tbuckley/cabot-search huggingface dataset:
Ethical Environment, Healthcare Work, and Patient Outcomes
Authors: Charlotte McDaniel, Emir Veledar, Stephen LeConte, Scott Peltier, Agata Maciuba
Journal: The American Journal of Bioethics (2006)

Click to increase image sizeClick to decrease image size ACKNOWLEDGMENTS The authors wish to express appreciation to the Fulbright Program for partial support for this project; to the University of Turku Hospital staff and administrators for their contributions; and to Prof. Aimo Salmi, MD, Vice Rector, University of Turku, for his support. Notes 1. Note: No studies employing SF-36 Finnish Version 1 were found. Although several studies have been conducted by the National Research & Development Centre for Welfare & Health (STAKES), Helsinki, Finland, employing SF-36 items, their scoring is different thereby rendering results less than comparable. 1 Missing items. 1 p < 0.05; Pearson correlations. 1 p < 0.05; Pearson correlations.
Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma
Authors: Yuka Aoki, Masanori Nojima, Hiromu Suzuki, Hiroshi Yasui, Reo Maruyama, Eiichiro Yamamoto, Masami Ashida, Mitsuhiro Itagaki, Hideki Asaoku, Hiroshi Ikeda, Toshiaki Hayashi, Kohzoh Imai, Mitsuru Mori, Takashi Tokino, Tadao Ishida, Minoru Toyota, Yasuhisa Shinomura
Journal: Genome Medicine (2012)

The aim of this study was to clarify the role of global hypomethylation of repetitive elements in determining the genetic and clinical features of multiple myeloma (MM).We assessed global methylation levels using four repetitive elements (long interspersed nuclear element-1 (LINE-1), Alu Ya5, Alu Yb8, and Satellite-α) in clinical samples comprising 74 MM samples and 11 benign control samples (7 cases of monoclonal gammopathy of undetermined significance (MGUS) and 4 samples of normal plasma cells (NPC)). We also evaluated copy-number alterations using array-based comparative genomic hybridization, and performed methyl-CpG binding domain sequencing (MBD-seq).Global levels of the repetitive-element methylation declined with the degree of malignancy of plasma cells (NPC>MGUS>MM), and there was a significant inverse correlation between the degree of genomic loss and the LINE-1 methylation levels. We identified 80 genomic loci as common breakpoints (CBPs) around commonly lost regions, which were significantly associated with increased LINE-1 densities. MBD-seq analysis revealed that average DNA-methylation levels at the CBP loci and relative methylation levels in regions with higher LINE-1 densities also declined during the development of MM. We confirmed that levels of methylation of the 5' untranslated region of respective LINE-1 loci correlated strongly with global LINE-1 methylation levels. Finally, there was a significant association between LINE-1 hypomethylation and poorer overall survival (hazard ratio 2.8, P = 0.015).Global hypomethylation of LINE-1 is associated with the progression of and poorer prognosis for MM, possibly due to frequent copy-number loss.
Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas
Authors: Scott D. Solomon, Marc A. Pfeffer, John J.V. McMurray, Rob Fowler, Peter Finn, Bernard Levin, Craig Eagle, Ernest Hawk, Mariajosé Lechuga, Ann G. Zauber, Monica M. Bertagnolli, Nadir Arber, Janet Wittes
Journal: Circulation (2006)

Cyclooxygenase-2 (COX-2) inhibitors have been shown to reduce colorectal adenomas but have been associated with increased cardiovascular risk.The Adenoma Prevention With Celecoxib (APC) trial studied celecoxib 200 mg twice daily and 400 mg twice daily and the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial used 400 mg once daily totest the efficacy and safety of celecoxib against placebo in reducing colorectal adenoma recurrence after polypectomy. An independent safety committee for both studies adjudicated and categorized serious cardiovascular events and then combined individual patient data from these long-term trials to improve the estimate of the cardiovascular risk and blood pressure changes associated with celecoxib compared with placebo. For adjudicated cardiovascular events, 77% and 54% in APC and PreSAP, respectively, had 37 months of follow-up. For APC and PreSAP combined, 83 patients experienced cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure. The hazard ratio for this prespecified composite end point was 2.6 (95% confidence interval [CI], 1.1 to 6.1) in patients taking 200 mg twice daily, 3.4 (95% CI, 1.5 to 7.9) in patients taking 400 mg twice daily in APC, and 1.3 (95% CI, 0.6 to 2.6) in patients taking 400 mg once daily in PreSAP (P for heterogeneity = 0.13 comparing the combined doses in APC with the dose in PreSAP). The overall hazard ratio for this composite end point was 1.9 (95% CI, 1.1 to 3.1). Both dose groups in APC showed significant systolic blood pressure elevations at 1 and 3 years (200 mg twice daily: 1 year, 2.0 mm Hg; 3 years,2.6 mm Hg; 400 mg twice daily: 1 year, 2.9 mm Hg; 3 years, 5.2 mm Hg); however, the 400 mg once daily group inPreSAP did not (P0.0001 between studies).Celecoxib at 200 or 400 mg twice daily or 400 mg once daily showed a nearly 2-fold-increased cardiovascular risk. The trend for a dose-related increase in cardiovascular events and blood pressure raises the possibility that lower doses or other dose intervals may be associated with less cardiovascular risk.
Engagement of CD4 and CD8 expressed on immature thymocytes induces activation of intracellular tyrosine phosphorylation pathways.
Authors: A Veillette, J C Zúñiga-Pflücker, J B Bolen, A M Kruisbeek
Journal: The Journal of Experimental Medicine (1989)

Accumulating data suggest that the target cells for selection events leading to establishment of the mature T cell repertoire are the functionally immature double-positive (CD4+/CD8+) thymocytes, and that the CD4 and CD8 antigens expressed on these cells play important roles in these processes. In an attempt to define the biochemical pathways implicated in these events, we have studied the effects of engagement of accessory molecules on tyrosine protein phosphorylation. The results of our experiments demonstrate that engagement of CD4 and CD8 expressed on double-positive thymocytes is coupled with a rapid tyrosine protein phosphorylation signal. Further analyses have revealed that these two surface molecules are physically associated with the internal membrane tyrosine protein kinase p56lck in immature thymocytes, and that the catalytic function of lck expressed in double-positive thymocytes is significantly enhanced upon engagement of CD4. These data provide evidence that tyrosine-specific protein phosphorylation pathways coupled to the CD4 and CD8 T cell surface antigens are functional in immature thymocytes, and therefore, formally prove that signaling functions of CD4 and CD8 molecules are operative in immature thymocytes.
Increased Myophosphorylase A in Malignant Hyperthermia
Authors: Joseph H. Willner, Donald S. Wood, Cesare Cerri, Beverly Britt
Journal: New England Journal of Medicine (1980)

BECAUSE susceptibility is usually acquired by autosomal-dominant inheritance, 1 many relatives of patients who have had attacks of malignant hyperthermia are at risk. Elevated serum creatine kinase...
Visceral Infection Caused by Leishmania tropica in Veterans of Operation Desert Storm
Authors: Alan J. Magill, Max Grogl, Robert A. Gasser, Wellington Sun, Charles N. Oster
Journal: New England Journal of Medicine (1993)

Visceral leishmaniasis, usually caused by Leishmania donovani, has rarely been reported from eastern Saudi Arabia, so it was not expected to affect the soldiers of Operation Desert Storm.
ERYTHREMIA (POLYCYTHEMIA) WITH A PSYCHOSIS
Authors: Max Levin
Journal: American Journal of Psychiatry (1930)

The case is that of a man who developed erythremia at 43 and a severe depression at 45 lasting until death at 47. Although proof is lacking, it seems possible that the erythremia was one of the factors responsible for the appearance of the psychosis. I am indebted to Dr.Solomon Solis-Cohen, Dr.David Riesman, Dr. H. K. Mohler, Dr. Everett S. Barr, Dr.Edward Weiss, Dr. C. F. Long, and Dr. H. Ruche for their kindness in placing at my disposal their records of the case.
Better care for Michael Stone might still not have prevented the killings
Authors: Clare Dyer
Journal: BMJ (2006)

Serious mistakes were made in the care and treatment of Michael Stone, the killer of Lin and Megan Russell, but better care might still not have avoided the killings, the report of an independent inquiry has concluded.

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Michael Stone has a severe antisocial personality disorder 

Credit: PA/EMPICS

Robert Francis QC, who chaired the inquiry into the involvement of the health, probation, and social services with Mr Stone before he bludgeoned the mother and daughter to death on a country lane in Kent in 1996, said: “This is …

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In Vivo Survival and Function of Transplanted Rat Cardiomyocytes
Authors: Ren-Ke Li, Donald A.G. Mickle, Richard D. Weisel, Ji Zhang, Molly K. Mohabeer
Journal: Circulation Research (1996)

Abstract Recent studies have demonstrated the feasibility of transplanting fetal mouse cardiomyocytes into the hearts of adult syngeneic mice. However, the function of the transplanted cardiomyocytes and their capacity to survive in fibrous connective tissue were not assessed. In the present study, we evaluated the viability and contractility of transplanted fetal and neonatal rat cardiomyocytes in the connective tissue of the adult rat hindlimb. Purified fetal or neonatal rat cardiomyocytes were cultured. These cells contained sarcomeres, formed junctions composed of desmosomes and fascia adherens, and contracted regularly and spontaneously. A fetal or neonatal cardiomyocyte suspension was injected into the subcutaneous tissue of adult rat hindlimbs. Cyclosporin A (5 mg/kg) was administered subcutaneously daily for the 3-month duration of the study, at which time the animals were killed. The transplanted cardiomyocytes formed ‘tissue’ in vivo that increased in size for the first 2 weeks and remained the same size at the third week. The tissue derived from the transplanted fetal cardiomyocytes contracted spontaneously at a rate of 73±12 bpm, and that from the neonatal cardiomyocytes contracted at a rate of 43±21 bpm. The electrocardiogram was similar to that seen in myocardium with an idioventricular rhythm. Histologically, the tissue appeared to be cardiac muscle with sarcomeres. Angiogenesis occurred in the cardiomyocyte graft. In summary, a cell suspension of cultured fetal and neonatal rat cardiomyocytes transplanted into the adult rat hindlimb formed contractile cardiac tissue in the subcutaneous connective tissue.
An unusual cause of chest pain
Authors: B. Casserly, M. K. Atalay, A. Poppas, J. R. Klinger, M. Abu-Hijleh
Journal: Thorax (2010)

the tissue is such that we were unable to have an equal age distribution.We also acknowledge that the three age groups are made up of subjects from different areas, and that these are not longitudinal data.Despite the above limitations, we consider the large number of subjects, whose deaths were not respiratory related, and the wide age range included provides a strong basis for establishing the time of appearance and pattern of thickening that occurs to the bronchial RBM, and its positive relationship with epithelial height, during normal development.These data indicate that future paediatric and adult biopsy studies assessing RBM thickness should include age-matched controls.
Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma.
Authors: B Mukherji, A Guha, N G Chakraborty, M Sivanandham, A L Nashed, J R Sporn, M T Ergin
Journal: The Journal of Experimental Medicine (1989)

T cell-mediated immune response against autologous melanoma cells was analyzed, at population and clonal levels, in 31 patients with recurrent and/or metastatic disease. Fresh PBL and lymph node lymphocytes (LNL) from melanoma-involved nodes were not cytotoxic against the respective melanoma cells. When activated in in vitro coculture (IVC) against the autologous melanoma cells in the presence of IL-2, a majority of the activated PBL and LNL became cytotoxic against the autologous targets. The activated effector cells were cloned in limiting dilution microcultures, and growing clones were phenotypically defined and were functionally characterized for cytotoxicity and for potential regulatory function. Functional T cell clones were obtained from 15 of 31 cases. Of these, CTL responses exhibiting cytotoxicity restricted against the autologous melanoma were seen in four cases. All four CTL clones were CD3+, CD8+, and CD4-. Three of these four CTL clones were studied extensively. All three of these CTL clones expressed MHC class I-restricted cytotoxicity. mAb anti-CD3 blocked cytotoxicity in two and enhanced cytotoxicity in the other. Neither autologous sera nor autologous nonactivated fresh PBL modulated the cytotoxic functions of the CTL clones at the effector phase. T cell lines exhibiting regulatory function were obtained in 11 cases. The regulatory T cell lines were CD3+, CD4+, and CD8-. In three cases CD4+ clones amplified the cytotoxic response in the PBL in coculture, while in eight other cases the T cell lines downregulated the cytotoxic responses. Such T cell-mediated down-regulations were either restricted to the autologous system, induced by D/DR antigens expressed by the autologous or allogeneic melanoma cells, or induced by stimulus other than D/DR antigens. Taken together, these findings clearly demonstrate the existence of T cell-mediated cytotoxic and regulatory responses against human melanoma.
Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma
Authors: Sanchaita Sriwal Sonar, Yen-Ming Hsu, Melanie Lynn Conrad, Gerard R. Majeau, Ayse Kilic, Ellen Garber, Yan Gao, Chioma Nwankwo, Gundi Willer, Jan C. Dudda, Hellen Kim, Véronique Bailly, Axel Pagenstecher, Paul D. Rennert, Harald Renz
Journal: Journal of Clinical Investigation (2010)

Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1-specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.
PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor
Authors: Federica Perrone, Luca Da Riva, Marta Orsenigo, Marco Losa, Genny Jocollè, Clara Millefanti, Elisa Pastore, Alessandro Gronchi, Marco Alessandro Pierotti, Silvana Pilotti
Journal: Neuro-Oncology (2009)

We investigated the activation of platelet-derived growth factor (PDGF) receptor A (PDGFRA), PDGF receptor B (PDGFRB), epidermal growth factor receptor (EGFR), and their downstream pathways in malignant peripheral nerve sheath tumors (MPNSTs). PDGFRA, PDGFRB, and EGFR were immunohistochemically, biochemically, cytogenetically, and mutationally analyzed along with the detection of their cognate ligands in 16 neurofibromatosis type 1 (NF1)-related and 11 sporadic MPNSTs. The activation of the downstream receptor pathways was also studied by means of v-akt murine thymoma viral oncogene homolog (AKT), extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin (mTOR) Western blotting experiments, as well as rat sarcoma viral oncogene homolog (RAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA), and phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutational analysis and fluorescence in situ hybridization. PDGFRA, PDGFRB, and EGFR were expressed/activated, with higher levels of EGFR expression/phosphorylation paralleling increasing EGFR gene copy numbers in the NF1-related cases (71%). Autocrine loop activation of these receptors along with their coactivation were suggested by the expression of the cognate ligands in the absence of mutations and the presence of receptor tyrosine kinase (RTK) heterodimers, respectively. Both MPNST groups showed AKT, ERK, and mTOR expression/phosphorylation. No BRAF, PI3KCA, or PTEN mutations were found in either group of MPNSTs, but 18% of the sporadic MPNSTs showed RAS mutations. PTEN monosomy segregated with the NF1-related cases (50%, p = 0.018), but PTEN protein was expressed in all but two cases. In conclusion, PDGFRA, PDGFRB, and EGFR seem to be promising molecular targets for tailored treatments in MPNST. In particular, the ligand- and heterodimerization-dependent RTK activation/expression coupled with a downstream signaling phosphorylation, mediated by the upstream receptors or RAS activation, may provide a rationale to apply combined RTK and mTOR inhibitor treatments both to sporadic and NF1-related cases.
A case of pulmonary alveolar microlithiasis with an intragenetic deletion in SLC34A2 detected by a genome-wide SNP study
Authors: Y Ishihara, K Hagiwara, K Zen, None Huqun, Y Hosokawa, A Natsuhara
Journal: Thorax (2009)

A case of pulmonary alveolar microlithiasis occurring in an inbred family is presented. A genome-wide analysis of the patient’s genomic DNA using a high-density single nucleotide polymorphism (SNP) array revealed a small intragenetic mutation at SLC34A2. The results suggest that the high-density SNP array has the power to identify a recessive disease gene(s) even in the analysis of only a single inbred patient.
Enhanced Contractility of Renal Afferent Arterioles From Angiotensin-Infused Rabbits
Authors: Dan Wang, Tina Chabrashvili, Christopher S. Wilcox
Journal: Circulation Research (2004)

We tested the hypothesis that cyclooxygenase (COX), thromboxane A2 synthase (TxA2-S), thromboxane prostanoid receptors (TP-Rs), or superoxide anion (O2-) mediates enhanced contractions of renal afferent arterioles (Aff) of angiotensin II (Ang II)-infused rabbits. Rabbits were infused with vehicle (sham), Ang II 60 ng x kg(-1) x min(-1) (Ang II 60) or 200 ng x kg(-1) x min(-1) (Ang II 200). There was a selective enhanced vasoconstriction of Affs from Ang II 60 rabbits to Ang II (Deltadiameter-78+/-8% versus -43+/-9%; P<0.01) that was normalized by a TP-R antagonist but not by a superoxide dismutase (SOD) mimetic. Affs from Ang II 200 rabbits had increased (P<0.01) mRNA for COX-2 and enhanced vasoconstriction to Ang II, U-46 619 (TP-R mimetic), and endothelin-1 that was normalized by ifetroban plus tempol together. Endothelium removal enhanced Ang II responses of Affs from sham rabbits but blunted responses from Ang II 200 rabbits and abolished responses to ifetroban. Affs from Ang II 200 rabbits had an endothelium-dependent contraction factor (EDCF) response to that was blunted (P<0.001) by a SOD mimetic or antagonists of COX-1 or TxA2-S but normalized by antagonists of COX-2 or TP-R. Thus, enhanced Ang II responses in Affs from rabbits infused with slow pressor Ang II are mediated independently by O2- in the vascular smooth muscle cells and by an EDCF that is principally a vasoconstrictor prostaglandin generated by COX-2 >-1 activating TP-Rs, whereas enhanced responses in rabbits infused with a lower Ang II dose are dependent on TP-R but not O2-.
SLC34A2 Gene Mutation May Explain Comorbidity of Pulmonary Alveolar Microlithiasis and Aortic Valve Sclerosis
Authors: Åsa Lina M. Jönsson, Ole Hilberg, Elisabeth M. Bendstrup, Susie Mogensen, Ulf Simonsen
Journal: American Journal of Respiratory and Critical Care Medicine (2012)
Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member
Authors: Jennifer M. O'Toole, Karen E. Rabenau, Kerri Burns, Dan Lu, Venkat Mangalampalli, Paul Balderes, Nicole Covino, Rajiv Bassi, Marie Prewett, Kimberly J. Gottfredsen, Megan N. Thobe, Yuan Cheng, Yiwen Li, Daniel J. Hicklin, Zhenping Zhu, Susan E. Waltz, Michael J. Hayman, Dale L. Ludwig, Daniel S. Pereira
Journal: Cancer Research (2006)

RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target. In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED50 = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC50 = 2 nmol/L). We found IMC-41A10 to be a potent inhibitor of receptor and downstream signaling, cell migration, and tumorigenesis. It antagonized MSP-induced phosphorylation of RON, mitogen-activated protein kinase (MAPK), and AKT in several cancer cell lines. In HT-29 colon, NCI-H292 lung, and BXPC-3 pancreatic cancer xenograft tumor models, IMC-41A10 inhibited tumor growth by 50% to 60% as a single agent, and in BXPC-3 xenografts, it led to tumor regressions when combined with Erbitux. Western blot analyses of HT-29 and NCI-H292 xenograft tumors treated with IMC-41A10 revealed a decrease in MAPK phosphorylation compared with control IgG-treated tumors, suggesting that inhibition of MAPK activity may be required for the antitumor activity of IMC-41A10. To our knowledge, this is the first demonstration that a RON antagonist and specifically an inhibitory antibody of RON negatively affects tumorigenesis. Another major contribution of this report is an extensive analysis of RON expression in approximately 100 cancer cell lines and approximately 300 patient tumor samples representing 10 major cancer types. Taken together, our results highlight the potential therapeutic usefulness of RON activity inhibition in human cancers.