tbuckley/cabot-search huggingface dataset:
High Prognostic Impact of Flow Cytometric Minimal Residual Disease Detection in Acute Myeloid Leukemia: Data From the HOVON/SAKK AML 42A Study
Authors: Monique Terwijn, Wim L.J. van Putten, Angèle Kelder, Vincent H.J. van der Velden, Rik A. Brooimans, Thomas Pabst, Johan Maertens, Nancy Boeckx, Georgine E. de Greef, Peter J.M. Valk, Frank W.M.B. Preijers, Peter C. Huijgens, Angelika M. Dräger, Urs Schanz, Mojca Jongen-Lavrecic, Bart J. Biemond, Jakob R. Passweg, Michel van Gelder, Pierre Wijermans, Carlos Graux, Mario Bargetzi, Marie-Cecile Legdeur, Jurgen Kuball, Okke de Weerdt, Yves Chalandon, Urs Hess, Leo F. Verdonck, Jan W. Gratama, Yvonne J.M. Oussoren, Willemijn J. Scholten, Jennita Slomp, Alexander N. Snel, Marie-Christiane Vekemans, Bob Löwenberg, Gert J. Ossenkoppele, Gerrit J. Schuurhuis
Journal: Journal of Clinical Oncology (2013)

Half the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers.In adults (younger than age 60 years) with AML enrolled onto the Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy).After all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (> 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment time-dependent covariate risk score and early or later CR.In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.
Cellobiose/mannitol sugar permeability test complements biopsy histopathology in clinical investigation of the jejunum.
Authors: S Strobel, W G Brydon, A Ferguson
Journal: Gut (1984)

Intestinal permeability to probe molecules has been shown to correlate closely with the presence or absence of villous atrophy in a jejunal biopsy. The purpose of this study was to establish if there exist groups of patients with functional derangement of intestinal permeability but normal histopathology of the small bowel mucosa. In 135 patients a cellobiose/mannitol permeability test was performed at the same time as jejunal biopsy. Diagnosis included coeliac disease, Crohn9s disease, irritable bowel syndrome, idiopathic diarrhoea, self diagnosed food allergy, atopic eczema and postinfectious malabsorption. The value of the cellobiose/mannitol test in identifying patients with abnormal jejunal biopsy histopathology was confirmed. The permeability test was abnormal in all 28 patients with partial or subtotal villous atrophy, and also in all 10 in whom there was a high intraepithelial lymphocyte count despite normal villi and crypts. Functional abnormality of the small intestine has not previously been reported in patients with this jejunal biopsy abnormality. Abnormalities of permeability were also found in patients with idiopathic diarrhoea, folate deficiency, postinfectious or traveller9s diarrhoea, small bowel Crohn9s disease, and atopic eczema. These results show that sugar permeability tests have more potential in clinical investigation than merely serving as screening tests before jejunal biopsy. There are groups of patients without morphological changes in the small bowel in whom intestinal permeability is abnormal.
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Authors: Paul B. Chapman, Axel Hauschild, Caroline Robert, John B. Haanen, Paolo Ascierto, James Larkin, Reinhard Dummer, Claus Garbe, Alessandro Testori, Michele Maio, David Hogg, Paul Lorigan, Celeste Lebbe, Thomas Jouary, Dirk Schadendorf, Antoni Ribas, Steven J. O'Day, Jeffrey A. Sosman, John M. Kirkwood, Alexander M.M. Eggermont, Brigitte Dreno, Keith Nolop, Jiang Li, Betty Nelson, Jeannie Hou, Richard J. Lee, Keith T. Flaherty, Grant A. McArthur
Journal: New England Journal of Medicine (2011)

Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.
The role of gene products of the I-J subregion in mixed lymphocyte reactions.
Authors: K Okuda, C S David, D C Shreffler
Journal: The Journal of Experimental Medicine (1977)

We have examined the MLR reaction in two sets of recombinants that differ in the I-J subregion. In both cases, significant stimulation was mediated by antigens controlled by genes in the I-J subregion. This stimulation was inhibitable by the addition of the culture of antisera directed against the I-J gene products on the stimulator cell. The specificity of this inhibition was shown by specific blocking of the relevant gene product on F1 hybrid stimulator cells. MLR stimulation was also eliminated by pretreatment of the stimulator population with anti-I-J sera plus complement. Pretreatment of F1 hybrid stimulator T cells with anti-I-J sera directed against either parental I-J product in the presence of complement, completely eliminated stimulation, indicating that there is no allelic exclusion of the relevant I-J products. Pretreatment with an anti-I-E/I-C serum and complement also eliminated stimulation, suggesting that the stimulating T cells express both I-J and I-E/I-C subregion products. This assay offers a potentially more direct and practical method for serological detection of the I-J products.
Physical work and chronic shoulder disorder. Results of a prospective population-based study
Authors: H Miranda, L Punnett, E Viikari-Juntura, M Heliövaara, P Knekt
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> A study of whether occupational physical load predicted subsequent chronic shoulder disorders. <h3>Methods:</h3> A comprehensive national survey was carried out among a representative sample (n = 7217) of the Finnish adult population in 1977–80. Twenty years later, 1286 participants from the previous survey were invited to be re-examined, and 909 (71%) participated. After excluding those with diagnosed shoulder disorders at baseline, 883 subjects were available for the analyses. <h3>Results:</h3> At follow-up, a physician diagnosed chronic shoulder disorders in 63 subjects (7%) using a standardised protocol. Work exposure to repetitive movements and vibration at baseline increased the risk of shoulder disorder: adjusted ORs 2.3 (95% CI 1.3 to 4.1) and 2.5 (1.2 to 5.2), respectively. Exposure to several physical factors increased the risk further, the adjusted OR was nearly 4 for at least three exposures. The adverse effects of physical work were seen even among those older than 75 years at follow-up. The statistically significant risk factors differed between genders: for men vibration and repetitive movements, and for women lifting heavy loads and working in awkward postures. Age and body mass index modified the effects of the physical exposures. The results remained similar after excluding those with any shoulder pain at baseline. <h3>Conclusions:</h3> This is the first prospective study in a general population showing that occupational physical loading increases the risk of a subsequent clinical shoulder disorder and the effects seem to be long-term. Early preventive measures at the workplace may have long-lasting health benefits for the shoulder.
Some of the People, Some of the Time
Authors: Penelope A. Bryant, Roy Robins-Browne, Jonathan R. Carapetis, Nigel Curtis
Journal: Circulation (2009)

Acute rheumatic fever is a major cause of heart disease in large parts of the world, but it remains unknown why only a small fraction of those who are infected with rheumatogenic group A streptococci develop an abnormal immune response that leads to acute rheumatic fever. An understanding of the mechanisms underlying host susceptibility can provide important insights into pathogenesis that in turn can inform new treatments. Extensive searches for susceptibility factors have been undertaken, including human leukocyte antigens, B-cell alloantigens, and cytokine genes. Although significant associations have been found between genetic factors and acute rheumatic fever, study results often conflict with each other. This review explores current understanding about host susceptibility to acute rheumatic fever and provides an overall perspective to the number of studies that have recently addressed this subject.
Procalcitonin as a diagnostic tool in lower respiratory tract infections and tuberculosis
Authors: A. Polzin, M. Pletz, R. Erbes, M. Raffenberg, H. Mauch, S. Wagner, G. Arndt, H. Lode
Journal: European Respiratory Journal (2003)

The diagnostic significance of procalcitonin concentrations in lower respiratory tract infections and tuberculosis is not known. A prospective analysis was, therefore, performed in patients with acute exacerbation of chronic bronchitis (AECB), community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP) and tuberculosis and their procalcitonin levels compared with those of patients with noninfectious lung diseases (controls). In addition, standard inflammatory parameter data were collected. A prospective clinical study was performed with four different groups of patients and a control group that consisted of patients with noninfectious lung diseases. A total of 129 patients were included: 25 with HAP, 26 CAP, 26 AECB, 27 tuberculosis, and 25 controls. C-reactive protein level, blood cell counts and procalcitonin concentration were evaluated on the first day after onset of clinical and inflammatory symptoms prior to treatment. The median procalcitonin concentrations in HAP, CAP, AECB and tuberculosis were not elevated in relation to the cut-off level of 0.5 ng·mL −1 . In the HAP group, in four of five patients who subsequently died, procalcitonin concentrations of &gt;0.5 ng·mL −1 were found. In acute lower respiratory infections, such as HAP, CAP and AECB, significantly elevated levels were found in comparison to the control group, but below the usual cut-off level. No differences were observed between tuberculosis and the control group. Relative to the current cut-off level of 0.5 ng·mL −1 , procalcitonin concentration is not a useful parameter for diagnosis of lower respiratory tract infections. However, compared to the control group, there were significantly elevated levels in patients with hospital-acquired pneumonia, community-acquired pneumonia and acute exacerbation of chronic bronchitis below the current cut-off level, which should be further investigated.
End-to-End Bronchial Anastomosis after Accidental Division of the Stem Bronchus
Authors: J. Mathey, G. Oustrieres
Journal: Thorax (1951)

In recent years reconstitution of bronchial continuity, after simple division or the removal of a circumferential section of the wall, has been the subject of experimental work.On the other hand, clinical observations of bronchial anastomosis in man are still rare.In the course of a difficult resection of the left lower lobe and lingula we accidentally divided the stem bronchus, and acquaintance with results obtained experimentally in animals enabled us to re-establish bronchial continuity and so to conserve the upper lobe. CASE HISTORYA woman, aged 27, was referred to us by Dr. Pruvost on September 28, 1949, suffering from bronchiectasis of her left lower lobe and lingula.In 1926, at the age of 3, she had had measles and left pulmonary congestion.In 1931 there had been further trouble in the lung, with haemoptyses and the appearance in radiographs of a triangular shadow at the left base.From this time on, the patient had had numerous acute episodes with purulent sputum and haemoptysis.In 1932 a left phrenicectomy was performed, but the acute episodes with purulent expectoration and haemoptyses, alternating with remissions, persisted up to 1948.
Inhibition of NEDD8-Activating Enzyme Induces Rereplication and Apoptosis in Human Tumor Cells Consistent with Deregulating CDT1 Turnover
Authors: Michael A. Milhollen, Usha Narayanan, Teresa A. Soucy, Petter O. Veiby, Peter G. Smith, Benjamin Amidon
Journal: Cancer Research (2011)

Abstract Loss of NEDD8-activating enzyme (NAE) function by siRNA knockdown or inhibition by the small molecule NAE inhibitor MLN4924 leads to increased steady-state levels of direct Cullin-RING ligase (CRL) substrates by preventing their ubiquitination and proteasome-dependent degradation. Many of these CRL substrates are involved in cell cycle progression, including a critical DNA replication licensing factor CDT1. Cell cycle analysis of asynchronous and synchronous cultures after NAE inhibition revealed effects on cell cycle distribution and activation of DNA break repair signaling pathways similar to that reported for CDT1 overexpression. The siRNA knockdown of cullins critical for the turnover of CDT1 recapitulated the aberrant rereplication phenotype while CDT1 knockdown was suppressing. Although NAE inhibition leads to deregulation of many CRL substrates, these data demonstrate that CDT1 accumulation mediates the DNA rereplication phenotype resulting from loss of NAE function. DNA rereplication is an unrecoverable cellular insult and the small molecule inhibitor MLN4924, currently in phase I trials, represents an unprecedented opportunity to explore this mechanism of cytotoxicity for the treatment of cancer. Cancer Res; 71(8); 3042–51. ©2011 AACR.
NABTT 0502: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme
Authors: David M. Peereboom, Manmeet S. Ahluwalia, Xiaobu Ye, Jeffrey G. Supko, Sarah L. Hilderbrand, Surasak Phuphanich, L. Burt Nabors, Myrna R. Rosenfeld, Tom Mikkelsen, Stuart A. Grossman
Journal: Neuro-Oncology (2013)

The signal transduction pathways of epidermal growth factor receptor and Ras are both important in the growth of glioblastoma multiforme (GBM). We hypothesized that inhibition of both pathways would improve the survival time of patients with recurrent GBM. Patients with recurrent/progressive GBM with 0–2 prior chemotherapy regimens received erlotinib 150 mg once daily and sorafenib 400 mg twice daily until progression. The primary endpoint was overall survival. Pharmacokinetic sampling was performed during cycle 1. The median overall survival was 5.7 months. Progression-free survival at 6 months was 14%. Toxicity was manageable. Clearance of erlotinib was markedly enhanced by sorafenib. The study did not meet its objective of a 30% increase in overall survival time compared with historical controls. Erlotinib and sorafenib have significant pharmacokinetic interactions that may negatively impact the efficacy of the combination regimen.
The association between smoking cessation and glycaemic control in patients with type 2 diabetes: a THIN database cohort study
Authors: Deborah Lycett, Linda Nichols, Ronan Ryan, Amanda Farley, Andrea Roalfe, Mohammed A Mohammed, Lisa Szatkowski, Tim Coleman, Richard Morris, Andrew Farmer, Paul Aveyard
Journal: The Lancet Diabetes & Endocrinology (2015)
The Rate of Molecular Adaptation in a Changing Environment
Authors: João M. Lourenço, Sylvain Glémin, Nicolas Galtier
Journal: Molecular Biology and Evolution (2013)

It is currently unclear whether the amino acid substitutions that occur during protein evolution are primarily driven by adaptation, or reflect the random accumulation of neutral changes. When estimated from genomic data, the proportion of adaptive amino acid substitutions, called α, was found to vary greatly across species, from nearly zero in humans to above 0.5 in Drosophila. These variations have been interpreted as reflecting differences in effective population size, adaptation being supposedly more efficient in large populations. Here, we investigate the influence of effective population size and other biological parameters on the rate of adaptive evolution by simulating the evolution of a coding sequence under Fisher's geometric formalism. We explicitly model recurrent environmental changes and the subsequent adaptive walks, followed by periods of stasis during which purifying selection dominates. We show that, under a variety of conditions, the effective population size has only a moderate influence on α, and an even weaker influence on the per generation rate of selective sweeps, modifying the prevalent view in current literature. The rate of environmental change and, interestingly, the dimensionality of the phenotypic space (organismal complexity) affect the adaptive rate more deeply than does the effective population size. We discuss the reasons why verbal arguments have been misleading on that subject and revisit the empirical evidence. Our results question the relevance of the "α" parameter as an indicator of the efficiency of molecular adaptation.
A role for AID in chromosome translocations between c-myc and the IgH variable region
Authors: Yair Dorsett, Davide F. Robbiani, Mila Jankovic, Bernardo Reina-San-Martin, Thomas R. Eisenreich, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2007)

Chromosome translocations between oncogenes and the region spanning the immunoglobulin (Ig) heavy chain (IgH) variable (V), diversity (D), and joining (J) gene segments (Ig V-J(H) region) are found in several mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences targeted by recombination activating genes 1 and 2 during antigen receptor assembly in pre-B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-J(H) region-associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-J(H) translocations, we searched for such events in both interleukin (IL) 6 transgenic (IL-6 tg) and AID(-/-) IL-6 tg mice. Here, we report that AID is required for c-myc to Ig V-J(H) translocations induced by IL-6.
Significant Microbiological Effect of Inhaled Tobramycin in Young Children with Cystic Fibrosis
Authors: Ronald L. Gibson, Julia Emerson, Sharon McNamara, Jane L. Burns, Margaret Rosenfeld, Ann Yunker, Nicole Hamblett, Frank Accurso, Mark Dovey, Peter Hiatt, Michael W. Konstan, Richard Moss, George Retsch-Bogart, Jeffrey Wagener, David Waltz, Robert Wilmott, Pamela L. Zeitlin, Bonnie Ramsey
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

We conducted a double-blind, placebo-controlled, multicenter, randomized trial to test the hypothesis that 300 mg of tobramycin solution for inhalation administered twice daily for 28 days would be safe and result in a profound decrease in Pseudomonas aeruginosa (Pa) density from the lower airway of young children with cystic fibrosis. Ninety-eight subjects were to be randomized; however, the trial was stopped early because of evidence of a significant microbiological treatment effect. Twenty-one children under age 6 years were randomized (8 active; 13 placebo) and underwent bronchoalveolar lavage at baseline and on Day 28. There was a significant difference between treatment groups in the reduction in Pa density; no Pa was detected on Day 28 in 8 of 8 active group patients compared with 1 of 13 placebo group patients. We observed no differences between treatment groups for clinical indices, markers of inflammation, or incidence of adverse events. No abnormalities in serum creatinine or audiometry and no episodes of significant bronchospasm were observed in association with active treatment. We conclude that 28 days of tobramycin solution for inhalation of 300 mg twice daily is safe and effective for significant reduction of lower airway Pa density in young children with cystic fibrosis.
Depression and Cardiovascular Disorders
Authors: Mary A. Whooley, Jonathan M. Wong
Journal: Annual Review of Clinical Psychology (2013)

During the past two decades, research in the field of depression and cardiovascular disorders has exploded. Multiple studies have demonstrated that depression is more prevalent in populations with cardiovascular disease, is a robust risk factor for the development of cardiovascular disease in healthy populations, and is predictive of adverse outcomes (such as myocardial infarction and death) among populations with preexisting cardiovascular disease. Mechanistic studies have shown that poor health behaviors, such as physical inactivity, medication nonadherence, and smoking, strongly contribute to this association. Small randomized trials have found that antidepressant therapies may improve cardiac outcomes. Based on this accumulating evidence, the American Heart Association has recommended routine screening for depression in all patients with coronary heart disease. This review examines the key epidemiological literature on depression and cardiovascular disorders and discusses our current understanding of the mechanisms responsible for this association. We also examine current recommendations for screening, diagnosis, and management of depression. We conclude by highlighting new research areas and discussing therapeutic management of depression in patients with cardiovascular disorders.
Glomerular hemodynamic effects of late pregnancy in rats with experimental membranous glomerulonephropathy.
Authors: C Baylis, A Deng, W G Couser
Journal: Journal of the American Society of Nephrology (1995)

In these studies, the Fx1A model of accelerated, passive Heymann nephritis was used to produce membranous glomerulonephropathy. Female rats were studied at 7 wk after the administration of the Fx1A antibody either in the virgin state or in late pregnancy. The goals of these experiments were to determine whether preexisting membranous glomerulonephropathy compromises the pregnancy and whether the pregnancy acutely worsens the renal function. Virgin rats with membranous glomerulonephropathy developed massive proteinuria and exhibited glomerular capillary hypertension but without declines in GFR. In late pregnancy, there was no worsening of the proteinuria and glomerular blood pressure fell to normal values. Both afferent and efferent arteriolar resistances increased in pregnant rats with membranous glomerulonephropathy compared with virgins, leading to falls in glomerular plasma flow and single-nephron GFR. There were no histologic abnormalities in the glomeruli of either virgin or late pregnant rats with membranous glomerulonephropathy, and both groups exhibited similar immunoglobulin G and complement deposits. Up to Day 19 (term is 22 days), the pregnancy in rats with membranous glomerulonephropathy appeared uneventful. Thus, this study indicates that the Fx1A model of membranous glomerulonephropathy does not compromise the course of the pregnancy, at least until close to term. Pregnancy lowers glomerular blood pressure in rats with membranous glomerulonephropathy because of both a fall in systemic blood pressure and the atypical renal vasoconstriction, which leads to declines in single-nephron GFR.