tbuckley/cabot-search huggingface dataset:
Abstract 4113: Kinase activity based biomarkers: Identification of prognostic and erlotinib response prediction markers in NSCLC patients
Authors: Rob Ruijtenbeek, Victor Thijssen, Eva Schaake, Liesbeth Houkes, Rik de Wijn, Michel van de Heuvel, Robert-Jan van Suylen, Rene van Pel, Petra Nederlof, Riet Hilhorst, Anne-Marie Dingemans, Houke Klomp
Journal: Cancer Research (2011)

Abstract Background: Reliable diagnostic tests are needed to identify early stage non-small cell lung carcinoma (NSCLC) patients with poor prognosis. Concomitantly there is a clear need for tests that enable the selection of patients who will benefit from targeted therapy with kinase inhibitors. We evaluated kinase activity profiles in two groups of early stage NSCLC patients, either for prognosis of long- or short-term survival, or for predicting erlotinib drug response. Method: Retrospective studies were performed on fresh frozen resection material of two groups of early stage NSCLC patients. The first group consisted of 48 short- and long-term survivors who underwent a complete surgical resection (5+ years follow-up). The second group consisted of 14 NSCLC patients who received 3 weeks of neo-adjuvant treatment with erlotinib prior to complete surgical resection. Response evaluation to neo-adjuvant treatment was based on histopathological examination of the surgical specimens. For both studies, kinase activity profiles of lysed cryosections of tumour tissues were generated in the presence and absence of protein tyrosine kinase inhibitors on PamChip® peptide micro-arrays, comprising 144 tyrosine containing peptides, derived from known phosphorylation sites of human proteins. Partial least square discriminant analysis was used to construct prediction models. ClustalW alignment algorithms were used to investigate the most informative phosphorylation sites. Results: Kinase activity profiles obtained in the absence of inhibitor did not distinguish between subgroups (long- versus short-term survival, responder or non-responder to TKI), whereas ratios of inhibited versus non-inhibited signals resulted in distinct classifiers predicting survival for the first group, and response for the second group. Multivariate unsupervised analysis with leave-one-out cross-validation resulted in an error rate for survival prediction of 29%. In the drug response prediction 13 out of 14 patients were correctly classified. Conclusion: This is the first study to show that kinase activity profiles of tumour tissue exposed to a kinase inhibitor can be used to identify NSCLC patients likely to respond to erlotinib treatment. Furthermore, based on kinase activity profiles of early stage NSCLC tumours, a prognostic classifier, for a set of 48 patients, was obtained. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4113. doi:10.1158/1538-7445.AM2011-4113
In vitro proliferation of primitive hemopoietic stem cells supported by stromal cells: evidence for the presence of a mechanism(s) other than that involving c-kit receptor and its ligand.
Authors: H Kodama, M Nose, Y Yamaguchi, J Tsunoda, T Suda, S Nishikawa, S Nishikawa
Journal: The Journal of Experimental Medicine (1992)

The preadipose cell line, PA6, can support long-term hemopoiesis. Frequency of the hemopoietic stem cells capable of sustaining hemopoiesis in cocultures of bone marrow cells and PA6 cells for 6 wk was 1/5.3 x 10(4) bone marrow cells. In the group of dishes into which bone marrow cells had been inoculated at 2.5 x 10(4) cells/dish, 3 of 19 dishes (16%) contained stem cells capable of reconstituting erythropoiesis of WBB6F1-W/Wv mice, indicating that PA6 cells can support the proliferation of primitive hemopoietic stem cells. When the cocultures were treated with an antagonistic anti-c-kit monoclonal antibody, ACK2, only a small number of day 12 spleen colony-forming units survived; and hemopoiesis was severely reduced. However, when the cocultures were continued with antibody-free medium, hemopoiesis dramatically recovered. To examine the proliferative properties of the ACK2-resistant stem cells, we developed a colony assay system by modifying our coculture system. Sequential observations of the development of individual colonies and their disappearance demonstrated that the stem cells having higher proliferative capacity preferentially survive the ACK2 treatment. Furthermore, cells of subclones of the PA6 clone that were incapable of supporting long-term hemopoiesis expressed mRNA for the c-kit ligand. These results suggest that a mechanism(s) other than that involving c-kit receptor and its ligand plays an important role in the survival and proliferation of primitive hemopoietic stem cells.
Sex is a major determinant of CYP3A4 expression in human liver
Authors: Renzo Wolbold, Kathrin Klein, Oliver Burk, Andreas K. Nüssler, Peter Neuhaus, Michel Eichelbaum, Matthias Schwab, Ulrich M. Zanger
Journal: Hepatology (2003)

Many drugs that are substrates of CYP3A4, the major human drug–metabolizing cytochrome P450 (CYP), show higher clearance in women than in men. Although this effect is believed to be related to drug metabolism, the underlying cause has not been elucidated. We investigated CYP3A4 in a large collection (n = 94) of well–characterized surgical liver samples and found 2–fold higher CYP3A4 levels in female compared with male samples ( P &lt; .0001) and a corresponding 50% increase in the CYP3A–dependent N –dealkylation of verapamil ( P &lt; .01). This expression difference was not due to preferential induction in women following higher drug exposure because it was even larger in a subgroup not previously exposed to drugs. Higher expression in women was also found for CYP3A4 messenger RNA (mRNA) transcripts, suggesting a pretranslational mechanism. Expression of the pregnane X receptor (PXR), which is crucially involved in CYP3A4 induction by xenobiotics, was strongly correlated to CYP3A4 at the mRNA level in all individuals as well as in the subgroup not exposed to drugs ( r = 0.81; P &lt; .0001), but no sex–dependent expression of PXR mRNA was found. The ABC transporter P–glycoprotein, which has been proposed to be implicated in the mechanism of sex–dependent drug clearance, was also not differentially expressed. The influence of drug treatment on expression was examined from patient drug histories, and strong induction of CYP3A4 by carbamazepine and St. John's wort was found. In conclusion, sex, in addition to PXR and drug exposure, is a major factor for CYP3A4 expression in humans, thus explaining many of the previous observations of sex–dependent drug clearance. (Hepatology 2003;38:978-988).
Healthcare for prisoners is compromised by use of temporary cells
Authors: Oona Mashta
Journal: BMJ (2008)

Public and prisoner safety is being jeopardised by the Government’s “inhumane, expensive and overstretched” use of temporary prison accommodation in England and Wales, the British Medical Association says.

Forensic doctors who staff cells at police stations and courts often lack the resources to deal with drug and mental health issues, doctors’ leaders insist.

Yet the number of inmates being held after sentencing in such accommodation has more than trebled over the past month from 65 to 408, latest figures from the Ministry of Justice show. 

Nor are these cells a cheap option, the BMA says. Holding a prisoner in a police cell costs the …
Elasticity Imaging of Atheroma With Transcutaneous Ultrasound
Authors: Hiroshi Kanai, Hideyuki Hasegawa, Masataka Ichiki, Fumiaki Tezuka, Yoshiro Koiwa
Journal: Circulation (2003)

Knowledge of the physical properties of atherosclerotic plaque is essential when evaluating its vulnerability in a clinical setting. Such knowledge, however, is still difficult to obtain with the various approaches developed to date.This article describes a noninvasive method for evaluating the regional elasticity (the elastic modulus in the circumferential direction) of tissue surrounding atherosclerotic plaque in which a novel phased tracking method is applied to measure minute changes in thickness of each of the multiple layers of the arterial wall during one heartbeat. By comparing the pathological findings with the distribution of elasticity, average elasticity of lipid and that of a mixture of smooth muscle and collagen fiber can be determined. On the basis of these reference parameters, each point is statistically categorized as lipid, mixture, or other. Thus, the plaque is electronically stained using transcutaneous ultrasound. By applying the method to the common carotid arteries, the presence of thin collagen fiber was clarified along the arterial axis for normal subjects, whereas soft inclusion of lipid was found for every plaque in subjects with hyperlipidemia.This novel method offers potential as a diagnostic technique for detection of plaque vulnerability with high spatial resolution.
Decreasing Length of Stay: Are There Effects on Outcomes of Psychiatric Hospitalization?
Authors: Paul B. Lieberman, Stephen A. Wiitala, Binette Elliott, Sandra McCormick, Stephanie B. Goyette
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The authors compared hospital outcomes for depressed patients hospitalized between 1988 and 1996. METHOD: Between 1988 and 1996, 206 depressed patients in three cohorts were evaluated at admission; of these, 161 (78.2%) were evaluated at discharge and 119 (78.3% of those followed [N=152]) 1 month later. Evaluation consisted of measures of symptoms, global functioning, self-concept, ego defenses, work and social functioning, and readmission. RESULTS: Lengths of stay significantly declined over time (26.5 versus 19.5 versus 8.3 days). At discharge, the most recently hospitalized group showed higher residual depression and lower residual global functioning scores than the other groups. Other measures did not differ among the groups at discharge. One month after discharge, the shortest-stay group continued to show lower global functioning, as well as lower quantity of work functioning. Readmission rates were equal. Within the shortest-stay group, no differences in outcome were found between patients treated in a partial hospital and those not so treated. CONCLUSIONS: Improvement during very brief admission is comparable to that in longer stays on many aspects of functioning. However, depressed patients discharged more quickly show significantly higher residual levels of depressive symptoms and lower levels of global functioning, which may place them at greater risk for adverse outcomes in the immediate posthospital period. (Am J Psychiatry 1998; 155:905–909)
Mechanisms of erythropoiesis inhibition by malarial pigment and malaria‐induced proinflammatory mediators in an in vitro model
Authors: Gordon A. Awandare, Prakasha Kempaiah, Daniel O. Ochiel, Paolo Piazza, Christopher C. Keller, Douglas J. Perkins
Journal: American Journal of Hematology (2010)

One of the commonest complications of Plasmodium falciparum malaria is the development of severe malarial anemia (SMA), which is, at least in part, due to malaria-induced suppression of erythropoiesis. Factors associated with suppression of erythropoiesis and development of SMA include accumulation of malarial pigment (hemozoin, PfHz) in bone marrow and altered production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, and nitric oxide (NO). However, studies investigating the specific mechanisms responsible for inhibition of red blood cell development have been hampered by difficulties in obtaining bone marrow aspirates from infants and young children, and the lack of reliable models for examining erythroid development. As such, an in vitro model of erythropoiesis was developed using CD34+ stem cells derived from peripheral blood to examine the effects of PfHz, PfHz-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media (CM-PfHz), TNF-α, and NO on erythroid cell development. PfHz only slightly suppressed erythroid cell proliferation and maturation marked by decreased expression of glycophorin A (GPA). On the other hand, CM-PfHz, TNF-α, and NO significantly inhibited erythroid cell proliferation. Furthermore, decreased proliferation in cells treated with CM-PfHz and NO was accompanied by increased apoptosis of erythropoietin-stimulated CD34+ cells. In addition, NO significantly inhibited erythroid cell maturation, whereas TNF-α did not appear to be detrimental to maturation. Collectively, our results demonstrate that PfHz suppresses erythropoiesis by acting both directly on erythroid cells, and indirectly via inflammatory mediators produced from PfHz-stimulated PBMC, including TNF-α and NO.
TCT-723 What Should The Default Vascular Access And Closure Strategy Be For Transcatheter Aortic Valve Replacement?
Authors: Sa'ar Minha, Marco A. Magalhaes, Israel Barbash, Itsik Ben Dor, Petros Okubagzi, Salem Badr, Hironori Kitabata, Joshua P. Loh, Alfazir Omar, Hideaki Ota, lakshmana Pendyala, Fang Chen, Augusto Pichard, Lowell F. Satler, William O. Suddath, Kenneth Kent, Rebecca Torguson, Ron Waksman
Journal: Journal of the American College of Cardiology (2013)
BMJ shortlisted trial of Edwards-SAPIEN valve does not include all randomised patients
Authors: M. A. Crilly
Journal: BMJ (2013)

I was surprised that the Edwards-SAPIEN aortic valve trial by Makkar et al was shortlisted for the “Research Paper of the Year award 2013” because a recent BMJ article highlighted how the investigators excluded 20% of the patients randomly allocated into it.1 2 3

The shortlisted paper reports on the two year mortality outcome of Edwards-SAPIEN valve insertion versus usual medical care in 358 …
Acute Effects of Dual-Site Right Atrial Pacing in Patients With Spontaneous and Inducible Atrial Flutter and Fibrillation
Authors: Atul Prakash, Sanjeev Saksena, Michael Hill, PhD, Ryszard B Krol, Anand N Munsif, Irakli Giorgberidze, Philip Mathew, Rahul Mehra
Journal: Journal of the American College of Cardiology (1997)
Mucocutaneous lymph-node syndrome (Kawasaki disease): probable soluble-complex disorder.
Authors: C Fossard, R A Thompson
Journal: BMJ (1977)

Mucocutaneous lymph-node syndrome (Kawasaki disease): probable soluble-complex disorderThe first description in English of the mucocutaneous lymph-node syndrome (MLNS)l was followed by reports from Hawaii, Canada, the United States, and, recently, Britain.We report a further case. Case reportA previously healthy 22-month-old Japanese boy born in Osaka had lived in England for 17 months.He became ill with fever, redness of the hands and feet, and a rash on the trunk and limbs and then developed facial oedema with diarrhoea and vomiting.He was admitted to hospital on the eighth day because of pain and swelling of the neck and inability to swallow.The patient was feverish, drowsy, and dehydrated, and had neck stiffness, facial oedema, conjunctivitis, cracked, bleeding lips, a red pharynx with prominent tongue papillae, and pronounced cervical adenitis.As the rash faded peripheral oedema became evident and was followed by a striking desquamation of the fingers spreading to the hands and arms.He returned home on the 22nd day, and five days later similar desquamation began on the toes and feet.During the second month we noted a transverse groove on the nails of the fingers and toes.At no time could we detect any abnormality of the cardiovascular system.He was given intravenous fluids and benzyl- penicillin for 48 hours followed by cloxacillin for 48 hours until a diagnosis was made on the fourth day.Numerous investigations on blood, urine, cerebrospinal fluid, and faeces failed to yield a pathogenic organism.The table gives the results of haematological studies.
Inherited biallelic CSF3R mutations in severe congenital neutropenia
Authors: Alexa Triot, Päivi M. Järvinen, Juan I. Arostegui, Dhaarini Murugan, Naschla Kohistani, José Luis Dapena Díaz, Tomas Racek, Jacek Puchałka, E. Michael Gertz, Alejandro A. Schäffer, Daniel Kotlarz, Dietmar Pfeifer, Cristina Díaz de Heredia Rubio, Mehmet Akif Ozdemir, Turkan Patiroglu, Musa Karakukcu, José Sánchez de Toledo Codina, Jordi Yagüe, Ivo P. Touw, Ekrem Unal, Christoph Klein
Journal: Blood (2014)
LYMPHOMATOSIS, MYELOMATOSIS, AND ENDOTHELIOMA OF CHICKENS CAUSED BY A FILTERABLE AGENT
Authors: J. Furth
Journal: The Journal of Experimental Medicine (1934)

When stimulated by a filterable agent of leukosis of chickens (Strain 2), endothelium may undergo seemingly unrestricted growth. These neoplasms of endothelium are usually unaccompanied by the formation of blood cells. Occasionally they produce hemocytoblasts, discharged like those of the normal marrow into vascular channels as also myelocytes about the vessels. The same agent that stimulates endothelium also stimulates erythroblasts, myelocytes, and hemocytoblasts to unrestricted growth without obviously affecting the endothelium; and the association of endothelioma and leukosis is the result of stimulation of several types of cells by a single virus. Myelocytes appear also to develop from mesenchymal or endothelial cells without the intermediary stage of hemocytoblasts. It is often impossible to determine whether the neoplasms caused by the virus of Strain 2 are of endothelial or mesenchymal origin, and it is possible that both types of cells may be stimulated by the same virus. Types of sarcoma like those described by Rous are not produced by the virus of Strain 2.
High Recombinant Frequency in Extraintestinal Pathogenic<i>Escherichia coli</i>Strains
Authors: Jerónimo Rodríguez-Beltrán, Jérôme Tourret, Olivier Tenaillon, Elena López, Emmanuelle Bourdelier, Coloma Costas, Ivan Matic, Erick Denamur, Jesús Blázquez
Journal: Molecular Biology and Evolution (2015)

Homologous recombination promotes genetic diversity by facilitating the integration of foreign DNA and intrachromosomal gene shuffling. It has been hypothesized that if recombination is variable among strains, selection should favor higher recombination rates among pathogens, as they face additional selection pressures from host defenses. To test this hypothesis we have developed a plasmid-based method for estimating the rate of recombination independently of other factors such as DNA transfer, selective processes, and mutational interference. Our results with 160 human commensal and extraintestinal pathogenic Escherichia coli (ExPEC) isolates show that the recombinant frequencies are extremely diverse (ranging 9 orders of magnitude) and plastic (they are profoundly affected by growth in urine, a condition commonly encountered by ExPEC). We find that the frequency of recombination is biased by strain lifestyle, as ExPEC isolates display strikingly higher recombination rates than their commensal counterparts. Furthermore, the presence of virulence factors is positively associated with higher recombination frequencies. These results suggest selection for high homologous recombination capacity, which may result in a higher evolvability for pathogens compared with commensals.
Abstract 4602: Blocking of p14/ARF and DX2 binding by novel small chemical can improve the chemo-sensitivity of small cell lung cancer and non-small cell lung carcinoma
Authors: Ah Young Oh, Youn-Sang Jung, Su-Jin Lee, Jung Hyun Jo, Ho Young Chun, Bum-Joon Park
Journal: Cancer Research (2014)

Abstract In recent, it has been reported that alternative splicing variant of AIMP2, AIMP2/DX2 (DX2), is frequently expressed in human lung cancer and is related with p53-mediated tumor suppression pathway. Here we show that DX2 can promote tumor progression and increase incidence, cooperatively with oncogenic K-Ras in transgenic mouse model. Moreover, it can induce small cell lung carcinoma (SCLC) as well as contribute to progression of non-small cell lung carcinoma (NSCLC). In fact, DX2 expression is elevated in human small cell lung cancer cell lines. Based on the cellular localization and responsibility of si-DX2, we revealed that DX2 is an inhibitor of p14/ARF. Elimination of DX2 can induce p14/ARF expression and DX2 Transgenic (Tg) mouse cells show the low expression of p19/ARF. Since DX2, but not its original product AIMP2, is selectively interacted with p14/ARF, we screened the specific binding inhibitor and obtained the single compound (SLC36) from about 9000 chemicals. This chemical can block the interaction of p14/ARF-DX2 and also AIMP2-DX2, but not the binding of p14/ARF-p53 or AIMP2-p53. In addition, it can induce p14/ARF expression and cell death in human lung cancer cell lines including SCLC cell lines. In our in vivo study, treatment of SLC36, combined with low dosage of adriamycin (1 mg/kg) can suppress the cancer incidence as well as progression in K-RasLA2 and K-Ras/DX2 double Tg model. These results indicate that DX2 can contribute to lung cancer progression and development, including SCLC, through inhibition of p14/ARF, and blocking of DX2-p14/ARF binding would be useful therapeutic strategy of human lung cancers including SCLC as well as NSCLC. Citation Format: Ah Young Oh, Youn-Sang Jung, Su-Jin Lee, Jung Hyun Jo, Ho Young Chun, Bum-Joon Park. Blocking of p14/ARF and DX2 binding by novel small chemical can improve the chemo-sensitivity of small cell lung cancer and non-small cell lung carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4602. doi:10.1158/1538-7445.AM2014-4602
Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy.
Authors: M R Bristow, F L Anderson, J D Port, L Skerl, R E Hershberger, P Larrabee, J B O'Connell, D G Renlund, K Volkman, J Murray
Journal: Circulation (1991)

BACKGROUND We measured the content and activities of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex and adrenergic neurotransmitter levels in left and right ventricular myocardial preparations derived from 77 end-stage failing human hearts from patients with idiopathic dilated cardiomyopathy (IDC) or ischemic dilated cardiomyopathy (ISCDC). METHODS AND RESULTS The results were compared with data obtained in 21 nonfailing hearts removed from organ donors. Compared with ISCDC ventricles, IDC left and right ventricles exhibited a greater degree of total beta- or beta 1-receptor downregulation. In contrast, compared with IDC right ventricles, isolated tissue preparations of ISCDC right ventricles exhibited a greater degree of subsensitivity to the inotropic effect of isoproterenol, indicating a relatively greater degree of functional uncoupling of right ventricular ISCDC beta-receptors from mechanical response. In addition, relative to IDC left ventricles, preparations of ISCDC left ventricle exhibited greater subsensitivity to beta-agonist-mediated adenylate cyclase stimulation, indicating functional uncoupling of left ventricular ISCDC beta-receptors from cyclic AMP generation. The uncoupling of beta-receptors in ISCDC left and right ventricles may have been a result of abnormalities in G protein activation of adenylate cyclase; compared with age- and cardiac function-matched respective left or right IDC ventricles, ISCDC left ventricles exhibited less stimulation of adenylate cyclase by NaF or forskolin but no change in Mn2+ stimulation, whereas ISCDC right ventricles exhibited less stimulation by the nonhydrolyzable guanine nucleotide Gpp (NH)p. Also, IDC right ventricles exhibited a "selective" (not present in IDC left ventricles or ISCDC ventricles) decrease in stimulation of adenylate cyclase by Mn2+. Tissue neurotransmitter levels and pertussis toxin-catalyzed ADP ribosylation were altered to similar extents in IDC and ISCDC: CONCLUSIONS These data indicate that potentially important differences exist in the regulatory behavior of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex in IDC versus ISCDC, differences that presumably relate to the distinct pathophysiologies of these two types of heart muscle disease.