tbuckley/cabot-search huggingface dataset:
Therapeutic drug monitoring in patients with cystic fibrosis and mycobacterial disease
Authors: M. Gilljam, S.E. Berning, C.A. Peloquin, B Strandvik, L.O. Larsson
Journal: European Respiratory Journal (1999)

The dominant role of inflammation in airways disease progression in cystic fibrosis (CF) is now well established and, based on recent findings, the possibility of an inappropriate inflammatory response in the lung of patients with CF has emerged. In order to characterize this response, the aim of the present work was to evaluate the levels of a number of pro- and anti-inflammatory cytokines in the sputum of CF children and to compare these levels to those observed in the sputum from non-CF children with diffuse bronchiectasis (DB). Three groups of patients were investigated: a group of 25 CF children (mean age: 12.2 yrs), a group of 10 non-CF children with DB (mean age 11.5 yrs), and a group of five healthy young adults (mean age 24 yrs). Elevated concentrations of pro-inflammatory cytokines, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-8 were found in children with CF and in non-CF children with DB, with significantly higher concentrations of IL-1beta in CF children. Analysis of the natural anti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) and type II TNF soluble receptor (sTNFRII) concentrations showed distinct patterns, with elevated levels of both inhibitors in CF patients, whereas only sTNFRII was found to be increased in non-CF children with DB. IL-10 data indicated low concentrations in the CF group. In all CF children, the concentrations of IL-6 in the airways were extremely low, independent of the clinical, bacteriological or functional status. By contrast, significantly increased IL-6 levels were found in non-CF children with DB. These results document distinct cytokine profiles in cystic fibrosis patients and noncystic fibrosis patients. They also suggest that impairment of interleukin-6 expression may represent an important component of the excessive inflammatory response observed in cystic fibrosis.
Using a Stem Cell–Based Signature to Guide Therapeutic Selection in Cancer
Authors: Igor Shats, Michael L. Gatza, Jeffrey T. Chang, Seiichi Mori, Jialiang Wang, Jeremy Rich, Joseph R. Nevins
Journal: Cancer Research (2010)

Given the very substantial heterogeneity of most human cancers, it is likely that most cancer therapeutics will be active in only a small fraction of any population of patients. As such, the development of new therapeutics, coupled with methods to match a therapy with the individual patient, will be critical to achieving significant gains in disease outcome. One such opportunity is the use of expression signatures to identify key oncogenic phenotypes that can serve not only as biomarkers but also as a means of identifying therapeutic compounds that might specifically target these phenotypes. Given the potential importance of targeting tumors exhibiting a stem-like phenotype, we have developed an expression signature that reflects common biological aspects of various stem-like characteristics. The consensus stemness ranking (CSR) signature is upregulated in cancer stem cell-enriched samples at advanced tumor stages and is associated with poor prognosis in multiple cancer types. Using two independent computational approaches we utilized the CSR signature to identify clinically useful compounds that could target the CSR phenotype. In vitro assays confirmed selectivity of several predicted compounds including topoisomerase inhibitors and resveratrol towards breast cancer cell lines that exhibit a high-CSR phenotype. Importantly, the CSR signature could predict clinical response of breast cancer patients to a neoadjuvant regimen that included a CSR-specific agent. Collectively, these results suggest therapeutic opportunities to target the CSR phenotype in a relevant cohort of cancer patients.
Monocyte-selective transendothelial migration: dissection of the binding and transmigration phases by an in vitro assay.
Authors: W A Muller, S A Weigl
Journal: The Journal of Experimental Medicine (1992)

We describe a quantitative assay of transendothelial migration (TEM) that allows us to selectively study the interaction of monocytes with confluent human endothelial cell (HEC) monolayers. The HEC are grown on hydrated collagen gels; the monocytes need not be purified. 100% of monocytes transmigrated the monolayer within 1 h at 37 degrees C and accumulated in the subendothelial collagen; TEM of lymphocytes was not detected within this time. Migration of neutrophils from the same donor was much slower and incomplete, with only 14% of PMN transmigrating in 2 h. This rapid TEM occurs in the absence of exogenous chemoattractants, and HEC in this system do not express cytokine-inducible leukocyte adhesion molecules. A slight modification of the TEM assay allowed us to separate binding to the apical HEC surface from TEM. We found that tight apical surface binding was the rate-limiting step for TEM. Two-thirds of this binding and TEM could be blocked by a monoclonal antibody against the leukocyte beta 2 integrin chain CD18. This assay will allow us to dissect the mechanisms of both the binding and transmigration stages of diapedesis.
LongSAGE profiling of nine human embryonic stem cell lines
Authors: Martin Hirst, Allen Delaney, Sean A Rogers, Angelique Schnerch, Deryck R Persaud, Michael D O'Connor, Thomas Zeng, Michelle Moksa, Keith Fichter, Diana Mah, Anne Go, Ryan D Morin, Agnes Baross, Yongjun Zhao, Jaswinder Khattra, Anna-Liisa Prabhu, Pawan Pandoh, Helen McDonald, Jennifer Asano, Noreen Dhalla, Kevin Ma, Stephanie Lee, Adrian Ally, Neil Chahal, Stephanie Menzies, Asim Siddiqui, Robert Holt, Steven Jones, Daniela S Gerhard, James A Thomson, Connie J Eaves, Marco A Marra
Journal: Genome biology (2007)

Abstract To facilitate discovery of novel human embryonic stem cell (ESC) transcripts, we generated 2.5 million LongSAGE tags from 9 human ESC lines. Analysis of this data revealed that ESCs express proportionately more RNA binding proteins compared with terminally differentiated cells, and identified novel ESC transcripts, at least one of which may represent a marker of the pluripotent state.
Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia
Authors: Marcus Järås, Peter G. Miller, Lisa P. Chu, Rishi V. Puram, Emma C. Fink, Rebekka K. Schneider, Fatima Al-Shahrour, Pablo Peña, L. Jordan Breyfogle, Kimberly A. Hartwell, Marie E. McConkey, Glenn S. Cowley, David E. Root, Michael G. Kharas, Ann Mullally, Benjamin L. Ebert
Journal: The Journal of Experimental Medicine (2014)

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML.
Mutual antagonism of rheumatoid arthritis and hay fever; a role for type 1/type 2 T cell balance
Authors: C. M Verhoef, J. A G van Roon, M. E Vianen, C. A F M Bruijnzeel-Koomen, F. P J G Lafeber, J. W J Bijlsma
Journal: Annals of the Rheumatic Diseases (1998)

The balance between interferon gamma (IFN gamma) and interleukin 4 (IL4) producing T cells (T1 and T2 cells) seems to be of importance in many (auto)immune disorders. In general, T1 cell activity is important in cellular immunity whereas T2 cell activity plays a part in humoral responses. T1 cell activity predominates in joints of patients with rheumatoid arthritis (RA) whereas T2 cell activity is characteristic of atopic syndromes. This study investigated whether the prevalence of hay fever in RA is low and if severity of RA (T1 cell activity) can be influenced by the concomitant occurrence of a T2 cell mediated disease (hay fever).The prevalence of hay fever was assessed in 643 consecutive (RA and non-RA) patients seen in our outpatient clinic and confirmed by skin test and specific IgE. Of this group the 12 RA patients with hay fever were compared with RA patients without hay fever (matched for age, sex, and disease duration).The prevalence of hay fever in RA patients is lower than in non-RA patients (4% versus 8%), and yields a relative risk for RA patients to develop hay fever of 0.48. RA patients with hay fever showed a lower disease activity (erythrocyte sedimentation rate, C reactive protein, Thompson joint score, and radiographic joint damage (Sharp) score) than RA patients without hay fever. The clinical data were related to peripheral blood T1/T2 cell balance: a lower IFN gamma/IL4 ratio was observed for RA patients with hay fever, indicating a comparatively increased T2 cell activity in RA patients with hay fever.These results argue in favour of the exploration of treatments aimed at regulation of a possible imbalance in T1/T2 cell activity in RA.
A7.2 Evaluation of the influence of a program of home-based exercises in disability due to neck pain in subjects with Fibromyalgia
Authors: Cristina Mesquita, Sofia Lopes, Inês Neves, Daniela Silva, Filipa Araújo, Alice Vitorino, Patrícia Lopes, Excelsa Moreira, Ana Carneiro
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Patients with fibromyalgia often feel disable in daily function and admit a great impact in quality of life due to their health condition. The recommendations of an exercise program are important, because individuals with FM are often inactive and physically deconditioned, they fear that exercise exacerbates symptoms. The exercise programs for individuals with fibromyalgia have poor adhesion primarily by the need for equipment, facilities and travel, and the presence of depressive symptoms. All these factors are relevant and take into account when designing the home-based exercise program. The objective of this study was investigate the effect of a home-based exercise program in disability caused by neck pain in patients with fibromyalgia. <h3>Materials and Methods</h3> Randomised controlled study, with 18 volunteers randomly divided into 2 groups. An exercise program was applied in individuals with fibromyalgia diagnosis, for a 12 weeks period and 3 times per week. This includes stretching exercises, neck and lumbar-pelvic mobility, lumbar-pelvic stabilization and relaxation. The evaluation was conducted in two stages, and for that we used the Portuguese versions of the Fibromyalgia Impact Questionnaire (FIQ) and the Neck Disability Index (NDI). For the statistical analysis used descriptive statistics and non-parametric tests. The software was IBM SPSS. <h3>Results</h3> There were more participants (55.6%) diminishing the score of NDI, specially in the exercise group (<i>p</i> = 0.676), and in both groups in FIQ (p = 1.000), compared with those with tendency to increase or maintain the score. The domain “Intensity of Pain” of the NDI, in the exercise group, was the domain with a higher number of participants demonstrating a tendency to diminishing the score (<i>p</i> = 0.609). <h3>Conclusions</h3> After 12 week intervention of a home-based program, there were no improvements in individuals with FM, however, it seems that the home-based exercise program could be efficient in diminishing the disability caused by neck pain.
Mycobacterial contamination of fibreoptic bronchoscopes.
Authors: N M Brown, E A Hellyar, J E Harvey, D S Reeves
Journal: Thorax (1993)

Contamination of bronchoalveolar lavage specimens by environmental mycobacteria in hospital water supplies may lead to diagnostic confusion, particularly in immunocompromised patients. Mycobacteria may become concentrated in the tubing of bronchoscope disinfecting machines. It is very difficult to eradicate these organisms once contamination has occurred.
The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement
Authors: Dragos Bumbacea, Sandra M. Arend, Fusun Eyuboglu, Jay A. Fishman, Delia Goletti, Michael G. Ison, Christine E. Jones, Beate Kampmann, Camille N. Kotton, Christoph Lange, Per Ljungman, Heather Milburn, Michele I. Morris, Elmi Muller, Patricia Muñoz, Anoma Nellore, Hans L. Rieder, Urban Sester, Nicole Theodoropoulos, Dirk Wagner, Martina Sester
Journal: European Respiratory Journal (2012)

Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-γ based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis -specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking.
D85N, a KCNE1 Polymorphism, Is a Disease-Causing Gene Variant in Long QT Syndrome
Authors: Yukiko Nishio, Takeru Makiyama, Hideki Itoh, Tomoko Sakaguchi, Seiko Ohno, Yin-Zhi Gong, Satoshi Yamamoto, Tomoya Ozawa, Wei-Guang Ding, Futoshi Toyoda, Mihoko Kawamura, Masaharu Akao, Hiroshi Matsuura, Takeshi Kimura, Toru Kita, Minoru Horie
Journal: Journal of the American College of Cardiology (2009)
Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia
Authors: M. D. Gammon, J. B. Schoenberg, H. Ahsan, H. A. Risch, T. L. Vaughan, W. H. Chow, H. Rotterdam, A. B. West, R. Dubrow, J. L. Stanford, S. T. Mayne, D. C. Farrow, S. Niwa, W. J. Blot, J. F. Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Incidence rates for adenocarcinomas of the esophagus and gastric cardia have risen steeply over the last few decades. To determine risk factors for these tumors, we conducted a multicenter, population-based, case-control study. Methods: The study included 554 subjects newly diagnosed with esophageal or gastric cardia adenocarcinomas, 589 subjects newly diagnosed with esophageal squamous cell carcinoma or other gastric adenocarcinomas, and 695 control subjects. Estimates of risk (odds ratios [ORs] and corresponding 95% confidence intervals [CIs]) were calculated for the four tumor types separately and for esophageal and gastric cardia adenocarcinomas combined. Results: Risk of esophageal and gastric cardia adenocarcinomas combined was increased among current cigarette smokers (OR = 2.4; 95% = 1.7-3.4), with little reduction observed until 30 years after smoking cessation; this risk rose with increasing intensity and duration of smoking. Risk of these tumors was not related to beer (OR = 0.8; 95% CI = 0.6-1.1) or liquor (OR = 1.1; 95% CI = 0.8-1.4) consumption, but it was reduced for drinking wine (OR = 0.6; 95% CI = 0.5-0.8). Similar ORs were obtained for the development of noncardia gastric adenocarcinomas in relation to tobacco and alcohol use, but higher ORs were obtained for the development of esophageal squamous cell carcinomas. For all four tumor types, risks were higher among those with low income or education. Conclusions: Smoking is a major risk factor for esophageal and gastric cardia adenocarcinomas, accounting for approximately 40% of cases. Implications: Because of the long lag time before risk of these tumors is reduced among exsmokers, smoking may affect early stage carcinogenesis. The increase in smoking prevalence during the first two thirds of this century may be reflected in the rising incidence of these tumors in the past few decades among older individuals. The recent decrease in smoking may not yet have had an impact.
Clinical Trials in Cardiology
Authors: Lem Moyé
Journal: Circulation Research (2014)

Controlled clinical trials conduct the research that completes the causal argument between a treatment and a disease's control. Yet, this pinnacle of clinical research is itself afflicted. Chronic problems with recruitment failure vitiate the potency of our research efforts. In addition, the collision of end-point multiplicity (the drive to measure multiple end points) with the requirement of statistical parsimony (ie, the need to reduce the number of interpretable end points to control the overall type I error) induces a core inefficiency in clinical trial productivity by reducing the number of endpoints findings that are generalizable to the population at large. Unless clinical trialists engage these problems with vigor and imagination, our pinnacle may be nothing more than an inflection point leading to decline.
Earlier Detection of Breast Cancer with Ultrasound Molecular Imaging in a Transgenic Mouse Model
Authors: Sunitha V. Bachawal, Kristin C. Jensen, Amelie M. Lutz, Sanjiv S. Gambhir, Francois Tranquart, Lu Tian, Jürgen K. Willmann
Journal: Cancer Research (2013)

While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MB(VEGFR2)) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MB(VEGFR2) than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001) when breast tissue (n = 315 glands) progressed from normal [1.65 ± 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 ± 1.16), DCIS (15.95 ± 1.31), and invasive cancer (78.1 ± 6.31) and highly correlated with ex vivo VEGFR2 expression [R(2) = 0.84; 95% confidence interval (CI), 0.72-0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78-88) and specificity of 89% (95% CI, 81-94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97-99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women.
Aneurysmal coronary artery disease.
Authors: P S Swaye, L D Fisher, P Litwin, P A Vignola, M P Judkins, H G Kemp, J G Mudd, A J Gosselin
Journal: Circulation (1983)

To examine the clinical and historical features and the natural history of aneurysmal coronary disease, we reviewed the registry data of the Coronary Artery Surgery Study (CASS). Nine hundred seventy-eight patients, representing 4.9% of the total registry population, were identified as having aneurysmal disease. No significant differences were noted between aneurysmal and nonaneurysmal coronary disease patients when features such as hypertension, diabetes, lipid abnormalities, family history, cigarette consumption, incidence of documented myocardial infarction, presence and severity of angina, and presence of peripheral vascular disease were examined. In addition, no difference in 5-year medical survival was noted between these two groups. These findings suggest that aneurysmal coronary disease does not represent a distinct clinical entity but is, rather, a variant of coronary atherosclerosis.
Chronic obstructive pulmonary disease in the older adult: what defines abnormal lung function?
Authors: D. M Mannino, A Sonia Buist, W. M Vollmer
Journal: Thorax (2006)

<b>Background:</b> The Global Initiative on Obstructive Lung Disease stages for chronic obstructive pulmonary disease (COPD) uses a fixed ratio of the post-bronchodilator forced expiratory volume in 1 second (FEV<sub>1</sub>)/forced vital capacity (FVC) of 0.70 as a threshold. Since the FEV<sub>1</sub>/FVC ratio declines with age, using the fixed ratio to define COPD may "overdiagnose" COPD in older populations. <b>Objective:</b> To determine morbidity and mortality among older adults whose FEV<sub>1</sub>/FVC is less than 0.70 but more than the lower limit of normal (LLN). <b>Methods:</b> The severity of COPD was classified in 4965 participants aged ⩾65 years in the Cardiovascular Health Study using these two methods and the age-adjusted proportion of the population who had died or had a COPD-related hospitalisation in up to 11 years of follow-up was determined. <b>Results:</b> 1621 (32.6%) subjects died and 935 (18.8%) had at least one COPD-related hospitalisation during the follow-up period. Subjects (n = 1134) whose FEV<sub>1</sub>/FVC fell between the LLN and the fixed ratio had an increased adjusted risk of death (hazard ratio (HR) 1.3, 95% CI 1.1 to 1.5) and COPD-related hospitalisation (HR 2.6, 95% CI 2.0 to 3.3) during follow-up compared with asymptomatic individuals with normal lung function. <b>Conclusion:</b> In this cohort, subjects classified as "normal" using the LLN but abnormal using the fixed ratio were more likely to die and to have a COPD-related hospitalisation during follow-up. This suggests that a fixed FEV<sub>1</sub>/FVC ratio of &lt;0.70 may identify at-risk patients, even among older adults.