tbuckley/cabot-search huggingface dataset:
APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis.
Authors: F M Giardiello, G M Petersen, S Piantadosi, S B Gruber, E I Traboulsi, G J Offerhaus, K Muro, A J Krush, S V Booker, M C Luce, S J Laken, K W Kinzler, B Vogelstein, S R Hamilton
Journal: Gut (1997)

BACKGROUND: Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q. AIMS: This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. METHODS: Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. RESULTS: FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p &lt; 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. CONCLUSIONS: Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) and predisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).
Effects of Tetramethoxystilbene on Hormone-Resistant Breast Cancer Cells: Biological and Biochemical Mechanisms of Action
Authors: Hoyong Park, Sarah E. Aiyar, Ping Fan, Jiping Wang, Wei Yue, Tatiana Okouneva, Corey Cox, Mary Ann Jordan, Laurence Demers, Hyungjun Cho, Sanghee Kim, Robert X.-D. Song, Richard J. Santen
Journal: Cancer Research (2007)

Abstract Secondary resistance to hormonal therapy for breast cancer commonly develops after an initial response to tamoxifen or aromatase inhibitors. Agents to abrogate these adaptive changes would substantially enhance the long-term benefits of hormonal therapy. Our studies with a stilbene derivative called TMS (2,3′,4,5′-tetramethoxystilbene) identified unexpected effects with potential utility for treatment of breast tumors secondarily resistant to hormonal therapy. TMS was originally developed as an inhibitor of cytochrome P450 1B1 to block the conversion of estradiol to 4-OH-estradiol. While studying this agent in three models of hormone resistance, we detected direct antitumor effects not related to its role as an inhibitor of catecholestrogens. During examination of the mechanisms involved, we showed that treatment with 3 μmol/L TMS for 24 h inhibited tubulin polymerization and microtubule formation, caused a cell cycle block at the G2-M phase, and induced apoptosis. TMS also inhibited activated focal adhesion kinase (FAK), Akt, and mammalian target of rapamycin (mTOR) and stimulated c-jun-NH2-kinase and p38 mitogen-activated protein kinase activity. With respect to antitumor effects, TMS at a concentrations of 0.2 to 0.3 μmol/L inhibited the growth of long-term tamoxifen-treated MCF-7 cells by 80% and fulvestrant-treated MCF-7 cells by 70%. In vivo studies, involving 8 weeks of treatment with TMS via a 30-mg s.c. implant, reduced tumor volume of tamoxifen-resistant MCF-7 breast cancer xenografts by 53%. Our data suggest that TMS is a promising therapeutic agent because of its unique ability to block several pathways involved in the development of hormone resistance. [Cancer Res 2007;67(12):5717–26]
A Phase I Trial of Perifosine (NSC 639966) on a Loading Dose/Maintenance Dose Schedule in Patients with Advanced Cancer
Authors: Lynn Van Ummersen, Kim Binger, Jennifer Volkman, Rebecca Marnocha, Kendra Tutsch, Jill Kolesar, Rhoda Arzoomanian, Dona Alberti, George Wilding
Journal: Clinical Cancer Research (2004)

Abstract Perifosine (NSC 639966) is a synthetic, substituted heterocyclic alkylphosphocholine that acts primarily at the cell membrane targeting signal transduction pathways. Early clinical trials were limited because of dose-limiting gastrointestinal toxicity, and parenteral dosing of this class of agents is not possible because of their hemolytic properties; therefore, related compounds with an improved therapeutic index were developed. Toxicity was minimized and efficacy improved by using a loading dose/maintenance dose schedule, and therefore, this schedule was carried into clinical trials. This phase I trial enrolled 42 patients with incurable solid malignancies. The starting doses were 100 mg p.o. × four doses (every 6 hours) load followed by a 50 mg p.o. once daily maintenance dose with escalation of either component in successive dose levels. No treatment related deaths occurred. The maximum-tolerated dose was determined to be 150 mg p.o. × four doses load and 100 mg p.o. once daily maintenance. Dose-limiting toxicities such as nausea, diarrhea, dehydration, and fatigue were seen early during the loading phase and were surmountable with the use of prophylactic 5-HT3 receptor antagonists, dexamethasone, and loperamide. Toxicities during the chronic phase were difficult to manage and, given that pharmacokinetic data showed biologically active serum concentrations (based on preclinical data), raised the question of less frequent maintenance dosing. Pharmacokinetic data confirmed the maintenance of stable drug levels with chronic dosing and the long half-life. One partial response was seen, as were multiple patients with stable disease beyond course 2. These results suggest perifosine activity in sarcoma and perhaps renal cell carcinoma (stable disease in two patients who continued for 6 and 14 courses), thus justifying additional investigation of this agent in a phase II sarcoma trial.
Long Noncoding RNAs as Inducers and Terminators of Vascular Development
Authors: Janika Viereck, Regalla Kumarswamy, Thomas Thum
Journal: Circulation (2015)

M ost of the human genome is transcribed. 1However, only <2% of the human genome consists of exonic regions in protein-coding genes. 2 Recent evidence highlights the importance of the noncoding portion of the genome, which previously was believed to be "junk."After their landmark discovery as master regulators of gene expression, microR-NAs (miRNAs; a class of small noncoding RNAs) received intense attention as investigators explored the possibilities for the development of novel therapeutic approaches for many human diseases, including heart failure. 3Similarly, long (>200 nt) noncoding RNAs (lncRNAs) are increasingly recognized as important modulators of gene expression in several physiological and pathological settings. 4,5Recent studies have emphasized the importance of lncRNAs as potential therapeutic targets or biomarkers for heart diseases. 6,
Is Regionally Selective D<sub>2</sub>/D<sub>3</sub>Dopamine Occupancy Sufficient for Atypical Antipsychotic Effect? An In Vivo Quantitative [<sup>123</sup>I]Epidepride SPET Study of Amisulpride-Treated Patients
Authors: Rodrigo A. Bressan, Kjell Erlandsson, Hugh M. Jones, Rachel Mulligan, Robert J. Flanagan, Peter J. Ell, Lyn S. Pilowsky
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D2-like receptors with modest striatal D2 receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D2/D3 dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors' goal was to evaluate whether treatment with amisulpride results in "limbic selective" D2/D3 receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [123I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a healthy volunteer comparison group (N=6). RESULTS: Eight amisulpride-treated patients (mean dose=406 mg/day) showed moderate levels of D2/D3 receptor occupancy in the striatum (56%), and significantly higher levels were seen in the thalamus (78%) and temporal cortex (82%). CONCLUSIONS: Treatment with amisulpride results in a similar pattern of limbic cortical over striatal D2/D3 receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D2 receptor occupancy and preferential occupancy of limbic cortical dopamine D2/D3 receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT2A receptor antagonism.
P1098 DOES THE INITIAL AND REVERSIBLE DECREASE OF EGFR DURING TRIPLE THERAPY WITH TELAPREVIR REVEAL A REAL RENAL TOXICITY?
Authors: C. Vong, A. Rousseau, P. Carrier, M. Essig, M. Debette-Gratien, J. Jacques, R. Legros, D. Sautereau, V. Loustaud-Ratti
Journal: Journal of Hepatology (2014)
Impact of Pre-Treatment Lactate Dehydrogenase (Ldh) Levels on Prognosis and Bevacizumab Efficacy in Advanced Colorectal Cancer Patients
Authors: A. Passardi, A. Farolfi, O. Nanni, D. Tassinari, D. Turci, L. Cavanna, A. Fontana, S. Ruscelli, C. Mucciarini, V. Lorusso, A. Ragazzini, D. Amadori
Journal: Annals of Oncology (2014)
Inhibition of carrageenan induced inflammation in the rat knee joint by substance P antagonist.
Authors: F.Y Lam, W.R Ferrell
Journal: Annals of the Rheumatic Diseases (1989)

The pathophysiology of acute joint inflammation remains unclear. Evidence is available to suggest a neurally mediated component to the inflammatory process. Acute joint inflammation in the rat knee, induced by intra-articular injection of 2% carrageenan, was reduced by 44% in animals whose knee had previously been injected with 1% capsaicin, while chronic joint denervation produced a 37% reduction. These results indicate a significant neurogenic component in this model of acute joint inflammation. Substance P may be the mediator of this response as intra-articular injection of this agent provoked an acute inflammatory response. Pretreatment of the test knee with the substance P antagonist d-Pro4,d-Trp7 9 10-SP(4-11), however, resulted in a 93% reduction of the inflammatory response to carrageenan. This unexpectedly large effect suggests that this substance P antagonist blocks both neurogenic and non-neurogenic mediators of inflammation. Sympathetic efferent fibres innervating the knee joint were not found to contribute to the neurogenic component of the inflammatory process.
STUDIES ON MALARIAL PARASITES
Authors: Quentin M. Geiman, Christian B. Anfinsen, Ralph W. McKee, Richard A. Ormsbee, Eric G. Ball
Journal: The Journal of Experimental Medicine (1946)

1. Methods of recovering adequate amounts of Plasmodium knowlesi from the monkey (Macaca, mulatta) for biochemical studies and in vitro cultivation are described. Concentrates of red blood cells parasitized with P. knowlesi can be obtained by differential sedimentation of parasitized blood because of physical and chemical changes produced by the parasites in the host cell and the plasma of the blood. 2. Two different techniques, the rocker-dilution and the rocker-perfusion methods, are described for the cultivation of malarial parasites. Details of the apparatus, assembly, and sterilization are given, as well as methods of counting and evaluating parasites. 3. In a series of 235 control experiments for 20 to 24 hours using three types of apparatus, the average rate of multiplication was 3.9. Each technique has specific value for studying the various aspects of metabolism, nutrition, and the action of antimalarial drugs.
Randomized Trial of Stents versus Bypass Surgery for Left Main Coronary Artery Disease
Authors: Seung-Jung Park, Young-Hak Kim, Duk-Woo Park, Sung-Cheol Yun, Jung-Min Ahn, Hae Geun Song, Jong-Young Lee, Won-Jang Kim, Soo-Jin Kang, Seung-Whan Lee, Cheol Whan Lee, Seong-Wook Park, Cheol-Hyun Chung, Jae-Won Lee, Do-Sun Lim, Seung-Woon Rha, Sang-Gon Lee, Hyeon-Cheol Gwon, Hyo-Soo Kim, In-Ho Chae, Yangsoo Jang, Myung-Ho Jeong, Seung-Jea Tahk, Ki Bae Seung
Journal: New England Journal of Medicine (2011)

Percutaneous coronary intervention (PCI) is increasingly used to treat unprotected left main coronary artery stenosis, although coronary-artery bypass grafting (CABG) has been considered to be the treatment of choice.We randomly assigned patients with unprotected left main coronary artery stenosis to undergo CABG (300 patients) or PCI with sirolimus-eluting stents (300 patients). Using a wide margin for noninferiority, we compared the groups with respect to the primary composite end point of major adverse cardiac or cerebrovascular events (death from any cause, myocardial infarction, stroke, or ischemia-driven target-vessel revascularization) at 1 year. Event rates at 2 years were also compared between the two groups.The primary end point occurred in 26 patients assigned to PCI as compared with 20 patients assigned to CABG (cumulative event rate, 8.7% vs. 6.7%; absolute risk difference, 2.0 percentage points; 95% confidence interval [CI], -1.6 to 5.6; P=0.01 for noninferiority). By 2 years, the primary end point had occurred in 36 patients in the PCI group as compared with 24 in the CABG group (cumulative event rate, 12.2% vs. 8.1%; hazard ratio with PCI, 1.50; 95% CI, 0.90 to 2.52; P=0.12). The composite rate of death, myocardial infarction, or stroke at 2 years occurred in 13 and 14 patients in the two groups, respectively (cumulative event rate, 4.4% and 4.7%, respectively; hazard ratio, 0.92; 95% CI, 0.43 to 1.96; P=0.83). Ischemia-driven target-vessel revascularization occurred in 26 patients in the PCI group as compared with 12 patients in the CABG group (cumulative event rate, 9.0% vs. 4.2%; hazard ratio, 2.18; 95% CI, 1.10 to 4.32; P=0.02).In this randomized trial involving patients with unprotected left main coronary artery stenosis, PCI with sirolimus-eluting stents was shown to be noninferior to CABG with respect to major adverse cardiac or cerebrovascular events. However, the noninferiority margin was wide, and the results cannot be considered clinically directive. (Funded by the Cardiovascular Research Foundation, Seoul, Korea, and others; PRECOMBAT ClinicalTrials.gov number, NCT00422968.).
Is vision continuous with cognition?: The case for cognitive impenetrability of visual perception
Authors: Zenon Pylyshyn
Journal: Behavioral and Brain Sciences (1999)

Although the study of visual perception has made more progress in the past 40 years than any other area of cognitive science, there remain major disagreements as to how closely vision is tied to cognition. This target article sets out some of the arguments for both sides (arguments from computer vision, neuroscience, psychophysics, perceptual learning, and other areas of vision science) and defends the position that an important part of visual perception, corresponding to what some people have called early vision, is prohibited from accessing relevant expectations, knowledge, and utilities in determining the function it computes--in other words, it is cognitively impenetrable. That part of vision is complex and involves top-down interactions that are internal to the early vision system. Its function is to provide a structured representation of the 3-D surfaces of objects sufficient to serve as an index into memory, with somewhat different outputs being made available to other systems such as those dealing with motor control. The paper also addresses certain conceptual and methodological issues raised by this claim, such as whether signal detection theory and event-related potentials can be used to assess cognitive penetration of vision. A distinction is made among several stages in visual processing, including, in addition to the inflexible early-vision stage, a pre-perceptual attention-allocation stage and a post-perceptual evaluation, selection, and inference stage, which accesses long-term memory. These two stages provide the primary ways in which cognition can affect the outcome of visual perception. The paper discusses arguments from computer vision and psychology showing that vision is "intelligent" and involves elements of "problem solving." The cases of apparently intelligent interpretation sometimes cited in support of this claim do not show cognitive penetration; rather, they show that certain natural constraints on interpretation, concerned primarily with optical and geometrical properties of the world, have been compiled into the visual system. The paper also examines a number of examples where instructions and "hints" are alleged to affect what is seen. In each case it is concluded that the evidence is more readily assimilated to the view that when cognitive effects are found, they have a locus outside early vision, in such processes as the allocation of focal attention and the identification of the stimulus.
Genome-wide significant risk associations for mucinous ovarian carcinoma
Authors: Linda E. Kelemen, Kate Lawrenson, Jonathan Tyrer, Qiyuan Li, Janet M. Lee, Ji Heui Seo, Catherine M. Phelan, Jonathan Beesley, Xiaoqing Chen, Tassja J. Spindler, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa V. Bandera, Yukie Bean, Matthias W. Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A. Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G. Campbell, Karen Carty, Jenny Chang-Claude, Y. Ann Chen, Zhihua Chen, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Ed Dicks, Jennifer A. Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana Eccles, Douglas T. Easton, Robert P. Edwards, Ursula Eilber, Arif B. Ekici, Svend Aage Engelholm, Peter A. Fasching, Brooke L. Fridley, Yu Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind Glasspool, Ellen L. Goode, Marc T. Goodman, Jacek Grownwald, Patricia Harrington, Philipp Harter, Hanis Nazihah Hasmad, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus Hogdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, Allan Jensen, Bu Tian Ji, Beth Y. Karlan, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Susanne K. Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W. Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen H Lu, Jan Lubinski, Lene Lundvall, Leon F.A.G. Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Iain McNeish, Usha Menon, Francesmary Modugno, Joanna Moes-Sosnowska, Kirsten B. Moysich, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Heli Nevanlinna, Noor Azmi Mat Adenan, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste Leigh Pearce, Tanja Pejovic, Liisa M. Pelttari, Jennifer Permuth-Wey, Malcolm C. Pike, Elizabeth M. Poole, Susan J. Ramus, Harvey A. Risch, Barry Rosen, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Joellen M. Schildkraut, Ira Schwaab, Xiao Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara Sucheston, Ingvild L. Tangen, Soo Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Shelley S. Tworoger, Anne M. Van Altena, Els Van Nieuwenhuysen, Ignace Vergote, Robert A. Vierkant, Wang Gohrke Shan, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Wlodzimierz Sawicki, Yin Ling Woo, Xifeng Wu, Anna H. Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Thomas A. Sellers, Matthew L. Freedman, Georgia Chenevix-Trench, Paul D.P. Pharoah, Simon A. Gayther, Andrew Berchuck
Journal: Nature Genetics (2015)
Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial
Authors: Susan E. Dorman, Radojka M. Savic, Stefan Goldberg, Jason E. Stout, Neil Schluger, Grace Muzanyi, John L. Johnson, Payam Nahid, Emily J. Hecker, Charles M. Heilig, Lorna Bozeman, Pei-Jean I. Feng, Ruth N. Moro, William MacKenzie, Kelly E. Dooley, Eric L. Nuermberger, Andrew Vernon, Marc Weiner
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.Objectives: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.Methods: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.Measurements and Main Results: A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration–time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).Conclusions: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months.Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).