tbuckley/cabot-search huggingface dataset:
A Small-Molecule Inhibitor Targeting the Mitotic Spindle Checkpoint Impairs the Growth of Uterine Leiomyosarcoma
Authors: Weiwei Shan, Patricia Y. Akinfenwa, Kari B. Savannah, Nonna Kolomeyevskaya, Rudolfo Laucirica, Dafydd G. Thomas, Kunle Odunsi, Chad J. Creighton, Dina C. Lev, Matthew L. Anderson
Journal: Clinical Cancer Research (2012)

Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies.Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo.We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts.Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease.
Dose-Response Relationship of Oral Insulin Spray in Healthy Subjects
Authors: Simona Cernea, Miriam Kidron, Jay Wohlgelernter, Pankaj Modi, Itamar Raz
Journal: Diabetes Care (2005)

OBJECTIVE—To evaluate the pharmacodynamic and pharmacokinetic properties and the dose-ranging effects of an oral insulin spray in comparison with subcutaneous regular insulin. RESEARCH DESIGN AND METHODS—In this randomized, five-way, cross-over study, seven healthy volunteers were assessed under euglycemic clamp and received four different doses of oral spray and one dose of subcutaneous regular insulin. RESULTS—The time to maximum insulin concentration was shorter for oral insulin than for subcutaneous insulin (25.9 ± 9 vs. 145.7 ± 49.5 min, P &amp;lt; 0.05). Maximum serum insulin levels (Cmax) were comparable between the subcutaneous and 20 puffs of oral insulin (39.1 ± 19.6 vs. 34.0 ± 7.4 μU/ml, NS). The Ins-AUC0–120 (area under the curve from 0 to 120 min for serum insulin) (339.8 ± 218, 681.3 ± 407, and 1,586.7 ± 8 μU/ml, P &amp;lt; 0.05) and Cmax (7.6 ± 2.8, 16.4 ± 9.3, and 39.1 ± 19.6 μU/ml, P &amp;lt; 0.005) proved a dose-response relationship for the three doses of oral insulin (5, 10, and 20 puffs, respectively). Oral insulin had an earlier onset of action (31.7 ± 12 vs. 77.8 ± 3 min, P &amp;lt; 0.05), earlier peak (44.2 ± 10 vs. 159.2 ± 68 min, P &amp;lt; 0.05), and a shorter duration of action (85.1 ± 25 vs. 319.2 ± 45 min, P &amp;lt; 0.05) compared with subcutaneous insulin. The maximum metabolic effect (1.7 ± 1.0, 3.09 ± 1.7, and 4.6 ± 1.5 mg · kg−1 · min−1, P &amp;lt; 0.05) and the GIR-AUC0–120 (amount of glucose infused from 0 to 120 min) (106.7 ± 74.3, 162.9 ± 116.1, and 254 ± 123 mg/kg) increased in a dose-dependent relationship for the three doses. CONCLUSIONS—Oral insulin was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action compared with subcutaneous regular insulin. A dose-response relationship in the absorption and metabolic effect of the oral insulin was noted.
The Evolution of T-cell Therapies for Solid Malignancies
Authors: Kristen Fousek, Nabil Ahmed
Journal: Clinical Cancer Research (2015)

Abstract Primary resistant, recurrent, and relapsed solid tumors are often nonresponsive to conventional antineoplastic therapies. Moreover, in responsive tumors, the therapeutic-to-toxic range of these interventions remains quite narrow, such that side effects of therapy are substantial. Targeted therapies, such as adoptive T-cell transfer, not only spare normal tissues but also use alternative killing mechanisms to which the tumor cells are usually not immune. Adoptive T-cell transfer for solid tumors faces unique challenges because of the inherent heterogeneity of tumor parenchyma, the complexity of the tumor microenvironment, and tumor occurrence in areas with limited therapeutic accessibility. In this review, we examine the recent evolution of various T-cell–based immunotherapeutics, the mechanisms of action behind their antitumor activity, their increasing complexity, and the prospect of building on previous successes in the treatment of solid tumors. Clin Cancer Res; 21(15); 3384–92. ©2015 AACR.
Upregulation of Myocardial Estrogen Receptors in Human Aortic Stenosis
Authors: Johannes Nordmeyer, Sarah Eder, Shokoufeh Mahmoodzadeh, Peter Martus, Jens Fielitz, Jan Bass, Nicole Bethke, Heinz R. Zurbrügg, Reinhard Pregla, Roland Hetzer, Vera Regitz-Zagrosek
Journal: Circulation (2004)

Background— Estrogen receptor (ER)–mediated effects have been associated with the modulation of myocardial hypertrophy in animal models and in humans, but ER expression in the human heart and its relation to hypertrophy-mediated gene expression have not yet been analyzed. We therefore investigated sex- and disease-dependent alterations of myocardial ER expression in human aortic stenosis together with the expression of hypertrophy-related genes. Methods and Results— ER-α and -β, calcineurin A-β, and brain natriuretic peptide (BNP) mRNA were quantified by real-time polymerase chain reaction in left ventricular biopsies from patients with aortic valve stenosis (n=14) and control hearts with normal systolic function (n=17). ER protein was quantified by immunoblotting and visualized by immunofluorescence confocal microscopy. ER-α mRNA and protein were increased 2.6-fold ( P =0.003) and 1.7-fold ( P =0.026), respectively, in patients with aortic valve stenosis. Left ventricular ER-β mRNA was increased 2.6-fold in patients with aortic valve stenosis ( P &lt;0.0001). ER-α and -β were found in the cytoplasm and nuclei of human hearts. A strong inverse correlation exists between ER-β and calcineurin A-β mRNA in patients with aortic valve stenosis ( r =−0.83, P =0.002) but not between ER-α or -β and BNP mRNA. Conclusions— ER-α and -β in the human heart are upregulated by myocardial pressure load.
The MET Receptor Tyrosine Kinase Is a Potential Novel Therapeutic Target for Head and Neck Squamous Cell Carcinoma
Authors: Tanguy Y. Seiwert, Ramasamy Jagadeeswaran, Leonardo Faoro, Varalakshmi Janamanchi, Vidya Nallasura, Mohamed El Dinali, Soheil Yala, Rajani Kanteti, Ezra E.W. Cohen, Mark W. Lingen, Leslie Martin, Soundararajan Krishnaswamy, Andres Klein-Szanto, James G. Christensen, Everett E. Vokes, Ravi Salgia
Journal: Cancer Research (2009)

Recurrent/metastatic head and neck cancer remains a devastating disease with insufficient treatment options. We investigated the MET receptor tyrosine kinase as a novel target for the treatment of head and neck squamous cell carcinoma (HNSCC). MET/phosphorylated MET and HGF expression was analyzed in 121 tissues (HNSCC/normal) by immunohistochemistry, and in 20 HNSCC cell lines by immunoblotting. The effects of MET inhibition using small interfering RNA/two small-molecule inhibitors (SU11274/PF-2341066) on signaling, migration, viability, and angiogenesis were determined. The complete MET gene was sequenced in 66 head and neck cancer tissue samples and eight cell lines. MET gene copy number was determined in 14 cell lines and 23 tumor tissues. Drug combinations of SU11274 with cisplatin or erlotinib were tested in SCC35/HN5 cell lines. Eighty-four percent of the HNSCC samples showed MET overexpression, whereas 18 of 20 HNSCC cell lines (90%) expressed MET. HGF overexpression was present in 45% of HNSCC. MET inhibition with SU11274/PF-2341066 abrogated MET signaling, cell viability, motility/migration in vitro, and tumor angiogenesis in vivo. Mutational analysis of 66 tumor tissues and 8 cell lines identified novel mutations in the semaphorin (T230M/E168D/N375S), juxtamembrane (T1010I/R988C), and tyrosine kinase (T1275I/V1333I) domains (incidence: 13.5%). Increased MET gene copy number was present with >10 copies in 3 of 23 (13%) tumor tissues. A greater-than-additive inhibition of cell growth was observed when combining a MET inhibitor with cisplatin or erlotinib and synergy may be mediated via erbB3/AKT signaling. MET is functionally important in HNSCC with prominent overexpression, increased gene copy number, and mutations. MET inhibition abrogated MET functions, including proliferation, migration/motility, and angiogenesis. MET is a promising, novel target for HNSCC and combination approaches with cisplatin or EGFR inhibitors should be explored.
Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia
Authors: James Shepherd, Stuart M. Cobbe, Ian Ford, Christopher G. Isles, A. Ross Lorimer, Peter W. Macfarlane, James H. McKillop, Christopher J. Packard
Journal: New England Journal of Medicine (1995)

Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease.
Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen.
Authors: A Penna, F V Chisari, A Bertoletti, G Missale, P Fowler, T Giuberti, F Fiaccadori, C Ferrari
Journal: The Journal of Experimental Medicine (1991)

The absence of readily manipulable experimental systems to study the cytotoxic T lymphocyte (CTL) response against hepatitis B virus (HBV) antigens has thus far precluded a definitive demonstration of the role played by this response in the pathogenesis of liver cell injury and viral clearance during HBV infection. To circumvent the problem that HBV infection of human cells in vitro for production of stimulator/target systems for CTL analysis is not feasible, a panel of 22 overlapping synthetic peptides covering the entire amino acid sequence of the HBV core (HBcAg) and e (HBeAg) antigens were used to induce and to analyze the HBV nucleocapsid-specific CTL response in nine patients with acute hepatitis B, six patients with chronic active hepatitis B, and eight normal controls. By using this approach, we have identified an HLA-A2-restricted CTL epitope, located within the NH2-terminal region of the HBV core molecule, which is shared with the e antigen and is readily recognized by peripheral blood mononuclear cells from patients with self-limited acute hepatitis B but less efficiently in chronic HBV infection. Our study provides the first direct evidence of HLA class I-restricted T cell cytotoxicity against HBV in humans. Furthermore, the different response in HBV-infected subjects who successfully clear the virus (acute patients) in comparison with patients who do not succeed (chronic patients) suggests a pathogenetic role for this CTL activity in the clearance of HBV infection.
Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial
Authors: M. Reck, I. Bondarenko, A. Luft, P. Serwatowski, F. Barlesi, R. Chacko, M. Sebastian, H. Lu, J.-M. Cuillerot, T.J. Lynch
Journal: Annals of Oncology (2012)
Systemic steroids in severe forms of COPD exacerbations: a question of balance?
Authors: Thomas Similowski, Samy Suissa
Journal: European Respiratory Journal (2014)

Systemic steroids in mechanically ventilated COPD: the absence of obvious benefit should make prescription the exception http://ow.ly/spRFxChronic obstructive pulmonary disease (COPD) is a lung disorder with systemic inflammatory-related consequences, for which there is no cure.Beside tobacco cessation (of which the beneficial effects are many), the only available therapeutic interventions in COPD target exercise-related dyspnoea and exacerbations.There is extensive solid evidence to support the use of bronchodilators and pulmonary rehabilitation to address these clinically relevant issues [1].The corpus of data supporting the beneficial effects of pulmonary rehabilitation is vast and has been built through the years by several convergent studies from independent investigators [2].It is widely acknowledged that locomotor muscles are dysfunctional in COPD [3], and also widely acknowledged that rehabilitation in COPD improves exercise tolerance, decreases the rate of exacerbations, ameliorates quality of life and might prolong survival in certain contexts (e.g. after an exacerbation of the disease) [2,4,5].Exercise training (or re-training) is a major driver of the success of pulmonary rehabilitation in COPD.Thus, the current state of the evidence suggests that patients with COPD who want to tackle their disease should quit smoking, inhale bronchodilating substances, be they associated or not with corticosteroids, and seriously think about rebuilding the strength and endurance of their meagre quadriceps.To do so, exercise is needed, but so is an adequate balance between muscle anabolism and muscle catabolism.
Selective maintenance of Drosophila tandemly arranged duplicated genes during evolution
Authors: Carlos Quijano, Pavel Tomancak, Jesus Lopez-Marti, Mikita Suyama, Peer Bork, Marco Milan, David Torrents, Miguel Manzanares
Journal: Genome biology (2008)

The physical organization and chromosomal localization of genes within genomes is known to play an important role in their function. Most genes arise by duplication and move along the genome by random shuffling of DNA segments. Higher order structuring of the genome occurs in eukaryotes, where groups of physically linked genes are co-expressed. However, the contribution of gene duplication to gene order has not been analyzed in detail, as it is believed that co-expression due to recent duplicates would obscure other domains of co-expression. We have catalogued ordered duplicated genes in Drosophila melanogaster, and found that one in five of all genes is organized as tandem arrays. Furthermore, among arrays that have been spatially conserved over longer periods than would be expected on the basis of random shuffling, a disproportionate number contain genes encoding developmental regulators. Using in situ gene expression data for more than half of the Drosophila genome, we find that genes in these conserved clusters are co-expressed to a much higher extent than other duplicated genes. These results reveal the existence of functional constraints in insects that retain copies of genes encoding developmental and regulatory proteins as neighbors, allowing their co-expression. This co-expression may be the result of shared cis-regulatory elements or a shared need for a specific chromatin structure. Our results highlight the association between genome architecture and the gene regulatory networks involved in the construction of the body plan.
The gut as target organ for oral immunovaccination with allergen DNA: new hope for patients with anaphylactic reactions to food?
Authors: S C BISCHOFF
Journal: Gut (1999)

Comment 

The management of patients with food allergy is unsatisfactory as the mechanisms underlying these reactions are not well understood and the diagnostic means to confirm food allergy on an objective basis are limited. Consequently, the clinical relevance of food allergy in the pathogenesis of gastrointestinal diseases is largely unclear.1 2 However, epidemiological studies suggest that food allergy is common, particularly in children, and often causes fatal reactions.3 4 The treatment options are often not successful as avoiding relevant food allergens may be extremely difficult, even if they could be clearly identified, and standard immunotherapy lacks efficacy. Because of the reported severe or even fatal reactions, which seem to be mostly IgE mediated, effective prophylactic and therapeutic strategies are urgently needed.5 6 

Roy et al report a new approach to the modulation of anaphylactic responses to food allergens using a murine model of peanut allergy. Susceptible strains of mice were treated orally with nanoparticles containing DNA …
The effects of intra-aortic counterpulsation on cardiac performance and metabolism in shock associated with acute myocardial infarction
Authors: Hiltrud Mueller, Stephen M. Ayres, E. Foster Conklin, Stanley Giannelli, James T. Mazzara, William T. Grace, Thomas F. Nealon
Journal: Journal of Clinical Investigation (1971)

The effect of intra-aortic counterpulsation (IACP, 22-94 hr) on hemodynamics and cardiac energetics was evaluated in 10 patients in shock after acute myocardial infarction. The data clearly indicate that IACP improves myocardial oxygenation, enhances peripheral perfusion, and probably improves myocardial contractility in the severely diseased heart. Before treatment, decreases in cardiac index (mean value, 1.22 liter/min per m(2)), systolic ejection rate (67 ml/sec), and time-tension index per minute (1280 mm Hg.sec/min) were observed. Systemic vascular resistance varied widely. Low coronary blood flow (68 ml/min per 100 g) was associated with increased myocardial oxygen extraction (79%), low coronary sinus oxygen tension (20 mm Hg), and abnormal myocardial lactate-pyruvate metabolism. During 4-6 hr of IACP, systolic pressure and left ventricular outflow resistance decreased by 18% and 24%, respectively, while cardiac index improved by 38%. Diastolic arterial pressure rose 98%. Increase in coronary blood flow from an average of 68 to 91 ml/100 g per min (P < 0.001) was significantly correlated with rise in mean arterial pressure (r = 0.685). This correlation was best expressed in a third-order curve, which intercepts the point of no flow at a mean aortic pressure of 30 mm Hg. The flow-pressure curve is relatively flat above 65-70 mm Hg, but becomes steeper as mean aortic pressure falls below this point. Myocardial oxygen consumption remained essentially unchanged during early IACP and tended to rise during the later stages. However, the relationship of cardiac work performed to oxygen availability was markedly improved. Myocardial lactate production of 6% shifted to 15% extraction (P < 0.001). After termination of IACP, hemodynamics and myocardial perfusion and metabolism remained improved in the four patients who could be reevaluated. Although the acute shock state was reversed in all patients, only one left the hospital. Extensive myocardial damage limits the long-term survival of such patients. Therefore early IACP seems desirable, when subtle evidence of pump failure after acute myocardial infarction occurs. Early use of IACP may prevent the development of severe coronary shock or may stabilize cardiac energetics in severe shock facilitating subsequent surgical intervention.
Lung Cancer in Never Smokers: Clinical Epidemiology and Environmental Risk Factors
Authors: Jonathan M. Samet, Erika Avila-Tang, Paolo Boffetta, Lindsay M. Hannan, Susan Olivo-Marston, Michael J. Thun, Charles M. Rudin
Journal: Clinical Cancer Research (2009)

Abstract More than 161,000 lung cancer deaths are projected to occur in the United States in 2008. Of these, an estimated 10 to 15% will be caused by factors other than active smoking, corresponding to 16,000 to 24,000 deaths annually. Thus lung cancer in never smokers would rank among the most common causes of cancer mortality in the United States if considered as a separate category. Slightly more than half of the lung cancers caused by factors other than active smoking occur in never smokers. As summarized in the accompanying article, lung cancers that occur in never smokers differ from those that occur in smokers in their molecular profile and response to targeted therapy. These recent laboratory and clinical observations highlight the importance of defining the genetic and environmental factors responsible for the development of lung cancer in never smokers. This article summarizes available data on the clinical epidemiology of lung cancer in never smokers, and several environmental risk factors that population-based research has implicated in the etiology of these cancers. Primary factors closely tied to lung cancer in never smokers include exposure to known and suspected carcinogens including radon, second-hand tobacco smoke, and other indoor air pollutants. Several other exposures have been implicated. However, a large fraction of lung cancers occurring in never smokers cannot be definitively associated with established environmental risk factors, highlighting the need for additional epidemiologic research in this area. (Clin Cancer Res 2009;15(18):5626–45)
Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping
Authors: Quan Q. Gao, Eugene Wyatt, Jeff A. Goldstein, Peter LoPresti, Lisa M. Castillo, Alec Gazda, Natalie Petrossian, Judy U. Earley, Michele Hadhazy, David Y. Barefield, Alexis R. Demonbreun, Carsten Bönnemann, Matthew Wolf, Elizabeth M. McNally
Journal: Journal of Clinical Investigation (2015)

Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. The antisense oligonucleotides used for exon skipping are designed to bypass premature stop codons in the target RNA and restore reading frame disruption. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. For Duchenne muscular dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We have now expanded the potential for exon skipping by testing whether an internal, in-frame truncation of a transmembrane protein γ-sarcoglycan is functional. We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations.