tbuckley/cabot-search huggingface dataset:
Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia
Authors: Jay P. Patel, Mithat Gönen, Maria E. Figueroa, Hugo Fernandez, Zhuoxin Sun, Janis Racevskis, Pieter Van Vlierberghe, Igor Dolgalev, Sabrena Thomas, Olga Aminova, Kety Huberman, Janice Cheng, Agnes Viale, Nicholas D. Socci, Adriana Heguy, Athena Cherry, Gail Vance, Rodney R. Higgins, Rhett P. Ketterling, Robert E. Gallagher, Mark Litzow, Marcel R.M. van den Brink, Hillard M. Lazarus, Jacob M. Rowe, Selina Luger, Adolfo Ferrando, Elisabeth Paietta, Martin S. Tallman, Ari Melnick, Omar Abdel-Wahab, Ross L. Levine
Journal: New England Journal of Medicine (2012)

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML.We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients.We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67).We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).
THERAPEUTIC AND TOXIC EFFECTS OF CHLORPROMAZINE AMONG 3,014 HOSPITALIZED CASES
Authors: REUBEN M. CARES, EDWARD ASRICAN, MAURICE FENICHEL, PAUL SACK, JEAN SEVERINO
Journal: American Journal of Psychiatry (1957)

1. There were 3,014 cases admitted to treatment with chlorpromazine in doses of 200 to 400 mgm. daily during an 18-month period beginning January, 1955. 2. Response to treatment was best in agitated states of most mental disease categories. It was poorest in akinetic states with a good proportion showing a deepening of their depression. Side-effects were infrequent and not serious, appearing in the first 2 weeks and often subsiding on continued therapy. There were no permanent sequelae even after more than 18 months of medication. 3. Jaundice occurred in 13 patients, an incidence of 43%. No relation was found between the jaundice and amount or duration of dosage. 4. Leukopenia below 2,000 white blood cells cu. mm. was found in 3 patients (.11%) all of whom recovered on withdrawal of treatment. 5. Serial tests for total serum bilirubin, serum alkaline phosphatase plus complete blood cell counts were done on 1,215 cases. These periodic checks may have helped in maintaining a low incidence of toxic complications by sustaining clinical alertness. 6. During chlorpromazine therapy, the serum alkaline phosphatase rose more frequently than did the total serum bilirubin. Only one-fifth of the cases with alkaline phosphatase values over 8 units were jaundiced, a weak positive correlation. 7. Serial serum bilirubin and leukocyte counts during the first 4 months are useful in detecting the onset of toxic jaundice and/or leukopenia.
Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells
Authors: Toshiyuki Nakamura, Atsushi Watanabe, Takahiro Fujino, Takashi Hosono, Makoto Michikawa
Journal: Molecular Neurodegeneration (2009)

Apolipoprotein E allele epsilon4 (apoE4) is a strong risk factor for developing Alzheimer's disease (AD). Secreted apoE has a critical function in redistributing lipids among central nervous system cells to maintain normal lipid homeostasis. In addition, previous reports have shown that apoE4 is cleaved by a protease in neurons to generate apoE4(1-272) fragment, which is associated with neurofibrillary tanglelike structures and mitochondria, causing mitochondrial dysfunction. However, it still remains unclear how the apoE fragment associates with mitochondria and induces mitochondrial dysfunction.To clarify the molecular mechanism, we carried out experiments to identify intracellular apoE-binding molecules and their functions in modulating mitochondria function. Here, we found that apoE4 binds to ubiquinol cytochrome c reductase core protein 2 (UQCRC2) and cytochrome C1, both of which are components of mitochondrial respiratory complex III, and cytochrome c oxidase subunit 4 isoform 1 (COX IV 1), which is a component of complex IV, in Neuro-2a cells. Interestingly, these proteins associated with apoE4(1-272) more strongly than intact apoE4(1-299). Further analysis showed that in Neuro-2a cells expressing apoE4(1-272), the enzymatic activities of mitochondrial respiratory complexes III and IV were significantly lower than those in Neuro-2a cells expressing apoE4(1-299).ApoE4(1-272) fragment expressed in Neuro2a cells is associated with mitochondrial proteins, UQCRC2 and cytochrome C1, which are component of respiratory complex III, and with COX IV 1, which is a member of complex IV. Overexpression of apoE4(1-272) fragment impairs activities of complex III and IV. These results suggest that the C-terminal-truncated fragment of apoE4 binds to mitochondrial complexes and affects their activities, and thereby leading to neurodegeneration.
The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat.
Authors: A S Manning, K Kinoshita, E Buschmans, D J Coltart, D J Hearse
Journal: Circulation Research (1985)

It has been proposed that increases in tissue cyclic adenosine monophosphate during ischemia may be responsible for the induction of arrhythmias that occur during the early minutes of ischemia. We have tested this hypothesis using the isolated perfused rat heart with coronary artery occlusion for 30 minutes. In control hearts, after a transient small rise, cyclic adenosine monophosphate content remained close to its preischemic value (3.0 +/- 0.1 nM/g dry weight) throughout the period of occlusion. Eight percent (1/12) of the hearts fibrillated. Ninety-two percent (11/12) of the hearts exhibited ventricular tachycardia, and the mean total number of premature ventricular complexes was 528 +/- 121. Inclusion of epinephrine (1.0 microM) in the perfusion fluid elevated cyclic adenosine monophosphate prior to coronary occlusion (to 10.7 +/- 0.6 nM/g dry weight) and also throughout the ischemic period. It also increased arrhythmias such that 83% (20/24) of hearts fibrillated, 100% exhibited ventricular tachycardia, and the mean number of premature ventricular complexes increased to 747 +/- 86. Inclusion of forskolin (0.2 microM), which stimulates adenyl cyclase independently of the beta-receptor, increased cyclic adenosine monophosphate content to a greater extent than epinephrine, to 14.1 +/- 0.9 nM/g dry weight before the onset of ischemia and to 8.2 +/- 0.4 nM/g dry weight after 30 minutes of ischemia. Despite the large increase in cyclic adenosine monophosphate, there was no increase in rhythm disturbances which were less than those seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Pulmonary parenchymal tissue volume measurements in graded degrees of pulmonary edema in dogs.
Authors: F L Glauser, A F Wilson, L Carothers, J Higi, D White, J Davis
Journal: Circulation Research (1975)

We investigated the accuracy and the sensitivity of a modification of the acetylene inhalation technique for the determination of lung tissue volume (Vt) during various grades of hemodynamic pulmonary edema in 23 dogs. After base-line acetylene measurements were obtained, intravascular driving force (pulmonary wedge pressure minus intravascular colloid osmotic pressure) was varied between -8 and +71 mm Hg by the inflation of an intra-aortic ballon and the infusion of isotonic saline. After 30 minutes at this new driving force, four timed acetylene samples were again collected. Vt (when factored by alveolar volume, VA) increased from base line to 0.23 plus or minus 0.07 ml/ml between a driving force of 0 and + 17 mm Hg. This same change in Vt/VA was accompanied by an increase in the lung wet weight-dry weight ratio from 3.84 plus or minus 0.31 to 5.2 plus or minus 0.25. Vt was 271 plus or minus ml compared with an actual lung wet weight of 288 plus or minus 57 g; Vt tended to overestimate lung wet weight in severe pulmonary edema. Alloxan-induced pulmonary edema (6 dogs) tended to parallel these data. We conclude that the acetylene method may ve a relatively accurate noninvasive method for the determination of increasing lung water in pulmonary edema.
The promiscuous receptor: a case for the guardian enzyme
Authors: J. W. Funder
Journal: Cardiovascular Research (1995)

Journal Article The promiscuous receptor: a case for the guardian enzyme Get access John W. Funder John W. Funder Baker Medical Research Institute, PO Box 348, Prahran, Vic. 3181, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 30, Issue 2, August 1995, Pages 177–180, https://doi.org/10.1016/S0008-6363(96)88515-4 Published: 01 August 1995 Article history Received: 13 February 1995 Accepted: 13 March 1995 Published: 01 August 1995
HIV Testing, Counseling, and Prophylaxis After Sexual Assault
Authors: Lawrence O. Gostin
Journal: JAMA (1994)

THE IMPACT of possible infection with the human immunodeficiency virus (HIV) in survivors of sexual assault<sup>1</sup>has received little attention in the first decade of the acquired immunodeficiency syndrome (AIDS) epidemic. This may be due in part to society's conflicting attitudes and beliefs concerning sexually transmitted diseases (STDs), AIDS, and rape. The meaning of STDs historically has been shaped by powerful social and cultural constructions. These diseases often have been viewed as the result of socially unacceptable sexuality, a morally based failure of impulse control by individuals, and fair punishment for transgressing societal norms.<sup>2,3</sup>Similar moralistic reasoning often underlies the conventional wisdom concerning rape and AIDS. Rape, a violent crime where sex is used as a weapon, has been seen as the result of inappropriate seductive behavior or a sudden change of heart on the part of the victim who initially had consented to a sexual encounter.<sup>4</sup>
Elevated expression of the NLRP3 inflammasome in neutrophilic asthma
Authors: Jodie L. Simpson, Simon Phipps, Katherine J. Baines, Kevin M. Oreo, Lakshitha Gunawardhana, Peter G. Gibson
Journal: European Respiratory Journal (2013)

Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1β is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1β requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1β endotype associated with the nucleotide-binding domain, leucine-rich repeat-containing family protein (NLRP)3/apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)/caspase-1 inflammasome is characteristic of patients with the neutrophilic subtype of asthma. Participants with asthma (n=85) and healthy controls (n=27) underwent clinical assessment, spirometry and sputum induction. Sputum was processed for differential cell count, gene expression and protein mediators. NLRP3 and caspase-1 expression was also determined by immunocytochemistry. Sputum macrophages were isolated (n=8) and gene expression of NLRP3 and IL-1β determined. There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1β in participants with neutrophilic asthma. Protein levels of IL-1β were significantly higher in those with neutrophilic asthma and correlated with sputum IL-8 levels. Sputum macrophages, as well as sputum neutrophils in neutrophilic asthma, expressed NLRP3 and caspase-1 protein. NLRP3 inflammasome is upregulated in neutrophilic asthma and may regulate the inflammation process observed in this asthma phenotype through production of IL-1β.
Oxidized LDL and its Compound Lysophosphatidylcholine Potentiate AngII-Induced Vasoconstriction by Stimulation of RhoA
Authors: Jan Galle, Alexander Mameghani, Steffen-Sebastian Bolz, Stepan Gambaryan, Maria Görg, Thomas Quaschning, Ulrike Raff, Holger Barth, Stefan Seibold, Christoph Wanner, Ulrich Pohl
Journal: Journal of the American Society of Nephrology (2003)

RhoA stimulates vascular tone by increasing smooth muscle Ca(2+) sensitivity, e.g., in atherosclerosis. This study was an investigation of the influence of oxidized LDL (OxLDL), which accumulates in atherosclerotic plaques, on vascular tone induced by angiotensin II (AngII), with particular emphasis on the RhoA pathway. OxLDL had no influence on unstimulated vascular tone of isolated rabbit aorta, but it potentiated contractile responses induced by AngII. The Ca(2+)-antagonist felodipin partially prevented potentiation of contractile responses, whereas the AT(1) receptor antagonist losartan blunted AngII responses in presence and in absence of OxLDL. Rho-kinase inhibition by Y27632 abolished potentiation of contractile responses, and RhoA inhibition by C3-like transferase partially prevented it, suggesting that OxLDL activated RhoA. Activation of RhoA was further analyzed by detection of its translocation to the cell membrane after stimulation with OxLDL. Western blot analysis of aorta homogenates, as well as direct visualization in cultured smooth muscle cells using confocal laser scan microscopy, revealed that OxLDL potently activated RhoA. The effect of OxLDL was mimicked by its compound lysophosphatidylcholine, and C3 inhibited both lysophosphatidylcholine and OxLDL-induced RhoA stimulation. In conclusion, OxLDL stimulates the RhoA pathway, resulting in potentiation of AngII-induced vasoconstriction. Lysophosphatidylcholine mimics the OxLDL effect, consistent with a causal role of this OxLDL compound. Stimulation of RhoA by OxLDL may contribute to vasospasm in atherosclerotic arteries.
<b> <i>In vivo</i> </b> Detection of Gastric Cancer in Rats by Electron Paramagnetic Resonance Imaging
Authors: Tomiko Mikuni, Guanglong He, Sergey Petryakov, Mohanad M. Fallouh, Yuanmu Deng, Ryu Ishihara, Periannan Kuppusamy, Masaharu Tatsuta, Jay L. Zweier
Journal: Cancer Research (2004)

Abstract Electron paramagnetic resonance imaging (EPRI) enables noninvasive spatial mapping of free radical metabolism and has recently been shown to provide in vivo physiologic information regarding alterations in the redox state of tumors and neoplastic tissues. With the use of nitroxide spin probes, it has been shown that certain tumors possess a highly reduced state. To determine whether EPRI can be used for early detection and visualization of gastric carcinoma based on its altered redox metabolism, studies were performed in a rat gastric cancer model induced by 1-methyl-3-nitro-1-nitrosoguanidine. Using a specialized 750 MHz resonator and EPRI instrument, a technique was developed for imaging nitroxide radicals in the whole stomach. In vivo three-dimensional EPRI of the stomach of rats with continuous intravenous administration of nitroxide 3-carboxamido-2,2,5,5-tetramethylpyrrolidine-N-oxyl (3-carbamoyl-proxyl) [3-CP] was performed. Whereas electron paramagnetic resonance images from untreated controls provide a uniform visualization of the stomach mucosa and wall, in the treated rats with gastric cancer, holes were present in the image at the locations of tumors. With localized spectroscopy, it was confirmed that the tumor regions were devoid of signal, and this was largely due to the presence of a more reduced state with rapid reduction of nitroxide. Pharmacokinetic studies indicated that 3-CP in tumors was rapidly reduced to an undetectable level, whereas the 3-CP levels in normal stomach tissue persisted. Near-infrared reflectance measurements of indocyanine green dye uptake indicated that there were no significant differences in tumor versus normal mucosal perfusion. From these results, we concluded that gastric cancer tumors could be distinguished from normal tissue based primarily on the marked difference in their rate of radical metabolism. Because alterations in cellular redox state and radical metabolism are of critical importance in tumor biology and treatment, this methodology should provide an important new tool for the study and visualization of gastric carcinoma and may also be of use in other cancer models.
Heparin-Coated Stent Placement for the Treatment of Stenoses in Small Coronary Arteries of Symptomatic Patients
Authors: Michael Haude, Thomas F.M. Konorza, Uldis Kalnins, Andrejs Erglis, Kari Saunamäki, Helmut D. Glogar, Eberhard Grube, Robert Gil, Antonio Serra, Hans G. Richardt, Peter Sick, Raimund Erbel
Journal: Circulation (2003)

Background— The role of stents, especially of heparin-coated stents for the treatment of stenoses in small coronary arteries, is still unclear. Therefore, we performed this prospective, randomized trial to evaluate the angiographic and clinical outcome after treatment of stenoses in small coronary arteries (2.0 to 2.6 mm) of symptomatic patients. Methods and Results— We randomly assigned 588 patients to angioplasty (n=195), bare stenting (n=196), or heparin-coated stenting (n=197). The primary end point was minimal lumen diameter (MLD) at 6 months. With comparable baseline parameters, the two stent arms showed a larger postinterventional MLD, larger acute gain, and smaller residual percent diameter stenosis, although a residual stenosis of 12±16% was achieved in the angioplasty arm, including a 27% crossover rate to stenting. Eighty percent of patients had follow-up angiography, which documented a borderline significantly larger MLD and smaller percent diameter stenosis for the two stent groups (1.34±0.48 mm and 42±20% after angioplasty, 1.47±0.48 mm and 36±20% after bare stenting, and 1.45±0.54 mm and 38±23% after heparin-coated stenting; P =0.049 and P =0.038, respectively), but restenosis rates were not different (32%, 25%, and 30%). Thrombotic events occurred in 1.0% after angioplasty and 0.5% after bare or heparin-coated stenting. Survival without myocardial infarction or target vessel revascularization at 250 days was 84.6% (angioplasty), 88.3% (bare stenting), and 88.3% (heparin-coated stenting; log-rank P =0.39). Conclusion— Compared with angioplasty with provisional stenting, bare and heparin-coated stenting confer superior angiographic results and a nonsignificant 24% reduction in clinical events, with no difference between bare and heparin-coated stenting in the treatment of stenoses in small coronary arteries.
Effect of Telephone vs Video Interpretation on Parent Comprehension, Communication, and Utilization in the Pediatric Emergency Department
Authors: K. Casey Lion, Julie C. Brown, Beth E. Ebel, Eileen J. Klein, Bonnie Strelitz, Colleen Kays Gutman, Patty Hencz, Juan Fernandez, Rita Mangione-Smith
Journal: JAMA Pediatrics (2015)

Consistent professional interpretation improves communication with patients who have limited English proficiency. Remote modalities (telephone and video) have the potential for wide dissemination.To test the effect of telephone vs. video interpretation on communication during pediatric emergency care.Randomized trial of telephone vs. video interpretation at a free-standing, university-affiliated pediatric emergency department (ED). A convenience sample of 290 Spanish-speaking parents of pediatric ED patients with limited English proficiency were approached from February 24 through August 16, 2014, of whom 249 (85.9%) enrolled; of these, 208 (83.5%) completed the follow-up survey (91 parents in the telephone arm and 117 in the video arm). Groups did not differ significantly by consent or survey completion rate, ED factors (eg, ED crowding), child factors (eg, triage level, medical complexity), or parent factors (eg, birth country, income). Investigators were blinded to the interpretation modality during outcome ascertainment. Intention-to-treat data were analyzed August 25 to October 20, 2014.Telephone or video interpretation for the ED visit, randomized by day.Parents were surveyed 1 to 7 days after the ED visit to assess communication and interpretation quality, frequency of lapses in interpreter use, and ability to name the child's diagnosis. Two blinded reviewers compared parent-reported and medical record-abstracted diagnoses and classified parent-reported diagnoses as correct, incorrect, or vague.Among 208 parents who completed the survey, those in the video arm were more likely to name the child's diagnosis correctly than those in the telephone arm (85 of 114 [74.6%] vs. 52 of 87 [59.8%]; P = .03) and less likely to report frequent lapses in interpreter use (2 of 117 [1.7%] vs. 7 of 91 [7.7%]; P = .04). No differences were found between the video and telephone arms in parent-reported quality of communication (101 of 116 [87.1%] vs. 74 of 89 [83.1%]; P = .43) or interpretation (58 of 116 [50.0%] vs. 42 of 89 [47.2%]; P = .69). Video interpretation was more costly (per-patient mean [SD] cost, $61 [$36] vs. $31 [$20]; P < .001). Parent-reported adherence to the assigned modality was higher for the video arm (106 of 114 [93.0%] vs .68 of 86 [79.1%]; P = .004).Families with limited English proficiency who received video interpretation were more likely to correctly name the child's diagnosis and had fewer lapses in interpreter use. Use of video interpretation shows promise for improving communication and patient care in this population.clinicaltrials.gov Identifier: NCT01986179.