tbuckley/cabot-search huggingface dataset:
Phase I Dose-Escalation Trial of Checkpoint Kinase 1 Inhibitor MK-8776 As Monotherapy and in Combination With Gemcitabine in Patients With Advanced Solid Tumors
Authors: Adil I. Daud, Michelle T. Ashworth, Jonathan Strosberg, Jonathan W. Goldman, David Mendelson, Gregory Springett, Alan P. Venook, Sabine Loechner, Lee S. Rosen, Frances Shanahan, David Parry, Stuart Shumway, Jennifer A. Grabowsky, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, Randi Isaacs, Pamela N. Munster
Journal: Journal of Clinical Oncology (2015)

We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies.Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine.As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease.MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.
The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer
Authors: Cécile Badoual, Grégory Bouchaud, Nour El Houda Agueznay, Erwan Mortier, Stéphane Hans, Alain Gey, Fahima Fernani, Séverine Peyrard, Pierre Laurent -Puig, Patrick Bruneval, Xavier Sastre, Ariane Plet, Laure Garrigue-Antar, Françoise Quintin-Colonna, Wolf H. Fridman, Daniel Brasnu, Yannick Jacques, Eric Tartour
Journal: Cancer Research (2008)

Abstract Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor α (TNFα), IL-17, etc.]. A correlation between high intratumoral IL-15 concentrations and poor clinical outcome in lung and head and neck cancer patients has been recently reported. The purpose of this study was to investigate the role of the soluble α chain of IL-15 receptor (sIL-15Rα), a natural regulator of IL-15, in head and neck cancer. Fifty-three newly diagnosed untreated head and neck cancer patients were included in this study. Quantification of sIL-15Rα was performed with a newly developed RIA. Increased serum sIL-15Rα concentrations were found in head and neck cancer patients and were closely correlated with poor clinical outcome both in terms of locoregional control and survival even on multivariate analysis. sIL-15Rα was mainly produced by tumor cells via proteolytic cleavage of IL-15Rα mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15Rα concentrations. Surprisingly, sIL-15Rα did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15–induced proinflammatory cytokines (IL-6, TNFα, and IL-17) that may promote tumor progression. This new tumor evasion mechanism based on amplification of the intratumoral inflammatory reaction is probably not restricted to head and neck cancer, as other tumors have been shown to release sIL-15Rα. Overall, these results support for the first time an original protumor role of sIL-15Rα in cancer. [Cancer Res 2008;68(10):3907–14]
Pyrosequencing reveals transient cystic fibrosis lung microbiome changes with intravenous antibiotics
Authors: Daniel J. Smith, Alison C. Badrick, Martha Zakrzewski, Lutz Krause, Scott C. Bell, Gregory J. Anderson, David W. Reid
Journal: European Respiratory Journal (2014)

Chronic airway infection in adults with cystic fibrosis (CF) is polymicrobial and the impact of intravenous antibiotics on the bacterial community composition is poorly understood. We employed culture-independent molecular techniques to explore the early effects of i.v. antibiotics on the CF airway microbiome. DNA was extracted from sputum samples collected from adult subjects with CF at three time-points (before starting treatment, and at day 3 and day 8–10 of i.v. antibiotics) during treatment of an infective pulmonary exacerbation. Microbial community profiles were derived through analysis of bacterial-derived 16S ribosomal RNA by pyrosequencing and changes over time were compared. 59 sputum samples were collected during 24 pulmonary exacerbations from 23 subjects. Between treatment onset and day 3 there was a significant reduction in the relative abundance of Pseudomonas and increased microbial diversity. By day 8–10, bacterial community composition was similar to pre-treatment. Changes in community composition did not predict improvements in lung function. The relative abundance of Pseudomonas falls rapidly in subjects with CF receiving i.v. antibiotic treatment for a pulmonary exacerbation and is accompanied by an increase in overall microbial diversity. However, this effect is not maintained beyond the first week of treatment.
Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection
Authors: Stefania Varchetta, Dalila Mele, Stefania Mantovani, Barbara Oliviero, Eleonora Cremonesi, Serena Ludovisi, Giuseppe Michelone, Mario Alessiani, Riccardo Rosati, Marco Montorsi, Mario U. Mondelli
Journal: Hepatology (2012)

Hepatitis C virus (HCV) persistence in the host results from inefficiencies of innate and adaptive immune responses. Most studies addressing the role of innate immunity concentrated on peripheral blood (PB) natural killer (NK) cells, whereas only limited information is available on intrahepatic (IH) NK cells. We therefore examined phenotypic and functional features of IH and PB NK cells in paired liver biopsy and venous blood samples from 70 patients with chronic HCV infection and 26 control persons subjected to cholecystectomy for gallstones as controls. Ex vivo isolated IH NK cells from HCV-infected patients displayed unique phenotypic features, including increased expression of NKp46-activating receptor in the face of reduced tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and cluster of differentiation (CD) 107a expression, which resulted in impaired degranulation compared with controls. To gain insights into the effect of HCV on NK cells, we exposed peripheral blood mononuclear cells (PBMCs) from patients and healthy donors to cell-culture–derived HCV (HCVcc) and measured NK cell degranulation, TRAIL, and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. Exposure of PBMCs to HCVcc significantly boosted NK degranulation, pERK1/2, and TRAIL expression in healthy donors, but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-alpha. Purified NK cells showed a minimal, though significant, increase in degranulation and TRAIL expression, both in patients and controls, after exposure to HCVcc. Conclusions : These findings indicate dysfunctional IH NK cell cytotoxicity associated with TRAIL down-regulation in chronic HCV infection, which may contribute to virus persistence. PB NK cell impairment upon exposure to HCVcc suggests the existence of an accessory cell-dependent NK cell lytic defect in chronic HCV infection predominantly involving the TRAIL pathway.
Acute respiratory failure in hyperleukocytotic acute myeloid leukemia: The role of perfusion lung scintigraphy
Authors: A. Nagler, B. Brenner, E. Zuckerman, A. Hazani, O. Israel
Journal: American Journal of Hematology (1988)

Abstract A patient with acute hyperleukocytotic myelogenous leukemia who presented with acute respiratory distress is reported. Clinical manifestations included dyspnea, tachypnea, hyperventilation, and cyanosis. Blood gas analysis revealed hypoxemia, hypocapnia, and metabolic acidosis. Chest X‐ray and perfusion lung scanning were normal. Pulmonary leukostastis syndrome (PLS) was later confirmed at autopsy. In a patient with hyperleukocytosis from acute nonlymphocytic leukemia and respiratory distress, a normal perfusion lung scintigraph should make one consider the PLS.
Determining the Best Dose for the Individual Patient
Authors: Ron H.J. Mathijssen, Walter J. Loos, Jaap Verweij
Journal: Journal of Clinical Oncology (2011)

Dosing an anticancer drug may look quite simple at ﬁrst sight.The dose should be high enough to experience efﬁcacy, but not toohigh to avoid severe adverse effects. So the ultimate dose should besomewhere in the middle, the range called the therapeutic window.Unfortunately,thisdosingrangeisrathernarrowformanycytotoxicagents, which renders optimal dosing quite difﬁcult to start with. Inaddition,thetherapeuticwindowisdifferentforeachindividual,givenenvironmental and genetic factors, which adds an additional level ofcomplexity.Measuringplasmaexposure(pharmacokinetics[PK])ofthedrugofinterestpermitsreﬁningthedosefortheindividualpatient.Althoughmeasuringplasmaconcentrationsisonlyasurrogateforthedrug concentrations in the tumor, the plasma area under the curve(AUC)ofconcentrationversustimeisgenerallyassumedtobesufﬁ-cientlyrelatedtothepharmacodynamics(adverseeffectsandefﬁcacy)ofthatdrug.Topotecanisoneofthoseanticancerdrugswithanarrowthera-peutic window. This topoisomerase I inhibitor exists in two forms: apharmacologically active lactone form and an inactive carboxylateform.
Screening for Diabetes and Prediabetes Should Be Cost-Saving in Patients at High Risk
Authors: Ranee Chatterjee, K.M. Venkat Narayan, Joseph Lipscomb, Sandra L. Jackson, Qi Long, Ming Zhu, Lawrence S. Phillips
Journal: Diabetes Care (2013)

OBJECTIVE Although screening for diabetes and prediabetes is recommended, it is not clear how best or whom to screen. We therefore compared the economics of screening according to baseline risk. RESEARCH DESIGN AND METHODS Five screening tests were performed in 1,573 adults without known diabetes—random plasma/capillary glucose, plasma/capillary glucose 1 h after 50-g oral glucose (any time, without previous fast, plasma glucose 1 h after a 50-g oral glucose challenge [GCTpl]/capillary glucose 1 h after a 50-g oral glucose challenge [GCTcap]), and A1C—and a definitive 75-g oral glucose tolerance test. Costs of screening included the following: costs of testing (screen plus oral glucose tolerance test, if screen is positive); costs for false-negative results; and costs of treatment of true-positive results with metformin, all over the course of 3 years. We compared costs for no screening, screening everyone for diabetes or high-risk prediabetes, and screening those with risk factors based on age, BMI, blood pressure, waist circumference, lipids, or family history of diabetes. RESULTS Compared with no screening, cost-savings would be obtained largely from screening those at higher risk, including those with BMI &amp;gt;35 kg/m2, systolic blood pressure ≥130 mmHg, or age &amp;gt;55 years, with differences of up to −46% of health system costs for screening for diabetes and −21% for screening for dysglycemia110, respectively (all P &amp;lt; 0.01). GCTpl would be the least expensive screening test for most high-risk groups for this population over the course of 3 years. CONCLUSIONS From a health economics perspective, screening for diabetes and high-risk prediabetes should target patients at higher risk, particularly those with BMI &amp;gt;35 kg/m2, systolic blood pressure ≥130 mmHg, or age &amp;gt;55 years, for whom screening can be most cost-saving. GCTpl is generally the least expensive test in high-risk groups and should be considered for routine use as an opportunistic screen in these groups.
Road to recovery graph
Authors: Adam Meakins
Journal: British Journal of Sports Medicine (2015)

Von Willebrand disease (VWD) is considered the most common congenital bleeding abnormality in the world and an accurate diagnosis is often very challenging. Clinical laboratories usually provide screening assays along with more complex assays to aid clinicians with the diagnosis. These assays measure different properties and activities of von Willebrand factor. They may be adversely affected by numerous preanalytical variables and often have variable performance characteristics that may contribute to an inadequate interpretation. This review describes methods used in the laboratory for diagnosing VWD and basic mechanisms of each of these assays. A thorough understanding of the assays and associated preanalytical variables in VWD testing is essential for accurate diagnosis. <b>ABBREVIATIONS:</b>ADAMTS13 - a disintegrin and metalloproteinase with a thrombospondin type 1 motif, DDAVP - 1-desamino-8-D-arginine vasopressin, EC - endothelial cell, VWD - von Willebrand disease, VWF - von Willebrand factor, VWF:Ag - von Willebrand factor antigen, VWF:CBA - von Willebrand factor collagen binding assay, VWF:RCo - von Willebrand factor ristocetin cofactor activity
Myocardial Glucose Uptake Is Regulated by Nitric Oxide via Endothelial Nitric Oxide Synthase in Langendorff Mouse Heart
Authors: Hideo Tada, Carl I. Thompson, Fabio A. Recchia, Kit E. Loke, Manuel Ochoa, Carolyne J. Smith, Edward G. Shesely, Gabor Kaley, Thomas H. Hintze
Journal: Circulation Research (2000)

Abstract —Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (−/−)], and its heterozygote [ecNOS (+/−)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N ω -nitro- l -arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (−/−), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/−) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/−) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g · beats/min, L-NAME increased glucose uptake from 0.1±0.1 to 3±0.4 μg/min · mg in ecNOS (+/−) mice and from 0.2±0.1 to 2.7±0.7 μg/min · mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (−/−) mice, 8-bromoguanosine 3′:5′-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S -nitroso- N -acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/−) mice, 1 H -[1,2,4]oxadiazolo[4,3,- a ]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.
Differential Efficacy of Caspase Inhibitors on Apoptosis Markers during Sepsis in Rats and Implication for Fractional Inhibition Requirements for Therapeutics
Authors: Nathalie Méthot, JingQi Huang, Nathalie Coulombe, John P. Vaillancourt, Dita Rasper, John Tam, Yongxin Han, John Colucci, Robert Zamboni, Steven Xanthoudakis, Sylvie Toulmond, Donald W. Nicholson, Sophie Roy
Journal: The Journal of Experimental Medicine (2004)

A rodent model of sepsis was used to establish the relationship between caspase inhibition and inhibition of apoptotic cell death in vivo. In this model, thymocyte cell death was blocked by Bcl-2 transgene, indicating that apoptosis was predominantly dependent on the mitochondrial pathway that culminates in caspase-3 activation. Caspase inhibitors, including the selective caspase-3 inhibitor M867, were able to block apoptotic manifestations both in vitro and in vivo but with strikingly different efficacy for different cell death markers. Inhibition of DNA fragmentation required substantially higher levels of caspase-3 attenuation than that required for blockade of other apoptotic events such as spectrin proteolysis and phosphatidylserine externalization. These data indicate a direct relationship between caspase inhibition and some apoptotic manifestations but that small quantities of uninhibited caspase-3 suffice to initiate genomic DNA breakdown, presumably through the escape of catalytic quantities of caspase-activated DNase. These findings suggest that putative caspase-independent apoptosis may be overestimated in some systems since blockade of spectrin proteolysis and other cell death markers does not accurately reflect the high degrees of caspase-3 inhibition needed to prevent DNA fragmentation. Furthermore, this requirement presents substantial therapeutic challenges owing to the need for persistent and complete caspase blockade.
Raised IgG antiglobulin factors in Still's disease.
Authors: G Torrigiani, B M Ansell, E E Chown, I M Roitt
Journal: Annals of the Rheumatic Diseases (1969)

Still's disease (juvenile chronic polyarthritis) differs markedly from adult rheumatoid arthritis in the relative incidence of rheumatoid factor.The sheep cell agglutination test was found to be positive in only 11 to 13 per cent. of Still's disease patients compared with 70 to 80 per cent. of affected adults (Bywaters, Carter, and Scott, 1959; Laaksonen, 1966).Similarly, using the sensitive agglutination test with human FII coated erythrocytes, only 26 per cent. of definite cases of Still's disease gave titres of 1: 200 or more in contrast with an incidence of 87 per cent. in cases of classical and definite rheumatoid arthritis (Zutshi, Ansell, Bywaters, Epstein, Holborrow, and Reading, 1969).Since antibodies of the IgM class tend to be par- ticularly effective in agglutination reactions, it is likely that the conventional tests for rheumatoid factor minimize any possible contribution from anti- globulin factors in other immunoglobulin classes.Accordingly, we have recently developed a technique for the quantitative assessment of antiglobulin factors in the IgG, IgM, and IgA classes (Torrigiani and Roitt, 1967).The method depends upon the adsorption of antiglobulins on to insoluble cross- linked rabbit y-globulin, their subsequent elution from this complex, and estimation by single radial immunodiffusion using specific anti-immunoglobulin antisera.It was found that in addition to IgM antiglobulin factors, IgA antibodies were present in 50 per cent.and IgG antiglobulins in 100 per cent. of sero-positive adult rheumatoid arthritis patients.In the present investigation we have looked for anti- globulin factors in the sera of children with Still's disease using this quantitative technique. Material and MethodsClinical Material.-Thisconsisted of 35 cases of Still's disease, 26 classified as active (Ansell and Bywaters, 1959) and nine as inactive (Table, opposite).
Smad2 Mediates Transforming Growth Factor-β Induction of Endothelial Nitric Oxide Synthase Expression
Authors: Marta Saura, Carlos Zaragoza, Wangsen Cao, Clare Bao, Manuel Rodríguez-Puyol, Diego Rodríguez-Puyol, Charles J. Lowenstein
Journal: Circulation Research (2002)

Transforming growth factor-β (TGF-β) increases expression of endothelial nitric oxide synthase (eNOS), although the precise mechanism by which it does so is unclear. We report that Smad2, a transcription factor activated by TGF-β, mediates TGF-β induction of eNOS in endothelial cells. TGF-β induces Smad2 translocation from cytoplasm to nucleus, where it directly interacts with a specific region of the eNOS promoter. Overexpression of Smad2 increases basal levels of eNOS, and further increases TGF-β stimulation of eNOS expression. Ectopic expression of Smurf, an antagonizer of Smad2, decreases Smad2 expression and blocks TGF-β induction of eNOS. Because Smad2 can interact with a variety of transcription factors, coactivators, and corepressors, Smad2 may thus act as an integrator of multiple signals in the regulation of eNOS expression.
Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas
Authors: Annick Desjardins, David A. Reardon, James E. Herndon, Jennifer Marcello, Jennifer A. Quinn, Jeremy N. Rich, Sith Sathornsumetee, Sridharan Gururangan, John Sampson, Leighann Bailey, Darell D. Bigner, Allan H. Friedman, Henry S. Friedman, James J. Vredenburgh
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma. Experimental Design: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n = 24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m2 for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging. Results: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura. Conclusion: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.