tbuckley/cabot-search huggingface dataset:
Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
Authors: Hagop Kantarjian, Neil P. Shah, Andreas Hochhaus, Jorge Cortes, Sandip Shah, Manuel Ayala, Beatriz Moiraghi, Zhixiang Shen, Jiri Mayer, Ricardo Pasquini, Hirohisa Nakamae, Françoise Huguet, Concepción Boqué, Charles Chuah, Eric Bleickardt, M. Brigid Bradley-Garelik, Chao Zhu, Ted Szatrowski, David Shapiro, Michele Baccarani
Journal: New England Journal of Medicine (2010)

Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML.In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons.After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar.Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)
Factors affecting in-hospital mortality in patients with chronic obstructive pulmonary disease exacerbation
Authors: Asli Gorek Dilektasli, Esra Uzaslan, Ezgi Demirdogen Cetinoglu, Nilufer Aylin Acet, Dane Ediger, Ercüment Ege
Journal: European Respiratory Journal (2013)

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. Acute exacerbation of COPD (AECOPD) is associated with increased mortality.

Material-Methods: We included COPD patients whom admitted to a tertiary reference center in Southern Marmara Region and hospitalized with acute exacerbation in the last two years. Medical records of the study participants were screened retrospectively in order to analyze in-hospital mortality and affecting factors on mortality in AECOPD patients.

Results: We identified a total of 242 patients hospitalized for AECOPD. Of these 86.4% (n=209) were male. The mean age of the group was 66.6±11 years old. 11 patients lost follow-up. 9 % (n=21) of the patients died. The median length of stay for hospitalization was longer in the lost patients (19.5 [min: 1-36] days vs. 10.0 [min: 1-36] days, p<0.05). The median Charlson comorbidity index was 3.0 [min: 0-12] in the overall group and total score was not different among alive and dead patients. On the other hand, mortality rate was higher in patients with concomitant lung cancer (23.8% vs. 7.5%, p<0.05). Comorbid conditions other than lung cancer were not affecting mortality outcome. C-reactive protein levels on admission were significantly higher in patients who died than the alive ones (1.96 [min: 0.3-29.8] mg/dL vs. 5.67[min: 0.3-26.4] mg/dL, p<0.05).

Conclusion: The mortality of AECOPD is high. AECOPD patients with lung cancer are at risk for poor outcome. And, high CRP levels during AECOPD episode correlate with short-term prognosis.
Mechanisms of Inactivation of the Receptor Tyrosine Kinase EPHB2 in Colorectal Tumors
Authors: Hafid Alazzouzi, Veronica Davalos, Antti Kokko, Enric Domingo, Stefan M. Woerner, Andrew J. Wilson, Lars Konrad, Päivi Laiho, Eloi Espín, Manel Armengol, Kohzoh Imai, Hiroyuki Yamamoto, John M. Mariadason, Johannes F. Gebert, Lauri A. Aaltonen, Simo Schwartz, Diego Arango
Journal: Cancer Research (2005)

Abstract The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/β-catenin. Premalignant lesions of the colon express high levels of EPHB2 but the expression of this kinase is reduced or lost in most colorectal carcinomas. In addition, inactivation of EPHB2 has been shown to accelerate tumorigenesis initiated by APC mutation in the colon and rectum. In this study, we investigated the molecular mechanisms responsible for the inactivation of EPHB2 in colorectal tumors. We show here the presence of mutations in repetitive sequences in exon 17 of EPHB2 in 6 of 29 adenomas with microsatellite instability (MSI), and 101 of 246 MSI carcinomas (21% and 41%, respectively). Moreover, we found EPHB2 promoter hypermethylation in 54 of the 101 colorectal tumors studied (53%). Importantly, EPHB2 expression was restored after treatment of EPHB2-methylated colon cancer cells with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. In conclusion, in this study, we elucidate the molecular mechanisms of inactivation of EPHB2 and show for the first time the high incidence of frameshift mutations in MSI colorectal tumors and aberrant methylation of the regulatory sequences of this important tumor suppressor gene.
Insulin-Like Growth Factor-1 Enhances Inflammatory Responses in Endothelial Cells
Authors: Wenyi Che, Nicole Lerner-Marmarosh, Qunhua Huang, Masaki Osawa, Shinsuke Ohta, Masanori Yoshizumi, Michael Glassman, Jiing-Dwan Lee, Chen Yan, Bradford C. Berk, Jun-ichi Abe
Journal: Circulation Research (2002)

Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-κB activation by tumor necrosis factor (TNF)-α and enhanced TNF-α–mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH 2 -terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab1) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-κB activation by TNF-α, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-κB transcriptional activation by TNF-α. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-α–induced c-Jun and NF-κB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-α signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-κB. Furthermore, the IGF-1–mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts
Authors: S PIERRE, C YANG, Z YUAN, J SEMINERIO, C MOUAS, K GARLID, P DOSSANTOS, Z XIE
Journal: Cardiovascular Research (2006)

Objective: Because ouabain activates several pathways that are critical to cardioprotective mechanisms such as ischemic preconditioning, we tested if this digitalis compound could protect the heart against ischemia–reperfusion injury through activation of the Na+,K+-ATPase/c-Src receptor complex.
Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia
Authors: Kristin Synnestvedt, Glenn T. Furuta, Katrina M. Comerford, Nancy Louis, Jorn Karhausen, Holger K. Eltzschig, Karl R. Hansen, Linda F. Thompson, Sean P. Colgan
Journal: Journal of Clinical Investigation (2002)

Under conditions of limited oxygen availability (hypoxia), multiple cell types release adenine nucleotides in the form of ATP, ADP, and AMP. Extracellular AMP is metabolized to adenosine by surface-expressed ecto-5′-nucleotidase (CD73) and subsequently activates surface adenosine receptors regulating endothelial and epithelial barrier function. Therefore, we hypothesized that hypoxia transcriptionally regulates CD73 expression. Microarray RNA analysis revealed an increase in CD73 and ecto-apyrase CD39 in hypoxic epithelial cells. Metabolic studies of CD39/CD73 function in intact epithelia revealed that hypoxia enhances CD39/CD73 function as much as 6 ± 0.5–fold over normoxia. Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1α expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression. Studies using luciferase reporter constructs revealed a significant increase in activity in cells subjected to hypoxia, which was lost in truncated constructs lacking the HIF-1 site. Mutagenesis of the HIF-1α binding site resulted in a nearly complete loss of hypoxia-inducibility. In vivo studies in a murine hypoxia model revealed that hypoxia-induced CD73 may serve to protect the epithelial barrier, since the CD73 inhibitor α,β-methylene ADP promotes increased intestinal permeability. These results identify an HIF-1–dependent regulatory pathway for CD73 and indicate the likelihood that CD39/CD73 protects the epithelial barrier during hypoxia.
Abstract P2-16-02: Bi-specific antibodies targeting signaling pathway crosstalk are a new breast cancer immunotherapeutic strategy
Authors: Yanliang Zhang, Edwige Gros, Sarabjit Chagar, Jian Cao, Heyue Zhou, Kouros Motamed, Gunnar F Kaufmann, Yanwen Fu
Journal: Cancer Research (2015)

Abstract All of the currently approved therapeutic anti-cancer antibodies are monospecific and therefore only capable of interfering with the biological function of a single molecular target. However, breast cancers mostly involve crosstalk of often synergistic signal transduction pathways, and thus, isolated blockade of a single signal transduction pathway is frequently met by escape mechanisms, such as upregulation of redundant pathways, rendering the monospecific immunotherapy less effective. Using chemical biology and molecular biology, Sorrento has developed new approaches to generate IgG-like bi-specific antibodies (BsAbs) targeting either two compensating signal transduction pathways, such as HER family members or a breast cancer specific antigen and an immuno-regulatory molecule such as PDL1 or PD1. The chemical biology method involves specific hetero-dimerization of two half antibody molecules using bio-orthogonal chemistry. The molecular biology approach utilizes phage display by either discovering common light chains for the two relevant antigens in combination with two distinct heavy chains or by selecting dual specific antibodies, namely a single antibody that can recognize two distinct antigens. Progress will be presented on bi-specific as well as dual specific antibodies against Her3 and Her4 as well as immunomodulatory BsAbs with data on in vitro characterization, cell-based functional assays, and in vivo models. Citation Format: Yanliang Zhang, Edwige Gros, Sarabjit Chagar, Jian Cao, Heyue Zhou, Kouros Motamed, Gunnar F Kaufmann, Yanwen Fu. Bi-specific antibodies targeting signaling pathway crosstalk are a new breast cancer immunotherapeutic strategy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-16-02.
Anomalous Pulmonary Venous Drainage
Authors: A. R. Muir
Journal: Thorax (1953)

Primary care givers commonly interpret shortages of time with patients as placing them between a rock and a hard place in respect of their professional obligations to fairly distribute available healthcare resources (justice) and to offer a quality of attentive care appropriate to patients’ states of personal vulnerability (compassion). The author argues that this a false and highly misleading conceptualisation of the basic structure of the ethical dilemma raised by the rationing of time in clinical settings. Drawing on an analysis of the Aristotelian virtue of <i>nemesis</i>, or “the sense of justice”, it is argued that, far from being a moral orientation distinct from justice, compassion is a justice response insofar as it is conceptualised as a rational, appropriate response to others’ adversity. The author then proceeds to point out that the perspective on justice and compassion as attributes of healthcare professionalism suggests a novel critical viewpoint on the ethics of managed forms of clinical rationing and the “scarcity paradigm” they engender: clinical conditions where primary care givers’ time is intentionally rendered a commodity in chronically short supply run a deficit of justice, because they fail to make adequate accommodations for the provision of the quality of care human beings deserve in situations of illness and injury, and when they are dying.
Identification of mutations in epidermal growth factor receptor may predict response to gefitinib in NSCLC
Authors: B S W Choo-Kang
Journal: Thorax (2004)

Background: With the rising mean age, more patients will be diagnosed with one or more other serious diseases at the time of lung cancer diagnosis.Little is known about the best way to treat elderly patients with comorbidity or the outcome of treatment.This study was undertaken to evaluate the independent effects of age and comorbidity on treatment and prognosis in patients with non-small cell lung cancer (NSCLC).Methods: All patients with NSCLC diagnosed between 1995 and 1999 in the southern part of the Netherlands (n = 4072) were included.Results: The proportion of patients with localised NSCLC who underwent surgery was 92% in patients younger than 60 years and 9% in those aged 80 years or older.In patients aged 60-79 years this proportion also decreased with comorbidity.In patients with non-localised NSCLC the proportion receiving chemotherapy was considerably higher for those aged less than 60 years (24%) than in those aged 80 or older (2%).The number of comorbid conditions had no significant influence on the treatment chosen for patients with non-localised disease.Multivariable survival analyses showed that age, tumour size, and treatment were independent prognostic factors for patients with localised disease, and stage of disease and treatment for those with non-localised disease.Comorbidity had no independent prognostic effect.Conclusions: It is questionable whether the less aggressive treatment of elderly patients with NSCLC is justified.
Carboxylation of Osteocalcin Affects Its Association With Metabolic Parameters in Healthy Children
Authors: Anna Prats-Puig, Marta Mas-Parareda, Elena Riera-Pérez, Dolors González-Forcadell, Concepció Mier, Montserrat Mallol-Guisset, Marta Díaz, Judit Bassols, Francis de Zegher, Lourdes Ibáñez, Abel López-Bermejo
Journal: Diabetes Care (2009)

OBJECTIVE Osteocalcin (OC), a bone-derived protein, was recently shown to regulate metabolic pathways in mice. Undercarboxylated OC (ucOC), but not carboxylated OC (cOC), increases adiponectin and insulin secretion. It is unclear if carboxylation of OC affects its association with metabolic parameters in humans. RESEARCH DESIGN AND METHODS The associations between ucOC, cOC, total and high-molecular-weight (HMW) adiponectin, and insulin secretion (homeostasis model assessment [HOMA]-β) were investigated in a population-based sample of healthy prepubertal children (n = 103; 49 boys and 54 girls). RESULTS Weight-dependent associations were observed between the different forms of OC and metabolic parameters. Higher cOC was related to lower HMW adiponectin (with a stronger association in leaner children; P &amp;lt; 0.001). Higher ucOC-to-cOC ratio was associated with higher HOMA-β (P &amp;lt; 0.01) in leaner children and associated with higher HMW adiponectin (P &amp;lt; 0.001) in heavier children. CONCLUSIONS In a weight-dependent manner, cOC and the proportion of ucOC are differentially related to HMW adiponectin and insulin secretion in healthy children.
Tyrosine Hydroxylase, the Rate-Limiting Enzyme in Catecholamine Biosynthesis
Authors: Fangwen Rao, Lian Zhang, Jennifer Wessel, Kuixing Zhang, Gen Wen, Brian P. Kennedy, Brinda K. Rana, Madhusudan Das, Juan L. Rodriguez-Flores, Douglas W. Smith, Peter E. Cadman, Rany M. Salem, Sushil K. Mahata, Nicholas J. Schork, Laurent Taupenot, Michael G. Ziegler, Daniel T. O’Connor
Journal: Circulation (2007)

Background— Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus and then tested variants for contributions to sympathetic function and blood pressure. Methods and Results— We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single-nucleotide polymorphisms were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h 2 ), as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that TH haplotype 2 likely arose ≈380 000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. Conclusions— We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH . The results suggest novel pathophysiological links between a key adrenergic locus, catecholamine metabolism, and blood pressure and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.
Generation of C5a in the absence of C3: a new complement activation pathway
Authors: Markus Huber-Lang, J Vidya Sarma, Firas S Zetoune, Daniel Rittirsch, Thomas A Neff, Stephanie R McGuire, John D Lambris, Roscoe L Warner, Michael A Flierl, Laszlo M Hoesel, Florian Gebhard, John G Younger, Scott M Drouin, Rick A Wetsel, Peter A Ward
Journal: Nature Medicine (2006)
“Universals of colour” from a linguistic point of view
Authors: Anna Wierzbicka
Journal: Behavioral and Brain Sciences (1999)

Saunders and van Brakel's observation that “linguistic evidence provides no grounds for the universality of basic color categories” also applies to the concept of “colour” itself. The language of “seeing” is rooted in human experience, and its basic frame of reference is provided by the universal rhythm of “light” days and “dark” nights and by the fundamental and visually salient features of human environment: the sky, the sun, vegetation, fire, the sea, the naked earth.
Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia
Authors: Anna Migliazza, Francesc Bosch, Hirokazu Komatsu, Eftihia Cayanis, Stefano Martinotti, Elena Toniato, Ernesto Guccione, Xiaoyan Qu, Minchen Chien, V. V. V. Murty, Gianluca Gaidano, Giorgio Inghirami, Peisen Zhang, Stuart Fischer, Sergey M. Kalachikov, James Russo, Isidore Edelman, Argiris Efstratiadis, Riccardo Dalla-Favera
Journal: Blood (2001)

Abstract Deletions of the 13q14 chromosome region are associated with B-cell chronic lymphocytic leukemia (B-CLL) and several other types of cancer, suggesting the presence of a tumor suppressor gene. In previous studies the minimal region of deletion (MDR) was mapped to a less than 300-kilobase (kb) interval bordered by the markers 173a12-82 and 138G4/1.3R. For the identification of the putative tumor suppressor gene, the entire MDR (approximately 347 kb) has been sequenced, and transcribed regions have been identified by exon trapping, EST-based full-length complementary DNA cloning, database homology searches, and computer-assisted gene prediction analyses. The MDR contains 2 pseudogenes and 3 transcribed genes: CAR, encoding a putative RING-finger containing protein; 1B4/Leu2, generating noncoding transcripts; and EST70/Leu1, probably representing another noncoding gene (longest open reading frame of 78 codons). These genes have been sequenced in 20 B-CLL cases with 13q14 hemizygous deletion, and no mutations were found. Moreover, no somatic variants were found in the entire MDR analyzed for nucleotide substitutions by a combination of direct sequencing and fluorescence-assisted mismatch analysis in 5 B-CLL cases displaying 13q14-monoallelic deletion. The nondeleted allele of theCAR and EST70/Leu1 genes was expressed in B-CLL specimens, including those with monoallelic loss, whereas no expression of 1B4/Leu2 was detectable in B-CLL, regardless of the 13q14 status. These results indicate that allelic loss and mutation of a gene within the MDR is an unlikely pathogenetic mechanism for B-CLL. However, haplo-insufficiency of one of the identified genes may contribute to tumorigenesis.