Pili-Floury
Journal: Intensive Care Medicine (2015)
Frequent and Focal <i>FGFR1</i> Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer
Authors: Jonathan Weiss, Martin L. Sos, Danila Seidel, Martin Peifer, Thomas Zander, Johannes M. Heuckmann, Roland T. Ullrich, Roopika Menon, Sebastian Maier, Alex Soltermann, Holger Moch, Patrick Wagener, Florian Fischer, Stefanie Heynck, Mirjam Koker, Jakob Schöttle, Frauke Leenders, Franziska Gabler, Ines Dabow, Silvia Querings, Lukas C. Heukamp, Hyatt Balke-Want, Sascha Ansén, Daniel Rauh, Ingelore Baessmann, Janine Altmüller, Zoe Wainer, Matthew Conron, Gavin Wright, Prudence Russell, Ben Solomon, Elisabeth Brambilla, Christian Brambilla, Philippe Lorimier, Steinar Sollberg, Odd Terje Brustugun, Walburga Engel-Riedel, Corinna Ludwig, Iver Petersen, Jörg Sänger, Joachim Clement, Harry Groen, Wim Timens, Hannie Sietsma, Erik Thunnissen, Egbert Smit, Daniëlle Heideman, Federico Cappuzzo, Claudia Ligorio, Stefania Damiani, Michael Hallek, Rameen Beroukhim, William Pao, Bert Klebl, Matthias Baumann, Reinhard Buettner, Karen Ernestus, Erich Stoelben, Jürgen Wolf, Peter Nürnberg, Sven Perner, Roman K. Thomas
Journal: Science Translational Medicine (2010)

FGFR1 amplification provides a therapeutic target for squamous cell lung cancer, which is resistant to other targeted lung cancer drugs.
A Novel Antiapoptotic Role for α<sub>1</sub>-Antitrypsin in the Prevention of Pulmonary Emphysema
Authors: Irina Petrache, Iwona Fijalkowska, Lijie Zhen, Terry R. Medler, Emile Brown, Pedro Cruz, Kang-Hyeon Choe, Laimute Taraseviciene-Stewart, Robertas Scerbavicius, Lee Shapiro, Bing Zhang, Sihong Song, Dan Hicklin, Norbert F. Voelkel, Terence Flotte, Rubin M. Tuder
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of α1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke–induced emphysema.Objectives: We propose that, in addition to its antielastolytic effects, α1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis.Methods, Measurements, and Main Results: Transduction of human α1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human α1-antitrypsin intravenously.Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by α1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of α1-antitrypsin.
Persistence of Asthma Symptoms during Adolescence
Authors: Stefano Guerra, Anne L. Wright, Wayne J. Morgan, Duane L. Sherrill, Catharine J. Holberg, Fernando D. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Little is known about rates and predictors of remission of childhood asthma after the onset of puberty. We used data collected at ages 6, 8, 11, 13, and 16 years from the Tucson Children's Respiratory Study, a population-based birth cohort. The onset of puberty was defined as the age of appearance of the first pubertal signs as reported by parents. Information on wheezing both before and after onset of puberty (mean ± SD follow-up from onset of puberty, 4.2 ± 1 year) was available for 781 children. Of these, 166 had asthma (either frequent wheezing or a physician-confirmed diagnosis plus any wheezing) in at least one survey before puberty. In this group, 58% of the children (97 of 166) reported the presence of wheezing after the onset of puberty (unremitting asthma). In contrast, only 30% (39 of 131) of the children with infrequent wheezing before puberty experienced wheezing episodes after the onset of puberty (unremitting wheezing). In addition to frequent wheezing before puberty, obesity, early onset of puberty, active sinusitis, and skin test sensitization were significant and independent predictors of unremitting asthma after the onset of puberty. Our findings from a population-based longitudinal cohort challenge the commonly held view that asthma usually remits during adolescence.
Resolution of peanut allergy: case-control study Science commentary: Why do some children grow out of peanut allergy?
Authors: J. O'B Hourihane, S. A Roberts, J. O Warner, J. O'B Hourihane, S. A Roberts, J. O Warner
Journal: BMJ (1998)

Principal-protected securities are the most popular form of structured hedge fund products, and constitute the largest segment of the structured hedge fund market. Financial institutions provide guarantees for the repayment of the principal amount of the protected securities at maturity. To date, structured hedge fund practitioners have used, by and large, the constant proportion portfolio insurance (CPPI) methodology to structure these securities, although some have used the Black-Scholes option (Option) pricing methodology as well. However, few, if any, of the practitioners have used the collateralized debt obligation (CDO) methodology in structuring these securities. The CDO methodology has been one of the most successful and popular methodologies in the structured fixed-income securities market. The CDO methodology obviates the need for a financial institution to guarantee the principal of the securities. This article is designed to illustrate the basic structural frameworks, investment processes, and benefits of the CDO, CPPI, and Option methodologies. The preference for a methodology in structuring a protected securities transaction depends on several factors, such as target investor, leverage, and cost. The author believes that as the market grows and becomes more competitive, the CDO methodology will become one of the structural alternatives for the principal-protected securities transactions.
Formoterol reduces asthmatic airway smooth muscle cell proliferation through p27 (Kip) which is supported by steroids
Authors: Michael Roth, Jun Zhong, Pieter Borger, Chong Teck S'ng, Michael Tamm
Journal: European Respiratory Journal (2012)

Background:  Airway remodelling in asthma is partly due to increased airway smooth muscle (ASM) mass. We and others reported earlier that steroids alone do not significantly reduce proliferation of ASM cells isolated from asthma patients.   Objective:  Here, we investigated the anti-proliferative signalling pathway of formoterol combined with three different steroids on ASM cell proliferation control.   Methods:  Proliferation was determined by cell count 3 days after stimulation. Drugs were used at concentrations 1nM – 1microM. Protein expression (p21, p27) was determined by immuno-blot and -staining. Cyclic AMP was inhibited by DDA pre-incubation.   Results:  Serum induced proliferation was reduced by steroids (dexamethasone, fluticasone, budesonide) in ASM cells of healthy controls but not of asthma patients. Formoterol dose dependently reduced cell proliferation by maximal 25% in both asthma and control ASM cells and this was paralleled by p27(Kip) activation in asthma ASM cells only. In combination the inhibitory effect of formoterol increased to 52% by dexamethasone, to 69% by budesonide and to 76% by fluticasone in healthy cells. In asthmatic ASM cells the combinded rug9s effect was 47%, 52%, an 56% respectively. Inhibition of proliferation of asthmatic ASM cells by formoterol occurred through cAMP and p27(Kip), which were both increased by the addition of steroids. The anti-proliferative effect of the combined drugs in control ASM cells involves p21(Waf1) and in asthmatic cells by p27(Kip).   Conclusion : Formoterol activates a disease specific cAMP dependent anti-proliferative signalling in asthmatic ASM cells which is supported by the addition of steroids.
Evaluation of Patients Treated with Natalizumab for Progressive Multifocal Leukoencephalopathy
Authors: Tarek A. Yousry, Eugene O. Major, Caroline Ryschkewitsch, Gary Fahle, Steven Fischer, Jean Hou, Blanche Curfman, Katherine Miszkiel, Nicole Mueller-Lenke, Esther Sanchez, Frederik Barkhof, Ernst-Wilhelm Radue, Hans R. Jäger, David B. Clifford
Journal: New England Journal of Medicine (2006)

Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients.We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI.Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000).A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.
Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial
Authors: Robert F Spiera, Jessica K Gordon, Jamie N Mersten, Cynthia M Magro, Mansi Mehta, Horatio F Wildman, Stacey Kloiber, Kyriakos A Kirou, Stephen Lyman, Mary K Crow
Journal: Annals of the Rheumatic Diseases (2011)

Objective To assess the safety and effectiveness of imatinib mesylate in the treatment of diffuse cutaneous systemic sclerosis (dcSSc). Methods In this phase IIa, open-label, single-arm clinical trial, 30 patients with dcSSc were treated with imatinib 400 mg daily. Patients were monitored monthly for safety assessments. Modified Rodnan skin scores (MRSS) were assessed every 3 months. Pulmonary function testing, chest radiography, echocardiography and skin biopsies were performed at baseline and after 12 months of treatment. Results Twenty-four patients completed 12 months of therapy. 171 adverse events (AE) with possible relation to imatinib were identified; 97.6% were grade 1 or 2. Twenty-four serious AE were identified, two of which were attributed to study medication. MRSS decreased by 6.6 points or 22.4% at 12 months (p=0.001). This change was evident starting at the 6-month time point (Δ=−4.5; p&lt;0.001) and was seen in patients with both early and late-stage disease. Forced vital capacity (FVC) improved by 6.4% predicted (p=0.008), and the diffusion capacity remained stable. The improvement in FVC was significantly greater in patients without interstitial lung disease. Health-related quality of life measures improved or remained stable. Blinded dermatopathological analysis confirmed a significant decrease in skin thickness and improvement in skin morphology. Conclusions Treatment with imatinib was tolerated by most patients in this cohort. Although AE were common, most were mild to moderate. In this open-label experience, improvements in skin thickening and FVC were observed. Further investigation of tyrosine kinase inhibition for dcSSc in a double-blind randomised placebo controlled trial is warranted. ClinicalTrials.gov , NCT00555581
Mnk1 Is Required for Angiotensin II–Induced Protein Synthesis in Vascular Smooth Muscle Cells
Authors: Mari Ishida, Takafumi Ishida, Hidekatsu Nakashima, Narimasa Miho, Kiyoshi Miyagawa, Kazuaki Chayama, Tetsuya Oshima, Masayuki Kambe, Masao Yoshizumi
Journal: Circulation Research (2003)

Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal–integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II–induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II–induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II–induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II–induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho, Rac, or Cdc42, abolished Ang II–induced Mnk1 activation. Finally, treatment of VSMCs with CGP57380, a novel specific kinase inhibitor of Mnk1, resulted in dose-dependent decreases in Ang II–stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy. In summary, these data demonstrated that (1) Ang II–induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMCs, and (2) Mnk1 is involved in Ang II–mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation. The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II–mediated pathological states.