tbuckley/cabot-search huggingface dataset:
Oncology Drug Discovery: Planning a Turnaround
Authors: Carlo Toniatti, Philip Jones, Hilary Graham, Bruno Pagliara, Giulio Draetta
Journal: Cancer Discovery (2014)

Abstract We have made remarkable progress in our understanding of the pathophysiology of cancer. This improved understanding has resulted in increasingly effective targeted therapies that are better tolerated than conventional cytotoxic agents and even curative in some patients. Unfortunately, the success rate of drug approval has been limited, and therapeutic improvements have been marginal, with too few exceptions. In this article, we review the current approach to oncology drug discovery and development, identify areas in need of improvement, and propose strategies to improve patient outcomes. We also suggest future directions that may improve the quality of preclinical and early clinical drug evaluation, which could lead to higher approval rates of anticancer drugs. Cancer Discov; 4(4); 397–404. ©2014 AACR.
Evaluation of Deuterated 18F- and 11C-Labeled Choline Analogs for Cancer Detection by Positron Emission Tomography
Authors: Timothy H. Witney, Israt S. Alam, David R. Turton, Graham Smith, Laurence Carroll, Diana Brickute, Frazer J. Twyman, Quang-Dé Nguyen, Giampaolo Tomasi, Ramla O. Awais, Eric O. Aboagye
Journal: Clinical Cancer Research (2012)

(11)C-Choline-positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts.(11)C-Choline, (11)C-methyl-[1,2-(2)H(4)]-choline ((11)C-D4-choline), and (18)F-D4-choline were synthesized to permit comparison. Biodistribution, metabolism, small-animal PET studies, and kinetic analysis of tracer uptake were carried out in human colon HCT116 xenograft-bearing mice.Oxidation of choline analogs to betaine was highest with (11)C-choline, with reduced oxidation observed with (11)C-D4-choline and substantially reduced with (18)F-D4-choline, suggesting that both fluorination and deuteration were important for tracer metabolism. Although all tracers were converted intracellularly to labeled phosphocholine (specific signal), the higher rate constants for intracellular retention (K(i) and k(3)) of (11)C-choline and (11)C-D4-choline, compared with (18)F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of (18)F-D4-choline in three tumors with similar radiotracer delivery (K(1)) and choline kinase α expression-HCT116, A375, and PC3-M-were the same, suggesting that (18)F-D4-choline has utility for cancer detection irrespective of histologic type.We have shown here that both deuteration and fluorination combine to provide protection against choline oxidation in vivo. (18)F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation.
The effect of fat on calcium absorption from a mixed meal in normal subjects, patients with malabsorptive disease, and patients with a partial gastrectomy
Authors: J. E. Agnew, C. D. Holdsworth
Journal: Gut (1971)

The absorption of (47)Ca Cl(2) taken with a milk and porridge meal was measured in normal subjects, patients with a partial gastrectomy, and patients with malabsorption. The addition of palm oil to the meal depressed calcium absorption, whereas the addition of medium-chain triglyceride had no effect. The contrasting effect of the two fats on calcium absorption was most marked in patients with a partial gastrectomy and least marked in patients with malabsorption. In patients with malabsorption, impairment of calcium absorption was most marked in the patients with a significant increase in faecal fat excretion. Absorption of calcium was greater in patients with a partial gastrectomy than in normal subjects.
Plasminogen activator inhibitor-1 regulates neutrophil influx during acute pyelonephritis
Authors: Joris J.T.H. Roelofs, Gwendoline J.D. Teske, Peter I. Bonta, Carlie J.M. de Vries, Joost C.M. Meijers, Jan J. Weening, Tom van der Poll, Sandrine Florquin
Journal: Kidney International (2008)
A Bispecific Enediyne-Energized Fusion Protein Containing Ligand-Based and Antibody-Based Oligopeptides against Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2 Shows Potent Antitumor Activity
Authors: Xiao-fang Guo, Xiao-fei Zhu, Yue Shang, Sheng-hua Zhang, Yong-su Zhen
Journal: Clinical Cancer Research (2010)

The cooverexpression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) observed in many human tumors and their synergistic interaction in the transformation of cells make these receptors important targets for the development of new targeted therapeutics. Targeting of EGFR and HER2 simultaneously has been pursued as a strategy with which to potentially increase efficiency and selectivity in therapy of certain cancers. This study was set to construct a bispecific energized fusion protein (Ec-LDP-Hr-AE) consisting of two oligopeptides against EGFR and HER2, and lidamycin, and investigate its antitumor efficacy.In vitro experiments measured the binding and internalization of bispecific Ec-LDP-Hr fusion protein. The potency of energized fusion proteins was also done in which the bispecific Ec-LDP-Hr-AE was compared with lidamycin (LDM) and its monospecific counterparts, Ec-LDP-AE and LDP-Hr-AE. In vivo, Ec-LDP-Hr-AE was given i.v. to nude mice bearing human ovarian carcinoma SK-OV-3 xenografts.Binding and internalization studies showed that bispecific fusion protein Ec-LDP-Hr bound to carcinoma cells specifically and then were internalized into the cytoplasm. Bispecific Ec-LDP-Hr-AE was more potent and selective in its cytotoxicity against different carcinoma cell lines than corresponding momospecific agents and LDM in vitro. In addition, Ec-LDP-Hr-AE significantly inhibited the growth of SK-OV-3 xenografts in nude mouse model. In vivo imaging study showed that FITC-labeled Ec-LDP-Hr was targeted and accumulated in the tumors.A ligand-based and an antibody-based oligopeptide fused to the enediyne antibiotic LDM created a new bispecific fusion protein with low molecular weight and more potent in vitro and in vivo antitumor activity (than momospecific fusion proteins).
14-3-3ζ Cooperates with ErbB2 to Promote Ductal Carcinoma In Situ Progression to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal Transition
Authors: Jing Lu, Hua Guo, Warapen Treekitkarnmongkol, Ping Li, Jian Zhang, Bin Shi, Chen Ling, Xiaoyan Zhou, Tongzhen Chen, Paul J. Chiao, Xinhua Feng, Victoria L. Seewaldt, William J. Muller, Aysegul Sahin, Mien-Chie Hung, Dihua Yu
Journal: Cancer Cell (2009)
Endothelial nitric oxide synthase +894 polymorphism is associated with recurrent salivary gland swelling and early onset in patients with primary Sjogren's syndrome
Authors: M. Pertovaara, J. Antonen, M. Hurme
Journal: Annals of the Rheumatic Diseases (2007)

Primary Sjogren’s syndrome (SS) is a chronic autoimmune disease that affects primarily the salivary and lacrimal glands. Nitric oxide (NO) has been implicated in the pathogenesis of SS and raised nitrite concentrations have been observed in the saliva of patients with SS.1 NO is a molecule that plays a key role in many physiological and pathological processes. It is produced in vivo from the aminoacid l-arginine by a family of nitric oxide synthases (NOS), of which three isoforms have been identified, i.e. neuronal, endothelial and inducible.2 Endothelial nitric oxide synthase (eNOS) is a constitutively expressed isoform of NOS. The eNOS gene entails several polymorphisms, of which for …
K-ras Mutations in Putative Preneoplastic Lesions in Human Colon
Authors: T. P. Pretlow, T. A. Brasitus, N. C. Fulton, C. Cheyer, E. L. Kaplan
Journal: JNCI Journal of the National Cancer Institute (1993)

A mutation in c-K-ras (KRAS2) has long been implicated as one of the important early events in the development of a large proportion of human colon cancers. Aberrant crypt foci, putative preneoplastic lesions identified microscopically in wholemounts of colons, have been shown to occur with high frequency in the colons of animals treated with colon carcinogens and in the grossly normal mucosas of patients with colon cancer.In this study, we asked whether the mutational activation of K-ras occurs in the aberrant crypt foci of human colon.Grossly normal colonic mucosas were obtained from seven patients during surgery and were provided to us by the Western Division of the Cooperative Human Tissue Network located at Case Western Reserve University. A total of 42 samples, consisting of aberrant crypt foci and similarly sized normal crypt areas, were microdissected from the grossly normal colonic mucosas. The DNA region containing codon 12 of K-ras was amplified by polymerase chain reaction and analyzed for mutations by dot-blot hybridization with specific oligonucleotide probes complementary to normal or mutant sequences.Mutations in codon 12 of K-ras were found in 11 (73%) of 15 aberrant crypt foci but not in any of 27 morphologically normal crypt areas from the same patients.The observed high frequency of K-ras mutations in these microscopically identifiable lesions makes mutation in K-ras the earliest identified gene-mutational event in human colon tumorigenesis, establishes that it often occurs prior to the development of polyps, and is consistent with the hypothesis that aberrant crypt foci are the earliest identified precursors of human colon cancer.Further analysis of aberrant crypt foci may identify yet unknown early genetic events that precede human colon cancer.
Polymeric Tubulysin-Peptide Nanoparticles with Potent Antitumor Activity
Authors: Thomas Schluep, Paula Gunawan, Ling Ma, Gregory S. Jensen, Julienne Duringer, Steven Hinton, Wolfgang Richter, Jungyeong Hwang
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines. However, they are also highly toxic in animal models. In order to improve the therapeutic index of this class of compounds, a nanoparticle prodrug of tubulysin A (TubA) was synthesized and evaluated in vitro and in vivo. Experimental Design: A thiol derivative of TubA was covalently attached to a linear, β-cyclodextrin based polymer through a disulfide linker (CDP-TubA). The polymer conjugate assembled into stable nanoparticles. Inhibition of tubulin polymerization and antiproliferative activity of the polymer conjugate were evaluated in vitro. The preclinical efficacy of CDP-TubA administered i.v. was evaluated in nude mice bearing s.c. implanted human HT29 colorectal and H460 non–small cell lung carcinoma tumors. Results: The IC50 of CDP-TubA (in Tub A equivalents) was 24, 5, and 10 nmol/L versus 3, 1, and 2 nmol/L for Tub A in NCI-H1299 (lung), HT-29 (colon), and A2780 (ovarian) cell lines, respectively. Tub A and the active thiol derivative were potent inhibitors of tubulin polymerization, whereas CDP-TubA showed minimal inhibition, indicating that target inhibition requires release of the peptide drug from the nanoparticles. The maximum tolerated dose of CDP-TubA was 6 mg/kg (in TubA equivalents) versus 0.05 mg/kg for TubA in nude mice. In vivo, a single treatment cycle of three weekly doses of CDP-TubA showed a potent antitumor effect and significantly prolonged survival compared with TubA alone. Conclusions: Cyclodextrin polymerized nanoparticles are an enabling technology for the safe and effective delivery of tubulysins for the treatment of cancer.
Sick-building syndrome
Authors: Carrie A Redlich, Judy Sparer, Mark R Cullen
Journal: The Lancet (1997)

Sick-building syndrome (SBS) is an increasingly common problem. Although objective physiological abnormalities are not generally found and permanent sequelae are rare, the symptoms of SBS can be uncomfortable, even disabling, and whole workplaces can be rendered non-functional. In assessment of patients with SBS complaints, specific buildingrelated illnesses suggested by history or physical examination should be ruled out. On-site assessment of buildings is extremely useful. Treatment involves both the patient and the building. Whenever possible, changes such as ventilation improvements and reduction of sources of environmental contamination should be initiated even if specific aetiological agents have not been identified.
Mononuclear cell modulation of connective tissue function: suppression of fibroblast growth by stimulation of endogenous prostaglandin production.
Authors: J H Korn, P V Halushka, E C LeRoy
Journal: Journal of Clinical Investigation (1980)

The role of immune cell products in modulating connective tissue metabolism was investigated. Supernates of both unstimulated and phytohemagglutinin-stimulated human mononuclear cell cultures suppressed fibroblast proliferation (up to 90%) and concomintantly stimulated fibroblast prostaglandin E(PGE) synthesis (20- to 70-fold). The growth suppression was, at least in part, a secondary result of the increased fibroblast PGE synthesis; growth suppression (a) paralled the increased fibroblast PGE synthesis, (b) was reversed by addition of inhibitors of prostaglandin synthesis (indomethacin, meclofenamate, and eicostaetraynoic acid), and (c) was reproduced by addition of exogenous PGE2 to fibroblast cultures. The prostaglandin-stimulatory, growth-suppressive activity was a product of non-T-lymphocyte, adherent cells and was present within 6 h of mononuclear cell culture. The activity was heat (56 degrees C) and trypsin sensitive, nondialyzable, and appeared in the 12,000-20,000 mol wt fractions by Sephadex G-100 chromatography. The activity in supernates of mononuclear cell cultures was removed by incubation with fibroblasts but not by similar incubation with peripheral blood mononuclear cells. Mononuclear cells release a factor(s) which modulates fibroblast proliferation by altering prostaglandin metabolism.
Performance status in patients with hepatocellular carcinoma: Determinants, prognostic impact, and ability to improve the Barcelona Clinic Liver Cancer system
Authors: Chia-Yang Hsu, Yun-Hsuan Lee, Cheng-Yuan Hsia, Yi-Hsiang Huang, Chien-Wei Su, Han-Chieh Lin, Rheun-Chuan Lee, Yi-You Chiou, Fa-Yauh Lee, Teh-Ia Huo
Journal: Hepatology (2012)

Performance status is included in the Barcelona Clinic Liver Cancer (BCLC) system for hepatocellular carcinoma (HCC). Few studies specifically evaluated the role of performance status in patients with HCC. This study investigated its distribution, determinants, and prognostic impact, aiming to improve the performance of the BCLC system. A total of 2,381 HCC patients were enrolled. Performance status was determined according to the Eastern Cooperative Oncology Group scale. The prognostic ability of the original and three modified BCLC systems in HCC patients was compared by the Akaike information criterion (AIC). There were 60, 17, 11, 8, and 4% of patients who were classified as performance status 0, 1, 2, 3, and 4, respectively. A worse performance status significantly correlated with age, alcoholism, hypoalbuminemia, hyperbilirubinemia, renal insufficiency, hyponatremia, and prothrombin time prolongation (all P < 0.001). Larger tumor burden, poorer residual liver function, more frequent vascular invasion, and diabetes mellitus were also observed in patients with worse performance status (all P < 0.001). Patients with poorer performance status more often received best supportive care (P < 0.001). In the Cox proportional hazards model, performance status was an independent prognostic predictor and the long-term survival tended to be worse in patients with progressively poor performance status (all P < 0.05). Reassigning patients with performance status 0 or 1 to stage B provided the lowest AIC among the four BCLC-based staging systems.Performance status is strongly associated with both tumoral and cirrhotic factors and accurately predicts long-term survival in HCC patients. Modification of the BCLC system based on performance status may further enhance its prognostic ability in patients with early to advanced cancer stage.
Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta
Authors: Manyu Li, Nicole M.J. Schwerbrock, Patricia M. Lenhart, Kimberly L. Fritz-Six, Mahita Kadmiel, Kathleen S. Christine, Daniel M. Kraus, Scott T. Espenschied, Helen H. Willcockson, Christopher P. Mack, Kathleen M. Caron
Journal: Journal of Clinical Investigation (2013)

The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.
Atrial Fibrillation: Modern Concepts and Management
Authors: Ashish Agarwal, Meghan York, Bharat K. Kantharia, Michael Ezekowitz
Journal: Annual Review of Medicine (2004)

Atrial fibrillation (AF) is a common cardiac arrhythmia responsible for significant morbidity and mortality. In recent years, progress has been made in determining the genetic abnormalities that may lead to AF. New trials have shown that rate control and anticoagulation are acceptable as a primary treatment strategy in many patients who have a high risk of recurrence. Newer and safer antiarrhythmics are now available. Pacemaker and implantable cardiac defibrillator technology is rapidly evolving and may play a significant role in future treatment and prevention of AF. Direct thrombin inhibitors are likely to add a user-friendly option to the current standard therapy for stroke prevention.
Pathogen-Sensing Plasmacytoid Dendritic Cells Stimulate Cytotoxic T-Cell Function in the Atherosclerotic Plaque Through Interferon-α
Authors: Alexander Niessner, Kayoko Sato, Elliot L. Chaikof, Ines Colmegna, Jörg J. Goronzy, Cornelia M. Weyand
Journal: Circulation (2006)

Unstable atherosclerotic plaque is characterized by an infiltrate of inflammatory cells. Both macrophages and T cells have been implicated in mediating the tissue injury leading to plaque rupture; however, signals regulating their activation remain unidentified. Infectious episodes have been suspected to render plaques vulnerable to rupture. We therefore explored whether plasmacytoid dendritic cells (pDCs) that specialize in sensing bacterial and viral products can regulate effector functions of plaque-residing T cells and thus connect host infection and plaque instability.pDCs were identified in 53% of carotid atheromas (n=30) in which they localized to the shoulder region and produced the potent immunoregulatory cytokine interferon (INF)-alpha. IFN-alpha transcript concentrations in atheroma tissues correlated strongly with plaque instability (P<0.0001). Plaque-residing pDCs responded to pathogen-derived motifs, CpG-containing oligodeoxynucleotides binding to toll-like receptor 9, with enhanced IFN-alpha transcription (P=0.03) and secretion (P=0.007). IFN-alpha emerged as a potent regulator of T-cell function, even in the absence of antigen recognition. Specifically, IFN-alpha induced a 10-fold increase of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the surface of CD4 T cells (P<0.0001) and enabled them to effectively kill vascular smooth muscle cells (P=0.0003).pDCs in atherosclerotic plaque sense microbial motifs and amplify cytolytic T-cell functions, thus providing a link between host-infectious episodes and acute immune-mediated complications of atherosclerosis.
Tracking the Ancestry of a Deeply Conserved Eumetazoan SINE Domain
Authors: O. Piskurek, D. J. Jackson
Journal: Molecular Biology and Evolution (2011)

Transposable elements (TEs), such as short interspersed elements (SINEs), evolve rapidly and are generally restricted to specific lineages. Here, we demonstrate that a central core of the previously described Deu-domain located within DeuSINEs (Nishihara et al. 2006) is widely distributed throughout the Metazoa. We characterize five new SINEs with this core sequence from the genomes of cnidarians, molluscs, annelids, and arthropods. Because this domain can be traced back to the cnidarian-bilaterian split >600 Ma, we propose naming it the "Nin" domain (the meaning of the Japanese character "Nin" is to endure and hide). Given that conserved noncoding DNA, such as that derived from the activity of SINEs, can be functionally relevant for the host genome (Sasaki et al. 2008), our findings highlight the need to understand these functions and the roles they may have played in supporting the evolution of multicellular genomes.
Narrative Medicine
Authors: Rita Charon
Journal: JAMA (2001)

The effective practice of medicine requires narrative competence, that is, the ability to acknowledge, absorb, interpret, and act on the stories and plights of others. Medicine practiced with narrative competence, called narrative medicine, is proposed as a model for humane and effective medical practice. Adopting methods such as close reading of literature and reflective writing allows narrative medicine to examine and illuminate 4 of medicine's central narrative situations: physician and patient, physician and self, physician and colleagues, and physicians and society. With narrative competence, physicians can reach and join their patients in illness, recognize their own personal journeys through medicine, acknowledge kinship with and duties toward other health care professionals, and inaugurate consequential discourse with the public about health care. By bridging the divides that separate physicians from patients, themselves, colleagues, and society, narrative medicine offers fresh opportunities for respectful, empathic, and nourishing medical care.