tbuckley/cabot-search huggingface dataset:
Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis
Authors: A. Amital, S. Dux, D. Shitrit, O. Shpilberg, M. R. Kramer
Journal: Thorax (2010)

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterised by the accumulation of lung surfactant in the alveoli. In most cases it is an autoimmune disease with antibodies directed against the growth factor granulocyte-macrophage colony stimulating factor (GM-CSF). Standard of care consists of whole lung lavages in symptomatic patients. An alternative treatment is GM-CSF injections. The case history is reported of a patient with PAP and severe dyspnoea and hypoxaemia. Whole lung lavages and GM-CSF initially resulted in partial remission. However, the patient9s condition deteriorated and her saturation during rest with high-flow oxygen treatment was 85%. The patient was treated with an anti-CD20 antibody rituximab which resulted in dramatic improvement. Room air saturation increased to 98% with exercise and she no longer required supplemental oxygen. The diffusion capacity for carbon monoxide increased from 27% to 48% of predicted and the chest x-rays improved. Rituximab may be useful in the treatment of patients with unresponsive PAP.
Highly Phosphorylated FOXO3A Is an Adverse Prognostic Factor in Acute Myeloid Leukemia
Authors: Steven M. Kornblau, Neera Singh, YiHua Qiu, Wenjing Chen, Nianxiang Zhang, Kevin R. Coombes
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The Forkhead transcription factors (FOXO) are tumor suppressor genes regulating differentiation, metabolism, and apoptosis that functionally interact with signal transduction pathways shown to be deregulated and prognostic in acute myelogenous leukemia (AML). This study evaluated the level of expression and the prognostic relevance of total and phosphorylated FOXO3A protein in AML. Experimental Design: We used reverse-phase protein array methods to measure the level of total and phosphoprotein expression of FOXO3A, in leukemia-enriched protein samples from 511 newly diagnosed AML patients. Results: The expression range was similar to normal CD34+ cells and similar in blood and marrow. Levels of total FOXO3A were higher at relapse compared with diagnosis. Levels of pFOXO3A or the ratio of phospho to total (PT) were not associated with karyotpe but were higher in patients with FLT3 mutations. Higher levels of pFOXO3A or PT-FOXO3A were associated with increased proliferation evidenced by strong correlation with higher WBC, percent marrow, and blood blasts and by correlation with higher levels of Cyclins B1, D1 and D3, pGSK3, pMTOR, and pStat5. Patients with High levels of pFOXO3A or PT-FOXO3A had higher rates of primary resistance and shorter remission durations, which combine to cause an inferior survival experience (P = 0.0002). This effect was independent of cytogenetics. PT-FOXO3A was a statistically significant independent predictor in multivariate analysis. Conclusions: High levels of phosphorylation of FOXO3A is a therapeutically targetable, independent adverse prognostic factor in AML. Clin Cancer Res; 16(6); 1865–74
Rearrangement and Expression of Immunoglobulin Light Chain Genes Can Precede Heavy Chain Expression during Normal B Cell Development in Mice
Authors: Tatiana I. Novobrantseva, Verena M. Martin, Roberta Pelanda, Werner Müller, Klaus Rajewsky, Andreas Ehlich
Journal: The Journal of Experimental Medicine (1999)

In mouse mutants incapable of expressing μ chains, VκJκ joints are detected in the CD43+ B cell progenitors. In agreement with these earlier results, we show by a molecular single cell analysis that 4–7% of CD43+ B cell progenitors in wild-type mice rearrange immunoglobulin (Ig)κ genes before the assembly of a productive VHDHJH joint. Thus, μ chain expression is not a prerequisite to Igκ light chain gene rearrangements in normal development. Overall, ∼15% of the total CD43+ B cell progenitor population carry Igκ gene rearrangements in wild-type mice. Together with the results obtained in the mouse mutants, these data fit a model in which CD43+ progenitors rearrange IgH and Igκ loci independently, with a seven times higher frequency in the former. In addition, we show that in B cell progenitors VκJκ joining rapidly initiates κ chain expression, irrespective of the presence of a μ chain.
A method for detecting positive selection at single amino acid sites
Authors: Y. Suzuki, T. Gojobori
Journal: Molecular Biology and Evolution (1999)

A method was developed for detecting the selective force at single amino acid sites given a multiple alignment of protein-coding sequences. The phylogenetic tree was reconstructed using the number of synonymous substitutions. Then, the neutrality was tested for each codon site using the numbers of synonymous and nonsynonymous changes throughout the phylogenetic tree. Computer simulation showed that this method accurately estimated the numbers of synonymous and nonsynonymous substitutions per site, as long as the substitution number on each branch was relatively small. The false-positive rate for detecting the selective force was generally low. On the other hand, the true-positive rate for detecting the selective force depended on the parameter values. Within the range of parameter values used in the simulation, the true-positive rate increased as the strength of the selective force and the total branch length (namely the total number of synonymous substitutions per site) in the phylogenetic tree increased. In particular, with the relative rate of nonsynonymous substitutions to synonymous substitutions being 5.0, most of the positively selected codon sites were correctly detected when the total branch length in the phylogenetic tree was > or = 2.5. When this method was applied to the human leukocyte antigen (HLA) gene, which included antigen recognition sites (ARSs), positive selection was detected mainly on ARSs. This finding confirmed the effectiveness of the present method with actual data. Moreover, two amino acid sites were newly identified as positively selected in non-ARSs. The three-dimensional structure of the HLA molecule indicated that these sites might be involved in antigen recognition. Positively selected amino acid sites were also identified in the envelope protein of human immunodeficiency virus and the influenza virus hemagglutinin protein. This method may be helpful for predicting functions of amino acid sites in proteins, especially in the present situation, in which sequence data are accumulating at an enormous speed.
Left Main Coronary Artery Compression Syndrome
Authors: Jonathan D. Dodd, Andrew Maree, Igor Palacios, Michael M. de Moor, Eline A.Q. Mooyaart, Michael D. Shapiro, Maros Ferencik, Thomas Brady, Suhny Abbara, Ricardo C. Cury, Udo Hoffmann
Journal: Circulation (2007)
Towards a balanced social psychology: Causes, consequences, and cures for the problem-seeking approach to social behavior and cognition
Authors: Joachim I. Krueger, David C. Funder
Journal: Behavioral and Brain Sciences (2004)

Mainstream social psychology focuses on how people characteristically violate norms of action through social misbehaviors such as conformity with false majority judgments, destructive obedience, and failures to help those in need. Likewise, they are seen to violate norms of reasoning through cognitive errors such as misuse of social information, self-enhancement, and an over-readiness to attribute dispositional characteristics. The causes of this negative research emphasis include the apparent informativeness of norm violation, the status of good behavior and judgment as unconfirmable null hypotheses, and the allure of counter-intuitive findings. The shortcomings of this orientation include frequently erroneous imputations of error, findings of mutually contradictory errors, incoherent interpretations of error, an inability to explain the sources of behavioral or cognitive achievement, and the inhibition of generalized theory. Possible remedies include increased attention to the complete range of behavior and judgmental accomplishment, analytic reforms emphasizing effect sizes and Bayesian inference, and a theoretical paradigm able to account for both the sources of accomplishment and of error. A more balanced social psychology would yield not only a more positive view of human nature, but also an improved understanding of the bases of good behavior and accurate judgment, coherent explanations of occasional lapses, and theoretically grounded suggestions for improvement.
Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress
Authors: I. Horvath, L. E Donnelly, A. Kiss, P. Paredi, S. A Kharitonov, P. J Barnes
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Chronic inflammatory diseases are associated with an increased production of oxidants. Induction of a stress protein, heme oxygenase (HO) HO-1, is a cytoprotective mechanism against oxidative cellular injury. HO-1 catabolises heme to bilirubin, free iron, and carbon monoxide (CO). <h3>METHODS</h3> Exhaled CO and sputum bilirubin levels were measured and HO-1 protein expression in airway macrophages was determined by Western blotting in asthmatic patients as levels of oxidants are raised in asthma and may induce HO-1. <h3>RESULTS</h3> Exhaled CO was significantly increased in 37 non-steroid treated asthmatic patients compared with 37 healthy subjects (5.8 (95% CI 5.20 to 6.39) ppm vs 2.9 (2.51 to 3.28) ppm; p&lt;0.0001) but was similar to normal in 25 patients who received corticosteroids (3.3 (95% CI 2.92 to 3.67) ppm; p&gt;0.05). In non-treated asthmatic patients more HO-1 protein was expressed in airway macrophages than in normal subjects. Bilirubin levels in induced sputum were also higher than in normal subjects. Inhalation of hemin, a substrate for HO, significantly increased exhaled CO from 3.8 (95% CI 2.80 to 4.87) ppm to 6.7 (95% CI 4.95 to 8.38 CI) ppm (p&lt;0.05) with a concomitant decrease in exhaled nitric oxide levels, suggesting an interaction between the two systems. <h3>CONCLUSIONS</h3> Increased exhaled CO levels and HO-1 expression may reflect induction of HO-1 which may be inhibited by steroids. Measurement of exhaled CO, an index of HO activity in non-smoking subjects, may therefore be clinically useful in the detection and management of asthma and possibly other chronic inflammatory lung disorders.
Ultrastructural aspects of the liver and its disorders
Authors: P J Scheuer
Journal: Gut (1980)

chapters on motility.Diet, and psycho- logical aspects, are not considered, and the liver is allotted little more than two chapters.The book has to compete with review articles which appear regularly in the journals.The editors have sought to provide a balance of topics within gastro- enterology, and, as a balanced and thoughtful text, it is the best available.It is a book that will be read with interest by gastroenterologists,
Transmission of Pseudomonas aeruginosa epidemic strain from a patient with cystic fibrosis to a pet cat
Authors: K Mohan, J L Fothergill, J Storrar, M J Ledson, C Winstanley, M J Walshaw
Journal: Thorax (2008)

Chronic infection with <i>Pseudomonas aeruginosa</i> is common in cystic fibrosis (CF) and certain strains are more transmissible and virulent than others. Of these, the Liverpool Epidemic Strain (LES) is highly transmissible and cross infection has been reported between patients with CF and healthy non-CF relatives. However, the risk of transmission from humans to animals is unknown. The first report of interspecies transmission of the LES strain of <i>P aeruginosa</i> from an adult patient with CF to a pet cat is described. This development further complicates the issue of infection control policies required to prevent the spread of this organism.
Multiple nonfunctional alleles of CCR5 are frequent in various human populations
Authors: Cédric Blanpain, Benhur Lee, Marie Tackoen, Bridget Puffer, Alain Boom, Frédérick Libert, Mathew Sharron, Valérie Wittamer, Gilbert Vassart, Robert W. Doms, Marc Parmentier
Journal: Blood (2000)
Specific Adverse Events Predict Survival Benefit in Patients Treated With Tamoxifen or Aromatase Inhibitors: An International Tamoxifen Exemestane Adjuvant Multinational Trial Analysis
Authors: Duveken B.Y. Fontein, Caroline Seynaeve, Peyman Hadji, Elysée T.M. Hille, Willemien van de Water, Hein Putter, Elma Meershoek-Klein Kranenbarg, Annette Hasenburg, Robert J. Paridaens, Jean-Michel Vannetzel, Christos Markopoulos, Yasuo Hozumi, John M.S. Bartlett, Stephen E. Jones, Daniel William Rea, Johan W.R. Nortier, Cornelis J.H. van de Velde
Journal: Journal of Clinical Oncology (2013)

Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment.A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation.Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.
Glycemic index, glycemic load and thyroid cancer risk
Authors: G. Randi, M. Ferraroni, R. Talamini, W. Garavello, S. Deandrea, A. Decarli, S. Franceschi, C. La Vecchia
Journal: Annals of Oncology (2007)

Risk of thyroid cancer has already been related to refined cereals and starch food, but the association has not been studied in terms of glycemic index (GI) and glycemic load (GL).We analyzed data from a case-control study conducted in Italy from 1986 to 1992 and including 399 histologically confirmed and incident cases of thyroid cancer and 616 control subjects. Information on dietary habits was derived through a food-frequency questionnaire and multivariate odds ratios (ORs) for GI and GL levels were estimated with adjustment for age, education, sex, area of residence, history of diabetes, body mass index, smoking, alcohol consumption, intake of fruit and vegetables, and noncarbohydrate energy intake.Compared with the lowest tertile, the ORs in subsequent tertiles were 1.68 and 1.73 for GI, and 1.76 and 2.17 for GL. The OR for highest tertile of GI compared with lowest one was 1.70 for papillary and 1.57 for follicular thyroid cancer. The ORs for GL were 2.17 for papillary and 3.33 for follicular thyroid cancer.Our study shows that high dietary levels of GI and GL are associated with thyroid cancer risk.
State Effects of Major Depression on the Assessment of Personality and Personality Disorder
Authors: Leslie C. Morey, M. Tracie Shea, John C. Markowitz, Robert L. Stout, Christopher J. Hopwood, John G. Gunderson, Carlos M. Grilo, Thomas H. McGlashan, Shirley Yen, Charles A. Sanislow, Andrew E. Skodol
Journal: American Journal of Psychiatry (2010)

Objective The authors sought to determine whether personality disorders diagnosed during a depressive episode have long-term outcomes more typical of those of other patients with personality disorders or those of patients with noncomorbid major depression. Method The authors used 6-year outcome data collected from the multisite Collaborative Longitudinal Personality Disorders Study (CLPS). Diagnoses and personality measures gathered from the study cohort at the index assessment using interview and self-report methods were associated with symptomatic, functional, and personality measures at 6-year follow-up. Of 668 patients initially recruited to the CLPS, 522 were followed for 6 years. All participants had either a DSM-IV diagnosis of one of four personality disorders (borderline, schizotypal, obsessive-compulsive, or avoidant) or a DSM-IV diagnosis of major depressive disorder with no accompanying personality disorder. Results Six-year outcomes for patients with comorbid personality disorder and major depressive disorder at the index evaluation were similar to those of patients with pure personality disorder and significantly worse than those of patients with pure major depressive disorder. Stability estimates of personality traits were similar for personality disorder patients with and without major depressive disorder at the index evaluation. Conclusions These results suggest that personality disorder diagnoses established during depressive episodes are a valid reflection of personality pathology rather than an artifact of depressive mood.
DNA repair and synthetic lethality
Authors: Gong‐she Guo, Feng‐mei Zhang, Rui‐jie Gao, Robert Delsite, Zhi‐hui Feng, Simon N Powell
Journal: International Journal of Oral Science (2011)

Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair‐defective tumors, in particular homologous recombination (HR), are highly sensitive to DNA‐damaging agents. Thus, HR‐defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly (adenosine diphosphate (ADP)‐ribose) polymerase (PARP) inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR‐defective tumor cells.
The Hazards of Endpoints
Authors: D. A. Berry
Journal: JNCI Journal of the National Cancer Institute (2010)

of development, we would plant seeds from each variety and spray the sprouting plants with pesticide. We would drop from further development those varieties that seem adversely affected. In the next phase, we would plant seeds from those varieties still under consideration and pull up the stalks 8 weeks later to weigh the ears. Small ear varieties would be discarded. In the next phase, 14 weeks after planting, we assess the sugar content of the kernels, discarding those with low concentrations. Then, we would consider hardiness and so on. We’d probably end up with lousy corn and we’d wonder if we had discarded a better overall variety along the way. One problem with this approach to choosing corn varieties is that we would have failed to address the relationships among the various effects. Another is that we would have failed to observe the effects of all the variables at maturity. But the biggest problem is the staccato learning process. Each experiment was a discrete unit rather than one part of a continual learning process in which the answers to relevant questions got stronger over time. In the clinical development of cancer drugs, we consider toxicity early on, then antitumor effect (or immunologic effect or other biomarker effect), and then clinical effect. We fail to assess and relate these effects over the patients’ follow-up, and we fail to associate them with the primary clinical endpoint in a longitudinal fashion. We must address the entire patient, including the patient’s course of disease over time. Especially important are tumor burden and factors that may be related to tumor burden. In the immunology setting, this includes measures such as T-cell proliferation. There are obstacles to building better drug and vaccine development. One is the notion that early endpoints should play a role in clinical trials only if they are surrogates for the primary endpoint. Another is the notion that we can use markers only if they
A proischaemic action of nisoldipine: relationship to a decrease in perfusion pressure and comparison to dipyridamole
Authors: D. Baumgart, T. Ehring, G. Heusch
Journal: Cardiovascular Research (1993)

Objective: The calcium antagonist nisoldipine has recently been reported to induce rather than to attenuate ischaemia in some patients with stable angina. The aim of the study was to investigate the mechanisms underlying this proischaemic effect. Methods: In 20 anaesthetised dogs systemic haemodynamic variables, regional myocardial blood flow (coloured microspheres), and systolic wall thickening (sonomicrometry) were measured during control conditions and following severe stenosis on the left circumflex coronary artery, before and after intravenous administration of equihypotensive doses of either nisoldipine (group I, n=10) or dipyridamole (group II, n=10). Finally, measurements were performed while the drug induced decreases in mean aortic pressure - 18(SD 6) mmHg in group I and 14(6) mm Hg in group II - were reversed by inflation of an intra-aortic balloon. Results: The stenosis decreased posterior wall thickening to 50% of control, and posterior subendocardial blood flow from 1.48(0.27) to 0.61(0.19) ml·min−1·g−1 in group I and from 1.49(0.23) to 0.62(0.18) ml·min−1·g−1 in group II. Subendocardial blood flow was further decreased after administration of either nisoldipine [0.37(0.20) ml·min−1·g−1, p<0.05 v stenosis] or dipyridamole [0.22(0.11) ml·min−1·g−l, p<0.05 v stenosis]. Regional myocardial blood flow in the anterior region was increased. The drug induced reduction of subendocardial blood flow decreased posterior wall thickening further from 9.3(2.1) to 6.2(3.9)% (p<0.05 v stenosis, group I) and from 9.1(1.7) to 4.3(2.4)% (p<0.05 v stenosis, group II). When the drug induced decrease in aortic pressure was reversed, subendocardial blood flow again increased in group I [0.63(0.19) ml·min−1·g−1, p<0.05 v stenosis and nisoldipine] whereas in group II it remained decreased [0.40(0.29) ml·min−1·g−1, NS v stenosis and dipyridamole]. There was restoration of posterior wall thickening in group I [10.4(3.8)%, p<0.05 v stenosis and nisoldipine], but not in group II [5.2(3.5)%, NS v stenosis and dipyridamole]. Conclusions: Nisoldipine and dipyridamole decrease subendocardial blood flow and contractile function distal to a severe stenosis when aortic pressure is decreased. No aggravation of ischaemia by nisoldipine is seen when hypotension is prevented. In contrast, dipyridamole in the absence of hypotension still induces a redistribution of flow at the expense of the ischaemic region. Cardiovascular Research 1993;27:1254-1259