tbuckley/cabot-search huggingface dataset:
Routine Morphine Infusion in Preterm Newborns Who Received Ventilatory Support
Authors: Sinno H. P. Simons, Monique van Dijk, Richard A. van Lingen, Daniella Roofthooft, Hugo J. Duivenvoorden, Niesje Jongeneel, Carin Bunkers, Enna Smink, K. J. S. Anand, John N. van den Anker, Dick Tibboel
Journal: JAMA (2003)

Newborns admitted to neonatal intensive care units (NICUs) undergo a variety of painful procedures and stressful events. Because the effect of continuous morphine infusion in preterm neonates has not been investigated systematically, there is confusion regarding whether morphine should be used routinely in this setting.To evaluate the effects of continuous intravenous morphine infusion on pain responses, incidence of intraventricular hemorrhage (IVH), and poor neurologic outcome (severe IVH, periventricular leukomalacia, or death).A randomized, double-blind, placebo-controlled trial conducted between December 2000 and October 2002 in 2 level III NICUs in the Netherlands of 150 newborns who had received ventilatory support (inclusion criteria: postnatal age younger than 3 days and ventilation for less than 8 hours; exclusion criteria: severe asphyxia, severe IVH, major congenital malformations, and administration of neuromuscular blockers).Intravenous morphine (100 microg/kg and 10 microg/kg per hour) or placebo infusion was given for 7 days (or less because of clinical necessity in several cases).The analgesic effect of morphine, as assessed using validated scales; the effect of morphine on the incidence of IVH; and poor neurologic outcome.The analgesic effect did not differ between the morphine and placebo groups, judging from the following median (interquartile range) pain scores: Premature Infant Pain Profile, 10.1 (8.2-11.6) vs 10.0 (8.2-12.0) (P =.94); Neonatal Infant Pain Scale, 4.8 (3.7-6.0) vs 4.8 (3.2-6.0) (P =.58); and visual analog scale, 2.8 (2.0-3.9) vs 2.6 (1.8-4.3) (P =.14), respectively. Routine morphine infusion decreased the incidence of IVH (23% vs 40%, P =.04) but did not influence poor neurologic outcome (10% vs 16%, P =.66). In addition, analyses were adjusted for the use of additional open-label morphine (27% of morphine group vs 40% of placebo group, P =.10).Lack of a measurable analgesic effect and absence of a beneficial effect on poor neurologic outcome do not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support. Follow-up is needed to evaluate the long-term effects of morphine infusions on the neurobehavioral outcomes of prematurity.
Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma
Authors: M Pufulete
Journal: Gut (2005)

<b>Background and aims:</b> A low dietary folate intake can cause genomic DNA hypomethylation and may increase the risk of colorectal neoplasia. The hypothesis that folic acid supplementation increases DNA methylation in leucocytes and colorectal mucosa was tested in 31 patients with histologically confirmed colorectal adenoma using a randomised, double blind, placebo controlled, parallel design. <b>Methods:</b> Subjects were randomised to receive either 400 μg/day folic acid supplement (n = 15) or placebo (n = 16) for 10 weeks. Genomic DNA methylation, serum and erythrocyte folate, and plasma homocysteine concentrations were measured at baseline and post intervention. <b>Results:</b> Folic acid supplementation increased serum and erythrocyte folate concentrations by 81% (95% confidence interval (CI) 57–104%; p&lt;0.001 <i>v</i> placebo) and 57% (95% CI 40–74%; p&lt;0.001 <i>v</i> placebo), respectively, and decreased plasma homocysteine concentration by 12% (95% CI 4–20%; p = 0.01 <i>v</i> placebo). Folic acid supplementation resulted in increases in DNA methylation of 31% (95% CI 16–47%; p = 0.05 <i>v</i> placebo) in leucocytes and 25% (95% CI 11–39%; p = 0.09 <i>v</i> placebo) in colonic mucosa. <b>Conclusions:</b> These results suggest that DNA hypomethylation can be reversed by physiological intakes of folic acid.
Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors
Authors: Kai Schledzewski, Cyrill Géraud, Bernd Arnold, Shijun Wang, Hermann-Josef Gröne, Tibor Kempf, Kai C. Wollert, Beate K. Straub, Peter Schirmacher, Alexandra Demory, Hiltrud Schönhaber, Alexei Gratchev, Lisa Dietz, Hermann-Josef Thierse, Julia Kzhyshkowska, Sergij Goerdt
Journal: Journal of Clinical Investigation (2011)

Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endothelial cells (LSEC). Besides the mannose receptor, stabilin-1 and stabilin-2 are the major scavenger receptors expressed by LSEC. To more clearly elucidate the functions of stabilin-1 and -2, we have generated mice lacking stabilin-1, stabilin-2, or both stabilin-1 and -2 (Stab1–/–Stab2–/– mice). Mice lacking either stabilin-1 or stabilin-2 were phenotypically normal; however, Stab1–/–Stab2–/– mice exhibited premature mortality and developed severe glomerular fibrosis, while the liver showed only mild perisinusoidal fibrosis without dysfunction. Upon kidney transplantation into WT mice, progression of glomerular fibrosis was halted, indicating the presence of profibrotic factors in the circulation of Stab1–/–Stab2–/– mice. While plasma levels of known profibrotic cytokines were unaltered, clearance of the TGF-β family member growth differentiation factor 15 (GDF-15) was markedly impaired in Stab1–/–Stab2–/– mice but not in either Stab1–/– or Stab2–/– mice, indicating that it is a common ligand of both stabilin-1 and stabilin-2. These data lead us to conclude that stabilin-1 and -2 together guarantee proper hepatic clearance of potentially noxious agents in the blood and maintain tissue homeostasis not only in the liver but also distant organs.
Dissecting out the genetic origins of Barrett's oesophagus
Authors: R. C Fitzgerald
Journal: Gut (2008)

Current dogma dating back to the 1970s suggests that the development of cancer occurs through clonal selection such that the primary tumour contains all the genes necessary to invade and metastasise.1 In this model heterogeneity within the tumour cell population arises as a result of genetic instability and as a result a variety of non-causative or hitchhiker mutations may be observed.2 Barrett’s oesophagus is an ideal system in which to study the genesis of cancer in the human since the oesophagus is readily accessible to biopsy and the metaplasia–dysplasia sequence can be observed longitudinally.

To date, detailed molecular studies of the Barrett’s epithelium have tended to depend on the analysis of an entire snap-frozen endoscopic biopsy or alternatively paraffin-embedded sections are probed for gene expression status using immunohistochemistry or in situ hybridisation methods. Although these in situ methods enable the construction of spatial maps this is at the expense of detailed information regarding the mechanisms underlying loss or gain of gene function. Advances in molecular biology mean that it is now possible to extract high-quality DNA from archival formalin-fixed paraffin-embedded material. Combined with microdissection and powerful DNA amplification techniques this enables analysis of the molecular status of specific genetic loci on a crypt-by-crypt basis with preservation of spatial information so that clonality can be determined. Using this innovative approach …
Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA–binding protein gene
Authors: Renee Reijo, Tien-Yi Lee, Pia Salo, Raaji Alagappan, Laura G. Brown, Michael Rosenberg, Steve Rozen, Tom Jaffe, Donald Straus, Outi Hovatta, Albert de la Chapelle, Sherman Silber, David C. Page
Journal: Nature Genetics (1995)
Occupational eosinophilic bronchitis in a foundry worker exposed to isocyanate and a baker exposed to flour
Authors: F. Di Stefano, L. Di Giampaolo, N. Verna, M. Di Gioacchino
Journal: Thorax (2005)

Eosinophilic bronchitis without asthma may occur as a consequence of occupational exposure. The cases of a foundry worker and a baker who developed symptoms, respectively, due to exposure to isocyanate and flour, are reported. Cough was not associated with variable airflow obstruction or with airway hyper-responsiveness and was responsive to inhaled corticosteroids. The eosinophilia detectable in their sputum was causally related to the occupational exposure in the workplace. The examination of induced sputum should be used in addition to the objective monitoring of lung function for workers who have asthma-like symptoms in an occupational setting.
Breathing Better or Wheezing Worse? The Changing Epidemiolgy of Asthma Morbidity and Mortality
Authors: K B Weiss, P J Gergen, D K Wagener
Journal: Annual Review of Public Health (1993)

In recent decades, there has been remarkable growth in scientific research examining the multiple ways in which racism can adversely affect health. This interest has been driven in part by the striking persistence of racial/ethnic inequities in health and ...Read More
An Imaging-Based Rapid Evaluation Method for Complement-Dependent Cytotoxicity Discriminated Clinical Response to Rituximab-Containing Chemotherapy
Authors: Yuji Mishima, Natsuhiko Sugimura, Yuko Matsumoto-Mishima, Yasuhito Terui, Kengo Takeuchi, Suzuka Asai, Daisuke Ennishi, Hiroaki Asai, Masahiro Yokoyama, Kiyotsugu Kojima, Kiyohiko Hatake
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Rituximab has greatly improved the efficacy of chemotherapy regimens for CD20-positive non-Hodgkin's lymphoma. However, although several mechanisms of action of rituximab have been identified, the exact therapeutic functions of these mechanisms remains to be clarified. In addition, there is no established prognostic marker to predict an individual response. This study verified the validity of ex vivo complement-dependent cytotoxicity (CDC) susceptibility as a predictor of pathologic tumor regression in patients undergoing rituximab-containing chemotherapy and examined whether CDC contributes to the mechanism of action of rituximab. Experimental Design: A rapid assay system was established to evaluate the tumoricidal activity of rituximab using a living cell–imaging technique. We analyzed lymph node biopsies obtained from 234 patients with suspected lymphomas and estimated the association between CDC susceptibility and the response to rituximab-containing chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma. Results: This study revealed that CDC susceptibility of lymphoma cells freshly obtained from patients was strongly associated with response to rituximab-containing chemotherapy in both diffuse large B-cell lymphoma and follicular lymphoma. This correlation was not apparent in cases that received chemotherapy without rituximab. Conclusions: The system that we have established allows a successful assessment of rituximab-induced CDC and can distinguish cases refractory to rituximab-containing chemotherapy. The association between CDC susceptibility and therapy response suggests that CDC is pivotal in the ability of chemotherapy including rituximab to induce remission.
Racial Disparities in Treatment and Survival Among Women With Early-Stage Breast Cancer
Authors: Dawn Hershman, Russell McBride, Judith S. Jacobson, Lois Lamerato, Kevin Roberts, Victor R. Grann, Alfred I. Neugut
Journal: Journal of Clinical Oncology (2005)

Purpose Black women with breast cancer are known to have poorer survival than white women. Suboptimal treatment may compromise the survival benefits of adjuvant chemotherapy. We analyzed the association of race and survival with duration of treatment and number of treatment cycles among women receiving chemotherapy for early-stage breast cancer. Patients and Methods Patients were women in the Henry Ford Health System tumor registry who were diagnosed with stage I/II breast cancer between January 1, 1996, and December 31, 2001, who received adjuvant chemotherapy. We calculated an observed/expected ratio of treatment duration and of completed chemotherapy cycles for each patient. Using Cox proportional hazards models, we analyzed the association of early treatment termination and treatment duration with all-cause mortality, controlling for age, race, stage, hormone receptor status, grade, comorbidity score, and doxorubicin use. Results Of 472 eligible patients, 28% (31% black, 23% white; P = .03) received fewer cycles of treatment than expected. Black race, receipt of ≤ 75% of the expected number of cycles, increasing age, hormone receptor negativity, and a comorbidity score of more than 1 were associated with poorer survival. Among the 344 patients receiving the expected number of cycles, 60% experienced delays. These delays did not reduce survival. Conclusion This study is the first to find that a substantial fraction of women with early-stage breast cancer terminated their chemotherapy prematurely and that early termination was associated with both black race and poorer survival. A better understanding of the determinants of suboptimal treatment may lead to interventions that can reduce racial disparities and improve breast cancer outcomes for all women.
Exempting dissenting patients from pay for performance schemes: retrospective analysis of exception reporting in the UK Quality and Outcomes Framework
Authors: T. Doran, E. Kontopantelis, C. Fullwood, H. Lester, J. M. Valderas, S. Campbell
Journal: BMJ (2012)

<b>Objective</b> To examine the reasons why practices exempt patients from the UK Quality and Outcomes Framework pay for performance scheme (exception reporting) and to identify the characteristics of general practices associated with informed dissent. <b>Design</b> Retrospective analysis. <b>Setting</b> Data for 2008-9 extracted from the clinical computing systems of general practices in England. <b>Participants</b> 8229 English family practices. <b>Main outcome measures</b> Rates of exception reporting for 37 clinical quality indicators, associations of patient and general practice factors with exception rates, and financial gain for practices relating to their use of exception reporting. <b>Results</b> The median rate of exception reporting was 2.7% (interquartile range 1.9-3.9%) overall and 0.44% (0.14-1.1%) for informed dissent, but variation in rates was wide between practices and across indicators. Common reasons for exception reporting were logistical (40.6% of exceptions), clinical contraindication (18.7%), and patient informed dissent (30.1%). Higher rates of informed dissent were associated with: higher numbers of registered patients, higher levels of local area deprivation, and failure of the practice to secure maximum remuneration in the previous year. Exception reporting increased the cost of the scheme by £30 844 500 (€36 877 700; $49 053 200) (£0.58 per patient), with two indicators accounting for a quarter of this additional cost. <b>Conclusions</b> The provision to exception report enables practices to exempt dissenting patients without being financially penalised. Relatively few patients were excluded for informed dissent, however, suggesting that the incentivised activities were broadly acceptable to patients.
Dissociation of E-4031 from the HERG channel caused by mutations of an amino acid results in greater block at high stimulation frequency
Authors: K Ishii
Journal: Cardiovascular Research (2003)

Objective: We have reported identification of the amino acid whose mutation reduces effects of quinidine on the HERG channel. Although the residue (isoleucine at 647) is not in the recently reported methanesulfonanilide binding site, a single concentration of E-4031 (10 μM) was less effective to I647 mutant channels than wild type HERG channel. We designed the present experiment to further investigate influence of mutations at 647 on the effects of methanesulfonanilides. Methods and results: HERG channels were expressed in Xenopus oocytes and their currents were measured by a two-microelectrode voltage clamp method. Of the two mutations initially studied (I647A and I647F), the I647F had a greater influence and differentially affected the effects of dofetilide and E-4031. The IC50 for dofetilide of the two mutant channels (I647A and I647F) was increased only 2-fold, but the IC50 for E-4031 was increased 6-fold (I647A) and 14-fold (I647F). Aromatic residues other than phenylalanine were then substituted for I647, and found to reduce the effects of E-4031. Whereas E-4031 dissociated from the mutant channels during rested state, dofetilide little dissociated. The mutant channels that showed recovery from E-4031 block were inhibited greater at 1 Hz than at 0.1 Hz. Conclusions: The present results indicate that dissociation of a drug from the HERG channel results in greater block at high frequency. Although the mechanism by which the mutations cause the dissociation of E-4031 is uncertain, it is noteworthy that one methanesulfonanilide dissociates from the channel more easily than another.
THE EFFECT OF PROTEOLYTIC DIGESTION PRODUCTS ON MULTIPLICATION AND MORPHOLOGICAL APPEARANCE OF MONOCYTES
Authors: Lillian E. Baker
Journal: The Journal of Experimental Medicine (1933)

It has been found that the enzymatic digestion products of proteins cause a rapid proliferation of blood monocytes in vitro. Digestion mixtures having anywhere from 12 to 68 per cent of their nitrogen in the amino form possess this property. For continued proliferation, heparin plasma or serum must be repeatedly supplied with the digests. Without them, multiplication continues for only a few days, the coagulum in which the cells are embedded liquefies around the central fragment, and the cells disintegrate. The enzymatic digests exert a marked effect on the morphological appearance of the cells and finally cause them to agglutinate. The extent of this effect is determined by the degree of hydrolysis of the digest, its concentration, and the length of time the cells are cultivated in it. The morphological appearance of the cells is also somewhat influenced by the nature of the plasma or serum used with the digest. Digests having very little free amino nitrogen produce short, round, granular cells. Those more highly hydrolyzed produce large, long, slender forms. An increase in the concentration of the digest in the medium causes a shortening and broadening of the cell and an increase in its granulations. Therefore, even a highly hydrolyzed digest may, if concentrated, give cells resembling those in a lower concentration of a less hydrolyzed one. The digests have a cumulative effect on the cells, as the time of cultivation is extended. Therefore, cultivation for a long period in a dilute solution may give the same effect as a shorter time in a higher concentration. A different effect is obtained if plasma is used with the digest than if serum is used, even when the plasma and serum are taken from the same animal. The monocytes cultivated in serum and digest are generally shorter, broader, and more granular than those cultivated in heparin plasma and digest. They also contain more fat and have a greater tendency to digest the clot. Agglutination of the cells takes place more readily in highly hydrolyzed products than in those slightly hydrolyzed. It is hastened by increase in concentration of the digest in the medium. It occurs more readily at the periphery of the culture and sooner in serum and digest than in heparin plasma and digest. Completely hydrolyzed proteins and mixtures of pure amino acids do not produce effects at all comparable to those of the enzymatic digests either in their effect on the rate of cell proliferation or their action on the morphology of the cell. Arsenic pentoxide in dilutions from 1:20,000 to 1:80,000 is the only other agent known to bring about agglutinations of the monocytes when cultivated in vitro. The early changes in the morphological appearance of the cell that are produced by these digests are reversible. When the digests are removed from the medium and the cells cultivated in plasma and Tyrode solution, they very gradually revert to their original form.
A Pathobiological Role of the Insulin Receptor in Chronic Lymphocytic Leukemia
Authors: Kamlai Saiya-Cork, Roxane Collins, Brian Parkin, Peter Ouillette, Erlene Kuizon, Lisa Kujawski, Harry Erba, Erica Campagnaro, Kerby Shedden, Mark Kaminski, Sami N. Malek
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The chromosomal deletion 11q affects biology and clinical outcome in chronic lymphocytic leukemia (CLL) but del11q-deregulated genes remain incompletely characterized. Experimental Design: We have employed integrated genomic profiling approaches on CLL cases with and without del11q to identify 11q-relevant genes. Results: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (∼10-fold higher mean levels than other genomic categories) was confirmed by quantitative PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through flow cytometry, compared with measurements in normal CD19+ B cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels. INSR stimulation by insulin in CLL cells ex vivo resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated spontaneous CLL cell apoptosis ex vivo. Higher INSR levels correlated with shorter time to first therapy and shorter overall survival (OS). In bivariate analysis, INSR expression predicted for rapid initial disease progression and shorter OS in ZAP-70–low/negative CLL. Finally, in multivariate analysis (ZAP-70 status, IgVH status, and INSR expression), we detected elevated HRs and trends for short OS for CLL cases with high INSR expression (analyzed inclusive or exclusive of cases with del11q). Conclusions: Our aggregate biochemical and clinical outcome data suggest biologically meaningful elevated INSR expression in a substantial subset of all CLL cases, including many cases with del11q. Clin Cancer Res; 17(9); 2679–92. ©2011 AACR.
Suppression of the Epithelial–Mesenchymal Transition by Grainyhead-like-2
Authors: Benjamin Cieply, Philip Riley, Phillip M. Pifer, Joseph Widmeyer, Joseph B. Addison, Alexey V. Ivanov, James Denvir, Steven M. Frisch
Journal: Cancer Research (2012)

Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-β dependence, we investigated the role of the Grainyhead gene, Grainyhead-like-2 (GRHL2) in oncogenic EMT. GRHL2 was downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir-200b/c as well as the TGF-β receptor antagonist, BMP2. Finally, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered an MET and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells.
Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON–TIMI 38 trial: a pharmacogenetic analysis
Authors: Jessica L Mega, Sandra L Close, Stephen D Wiviott, Lei Shen, Joseph R Walker, Tabassome Simon, Elliott M Antman, Eugene Braunwald, Marc S Sabatine
Journal: The Lancet (2010)