tbuckley/cabot-search huggingface dataset:
Dextromethorphan As a Phenotyping Test to Predict Endoxifen Exposure in Patients on Tamoxifen Treatment
Authors: Anne-Joy M. de Graan, Sebastiaan F. Teunissen, Filip Y.F.L. de Vos, Walter J. Loos, Ron H.N. van Schaik, Felix E. de Jongh, Aad I. de Vos, Robbert J. van Alphen, Bronno van der Holt, Jaap Verweij, Caroline Seynaeve, Jos H. Beijnen, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2011)

Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics.In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated.A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure.Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.
<i>Plasmodium falciparum</i> Phospholipase C Hydrolyzing Sphingomyelin and Lysocholinephospholipids Is a Possible Target for Malaria Chemotherapy
Authors: Kentaro Hanada, Nirianne Marie Q. Palacpac, Pamela A. Magistrado, Ken Kurokawa, Ganesh Rai, Daiji Sakata, Tomoko Hara, Toshihiro Horii, Masahiro Nishijima, Toshihide Mitamura
Journal: The Journal of Experimental Medicine (2001)

Sphingomyelinase (SMase) is one of the principal enzymes in sphingomyelin (SM) metabolism. Here, we identified a Plasmodium falciparum gene (PfNSM) encoding a 46-kD protein, the amino acid sequence of which is ∼25% identical to that of bacteria SMases. Biochemical analyses of the recombinant protein GST-PfNSM, a fusion protein of the PfNSM product with glutathione-S-transferase, reveal that this enzyme retained similar characteristics in various aspects to SMase detected in P. falciparum–infected erythrocytes and isolated parasites. In addition, the recombinant protein retains hydrolyzing activity not only of SM but also of lysocholinephospholipids (LCPL) including lysophosphatidylcholine and lysoplatelet-activating factor, indicating that PfNSM encodes SM/LCPL-phospholipase C (PLC). Scyphostatin inhibited SM/LCPL-PLC activities of the PfNSM product as well as the intraerythrocytic proliferation of P. falciparum in a dose-dependent manner with ID50 values for SM/LCPL-PLC activities and the parasite growth at 3–5 μM and ∼7 μM, respectively. Morphological analysis demonstrated most severe impairment in the intraerythrocytic development with the addition of scyphostatin at trophozoite stage than at ring or schizont stages, suggesting its effect specifically on the stage progression from trophozoite to schizont, coinciding with the active transcription of PfNSM gene.
Cited1 Is a Bifunctional Transcriptional Cofactor That Regulates Early Nephronic Patterning
Authors: Sergey Plisov, Michael Tsang, Genbin Shi, Scott Boyle, Kiyoshi Yoshino, Sally L. Dunwoodie, Igor B. Dawid, Toshi Shioda, Alan O. Perantoni, Mark P. de Caestecker
Journal: Journal of the American Society of Nephrology (2005)

In a screen to identify factors that regulate the conversion of mesenchyme to epithelium during the early stages of nephrogenesis, it was found that the Smad4-interacting transcriptional cofactor, Cited1, is expressed in the condensed cap mesenchyme surrounding the tip of the ureteric bud (UB), is downregulated after differentiation into epithelia, and has the capacity to block UB branching and epithelial morphogenesis in cultured metanephroi. Cited1 represses Wnt/beta-catenin but activates Smad4-dependent transcription involved in TGF-beta and Bmp signaling. By modifying these pathways, Cited1 may coordinate cellular differentiation and survival signals that regulate nephronic patterning in the metanephros.
Long-Term Effects of Increased Glucose Entry on Mouse Hearts During Normal Aging and Ischemic Stress
Authors: Ivan Luptak, Jie Yan, Lei Cui, Mohit Jain, Ronglih Liao, Rong Tian
Journal: Circulation (2007)

A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile, but its role in the pathogenesis of cardiac diseases is incompletely understood.We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared with wild-type litter mates, the GLUT1-TG mice showed a normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure-volume studies in isolated perfused hearts in the 2-year period. Furthermore, when hearts were subjected to ischemia-reperfusion, cardiac function of young and old GLUT1-TG recovered to the same level (86% and 83%, respectively) and exceeded that of both young and old wild-type hearts (52% and 35%, respectively; P<0.05). Nuclear magnetic resonance spectroscopic measurements with 31P showed delayed ATP depletion, reduced acidosis during ischemia, and improved recovery of high-energy phosphate content in old GLUT1-TG hearts (P<0.05 versus old wild-type). During reperfusion, glucose oxidation was 3-fold higher and fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared with old wild-type (P<0.05), which suggests that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts.We have demonstrated that a normal heart is able to adapt to long-term increases in basal glucose entry into cardiomyocytes without development of glucotoxicity. Furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.
Genetic Risk Score Constructed Using 14 Susceptibility Alleles for Type 2 Diabetes Is Associated With the Early Onset of Diabetes and May Predict the Future Requirement of Insulin Injections Among Japanese Individuals
Authors: Minoru Iwata, Shiro Maeda, Yutaka Kamura, Atsuko Takano, Hiromi Kato, Shihou Murakami, Kiyohiro Higuchi, Atsushi Takahashi, Hayato Fujita, Kazuo Hara, Takashi Kadowaki, Kazuyuki Tobe
Journal: Diabetes Care (2012)

We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes.We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to β-cell function (β-GRS) and then assessing the association between each GRS and the clinical features.Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 × 10(-21)). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = -0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = -0.032, SE = 0.0140, P = 0.022), and C-peptide index (β = -0.031, SE = 0.012, P = 0.0125).Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell-preserving therapy.
Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.
Authors: M Ziche, L Morbidelli, E Masini, S Amerini, H J Granger, C A Maggi, P Geppetti, F Ledda
Journal: Journal of Clinical Investigation (1994)

We evaluated the effects of nitric oxide (NO) generators and endogenous production of NO elicited by substance P (SP) in the angiogenesis process. Angiogenesis was monitored in the rabbit cornea in vivo and in vitro by measuring the growth and migration of endothelial cells isolated from coronary postcapillary venules. The angiogenesis promoted in the rabbit cornea by [Sar9]-SP-sulfone, a stable and selective agonist for the tachykinin NK1 receptor, and by prostaglandin E1 (PGE1), was potentiated by sodium nitroprusside (SNP). Conversely, the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), given systemically, inhibited angiogenesis elicited by [Sar9]-SP-sulfone and by PGE1. Endothelial cells exposed to SNP exhibited an increase in thymidine incorporation and in total cell number. Exposure of the cells to NO generating drugs, such as SNP, isosorbide dinitrate, and glyceryl trinitrate, produced a dose-dependent increase in endothelial cell migration. Capillary endothelial cell proliferation and migration produced by SP were abolished by pretreatment with the NO synthase inhibitors N omega-mono-methyl-L-arginine (L-NMMA), N omega-nitro-L-arginine (L-NNA), and L-NAME. Exposure of the cells to SP activated the calcium-dependent NO synthase. Angiogenesis and endothelial cell growth and migration induced by basic fibroblast growth factor were not affected by NO synthase inhibitors. These data indicate that NO production induced by vasoactive agents, such as SP, functions as an autocrine regulator of the microvascular events necessary for neovascularization and mediates angiogenesis.
Functional Analysis of PKD1 Transgenic Lines Reveals a Direct Role for Polycystin-1 in Mediating Cell-Cell Adhesion
Authors: Andrew J. Streets, Linda J. Newby, Michael J. O’Hare, Nikolay O. Bukanov, Oxana Ibraghimov-Beskrovnaya, Albert C.M. Ong
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The PKD1 protein, polycystin-1, is a large transmembrane protein of uncertain function and topology. To study the putative functions of polycystin-1, conditionally immortalized kidney cells transgenic for PKD1 were generated and an interaction between transgenic polycystin-1 and endogenous polycystin-2 has been recently demonstrated in these cells. This study provides the first functional evidence that transgenic polycystin-1 directly mediates cell-cell adhesion. In non-permeabilized cells, polycystin-1 localized to the lateral cell borders with N-terminal antibodies but not with a C-terminal antibody; there was a clear difference in surface intensity between transgenic and non-transgenic cells. Compared with non-transgenic cells, transgenic cells showed a dramatic increase in resistance to the disruptive effect of a polycystin-1 antibody raised to the PKD domains of polycystin-1 (IgPKD) in both cell adhesion and cell aggregation assays. The differential effect on cell adhesion between transgenic and non-transgenic cells could be reproduced using recombinant fusion proteins encoding non-overlapping regions of the IgPKD domains. In contrast, antibodies raised to other extracellular domains of polycystin-1 had no effect on cell adhesion. Finally, the specificity of this finding was confirmed by the lack of effect of IgPKD antibody on cell adhesion in a PKD1 cystic cell line deficient in polycystin-1. These results demonstrate that one of the primary functions of polycystin-1 is to mediate cell-cell adhesion in renal epithelial cells, probably via homophilic or heterophilic interactions of the PKD domains. Disruption of cell-cell adhesion during tubular morphogenesis may be an early initiating event for cyst formation in ADPKD. E-mail: [email protected]
Ethics and the Law: Is There Common Ground on Informed Consent for Disparities in Hospital Outcomes?
Authors: Nadine Housri, Mary Coombs, Babak J. Orandi, Timothy M. Pawlik, Leonidas G. Koniaris
Journal: Annals of Internal Medicine (2011)

The association between procedure volume at institutions and outcomes of cancer surgeries has been widely published in the medical literature; discussed in the lay press; and, during the past 15 years, incorporated into quality improvement endeavors. In certain cases, institutional volume has become a proxy for quality. Despite the vast amount of retrospective data on this topic, physicians generally have been unsure how to approach the information and interpret it for their patients. Even more challenging to some physicians has been deciding whether the data oblige them to either direct patients with cancer to high-volume centers for care or discuss the data with these patients as part of informed consent. An additional challenge is that physicians must understand laws related to these issues and that these laws are unclear. This article reviews the ethical arguments for including disparities in hospital outcomes as part of informed consent and examines whether legal precedent can shed light on this debate.
Comment on Hillis et al. The Relative and Combined Ability of High-Sensitivity Cardiac Troponin T and N-Terminal Pro-B-Type Natriuretic Peptide to Predict Cardiovascular Events and Death in Patients With Type 2 Diabetes. Diabetes Care 2014;37:295–303
Authors: Stephanie Neuhold, Richard Pacher, Martin Hülsmann
Journal: Diabetes Care (2014)

We have read the study by Hillis et al. (1) about N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the context of diabetes with great interest. After our publications on this topic (2,3) and the Casale Monferrato Study (4), this is now the third well-adjusted cohort showing the ability of NT-proBNP as a risk marker for cardiovascular disease in this setting. We agree that the clinical relevance still has to be proven in future trials. In particular, the question of whether biomarkers like NT-proBNP or troponin can identify subgroups of patients who benefit the most from therapy is of considerable importance. Due to limited resources, there are conflicts of interest between low-risk and high-risk patients. This, by the way, resulted …
Skills Training or Occupational Therapy for Persistent Schizophrenia
Authors: MARGARET DRAKE, CAROL TUBBS, JOYCE TITUS, LORRAINE STREET, PETER GIROUX, BETTE GROAT, DONA LEE ANDREWS, ROBIN DAVIS, ROSEMARY TENNANT, AMELIA BARBARA EDWARDS, PATSY HESTER
Journal: American Journal of Psychiatry (1999)
Urinary excretion of beta 2-microglobulin predicts renal outcome in patients with idiopathic membranous nephropathy.
Authors: L J Reichert, R A Koene, J F Wetzels
Journal: Journal of the American Society of Nephrology (1995)

In patients with membranous nephropathy, treatment should be limited to those at risk for disease progression. Urinary beta 2-microglobulin excretion was measured in 30 patients with membranous nephropathy, a nephrotic syndrome, and normal renal function (endogenous creatinine clearance > 80 mL/min), who were subsequently monitored for a median of 48 months. Renal function deteriorated in 11 of the 14 patients with a beta 2-microglobulin excretion > 500 ng/min and in only 2 of the 16 patients with a beta 2-microglobulin excretion < or = 500 ng/min (P < 0.001). The measurement of urinary beta 2-microglobulin excretion thus contributes to the identification of patients with membranous nephropathy at high risk for developing renal insufficiency and may provide guidance for early immunosuppressive treatment.
Large Scale Implementation of a Respiratory Therapist– driven Protocol for Ventilator Weaning
Authors: E. WESLEY ELY, PATRICIA A. BENNETT, DAVID L. BOWTON, SEAN M. MURPHY, ALLISON M. FLORANCE, EDWARD F. HAPONIK
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We prospectively investigated the large-scale implementation of a respiratory-therapist–driven protocol (TDP) that included 117 respiratory care practitioners (RCPs) managing 1,067 patients with respiratory failure over 9,048 patient days of mechanical ventilation. During a 12-mo period, we reintroduced a previously validated protocol that included a daily screen (DS) coupled with spontaneous breathing trials (SBTs) and physician prompt, as a TDP without daily input from a physician or "weaning team." With graded, staged educational interventions at 2-mo intervals, RCPs had a 97% completion rate and a 95% correct interpretation rate for the DS. The frequency with which patients who passed the DS underwent SBTs increased throughout the implementation process (p < 0.001). As the year progressed, RCPs more often considered SBTs once patients had passed a DS (p < 0.001), and physicians ordered more SBTs (46 versus 65%, p = 0.004). Overall, SBTs were ordered more often on the medicine than on the surgical services (81 versus 63%, p = 0.001), likely reflecting medical intensivists' prior use of this protocol. Important barriers to protocol compliance were identified through a questionnaire (89 respondents, 76%), and included: Physician unfamiliarity with the protocol, RCP inconsistency in seeking an order for an SBT from the physician, specific reasons cited by the physician for not advancing the patient to a SBT, and lack of stationary unit assignments by RCPs performing the protocol. We conclude that implementation of a validated weaning strategy is feasible as a TDP without daily supervision from a weaning physician or team. RCPs can appropriately perform and interpret DS data more than 95% of the time, but significant barriers to SBTs exist. Through a staged implementation process, using periodic reinforcement of all participants in ventilator management, improved compliance with this large-scale weaning protocol can be achieved.
ASC/caspase-1/IL-1β signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury
Authors: Naoko Kamo, Bibo Ke, Amir A. Ghaffari, Xiu-da Shen, Ronald W. Busuttil, Genhong Cheng, Jerzy W. Kupiec-Weglinski
Journal: Hepatology (2013)

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation and the consequent secretion of interleukin-1β (IL-1β), which is associated with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known about the mechanisms by which the ASC/caspase-1/IL-1β axis exerts its function in hepatic IRI. This study was designed to explore the functional roles and molecular mechanisms of ASC/caspase-1/IL-1β signaling in the regulation of inflammatory responses in vitro and in vivo. With a partial lobar liver warm ischemia (90 minutes) model, ASC-deficient and wild-type mice (C57BL/6) were sacrificed at 6 hours of reperfusion. Separate animal cohorts were treated with an anti-IL-1β antibody or control immunoglobulin G (10 mg/kg/day intraperitoneally). We found that ASC deficiency inhibited caspase-1/IL-1β signaling and led to protection against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic functions, and down-regulation of high mobility group box 1 (HMGB1)-mediated, toll-like receptor 4 (TLR4)-driven inflammation. Interestingly, the treatment of ASC-deficient mice with recombinant HMGB1 re-created liver IRI. Moreover, neutralization of IL-1β ameliorated the hepatocellular damage by inhibiting nuclear factor kappa B (NF-κB)/cyclooxygenase 2 signaling in IR-stressed livers. In parallel in vitro studies, the knockout of ASC in lipopolysaccharide-stimulated bone marrow-derived macrophages depressed HMGB1 activity via the p38 mitogen-activated protein kinase pathway and led to the inhibition of TLR4/NF-κB and ultimately the depression of proinflammatory cytokine programs.ASC-mediated caspase-1/IL-1β signaling promotes HMGB1 to produce a TLR4-dependent inflammatory phenotype and leads to hepatocellular injury. Hence, ASC/caspase-1/IL-1β signaling mediates the inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide a rationale for a novel therapeutic strategy for managing liver injury due to IR.
Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2
Authors: Stefan Joos, Christiane K. Menz, Gunnar Wrobel, Reiner Siebert, Stefan Gesk, Sibylle Ohl, Gunhild Mechtersheimer, Lorenz Trümper, Peter Möller, Peter Lichter, Thomas F. E. Barth
Journal: Blood (2002)
IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants
Authors: William J. Burlingham, Robert B. Love, Ewa Jankowska-Gan, Lynn D. Haynes, Qingyong Xu, Joseph L. Bobadilla, Keith C. Meyer, Mary S. Hayney, Ruedi K. Braun, Daniel S. Greenspan, Bagavathi Gopalakrishnan, Junchao Cai, David D. Brand, Shigetoshi Yoshida, Oscar W. Cummings, David S. Wilkes
Journal: Journal of Clinical Investigation (2007)

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture's syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.
Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival
Authors: Mari M. Kitahata, Stephen J. Gange, Alison G. Abraham, Barry Merriman, Michael S. Saag, Amy C. Justice, Robert S. Hogg, Steven G. Deeks, Joseph J. Eron, John T. Brooks, Sean B. Rourke, M. John Gill, Ronald J. Bosch, Jeffrey N. Martin, Marina B. Klein, Lisa P. Jacobson, Benigno Rodriguez, Timothy R. Sterling, Gregory D. Kirk, Sonia Napravnik, Anita R. Rachlis, Liviana M. Calzavara, Michael A. Horberg, Michael J. Silverberg, Kelly A. Gebo, James J. Goedert, Constance A. Benson, Ann C. Collier, Stephen E. Van Rompaey, Heidi M. Crane, Rosemary G. McKaig, Bryan Lau, Aimee M. Freeman, Richard D. Moore
Journal: New England Journal of Medicine (2009)

The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.