tbuckley/cabot-search huggingface dataset:
Differential Features of Colorectal Cancers Fulfilling Amsterdam Criteria without Involvement of the Mutator Pathway
Authors: Xavier Llor, Elisenda Pons, Rosa M. Xicola, Antoni Castells, Cristina Alenda, Virgínia Piñol, Montserrat Andreu, Sergi Castellví-Bel, Artemio Payá, Rodrigo Jover, Xavier Bessa, Anna Girós, Anna Roca, Miquel A. Gassull
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer. Whereas it has been known that mismatch repair gene mutations are the underlying cause of HNPCC, an undetermined number of patients do not have these alterations. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features. Experimental Design: This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations. Results: Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers. Conclusions: We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.
Expression of cystic fibrosis transmembrane regulator Cl- channels in heart.
Authors: P C Levesque, P J Hart, J R Hume, J L Kenyon, B Horowitz
Journal: Circulation Research (1992)

Cyclic AMP (cAMP)-dependent chloride channels modulate changes in resting membrane potential and action potential duration in response to autonomic stimulation in heart. A growing body of evidence suggests that there are marked similarities in the properties of the cAMP-dependent chloride channels in heart and cystic fibrosis transmembrane regulator (CFTR) chloride channels found in airway epithelia or in cells expressing the CFTR gene product. We isolated poly A+ mRNA from rabbit ventricle and converted it to cDNA for amplification using the polymerase chain reaction (PCR). A fragment corresponding to the nucleotide-binding domain 1 (NBD1) of the CFTR transcript was cloned. Comparison of the amino acid sequence of NBD1 of human CFTR with the deduced sequence of the rabbit heart PCR product indicated 98% identity. Northern blot analysis, using the heart amplification product as a cDNA probe, demonstrated expression of homologous transcripts in human atrium, guinea pig and rabbit ventricle, and dog pancreas. Xenopus oocytes injected with poly A+ mRNA extracted from rabbit and guinea pig ventricle or dog pancreas expressed robust time-independent chloride currents in response to an elevation of cAMP. We conclude that CFTR chloride channels are expressed in heart and are responsible for the observed cAMP-dependent chloride conductance.
Comparison of clinical features between patients of lung cancer with combined pulmonary fibrosis and emphysema syndrome and those with interstitial pneumonia
Authors: Hironori Uruga, Takeshi Fujii, Atsuko Kurosaki, Shigeo Hanada, Sayaka Mochiduki, Shinko Suzuki, Hisashi Takaya, Atsushi Miyamoto, Nasa Morokawa, Sakashi Fujimori, Tadasu Kono, Kazuma Kishi
Journal: European Respiratory Journal (2012)

Purpose : Patients with combined pulmonary fibrosis and emphysema syndrome(CPFE) and those with interstitial pneumonia(IP) have a high risk of developing lung cancer. The present study compared the clinical features of patients with lung cancer and CPFE with those of patients with lung cancer and IP.  Methods : 48 patients with lung cancer and CPFE(CPFE group) and 30 patients with lung cancer and IP(IP group) had surgery and were included this study.  Results : All patients in the CPFE group and 24 of 30 patients in the IP group were current or ex-smokers(p = 0.01)(Table 1). The CPFE group tended to have more patients with IPF than the IP group(p=0.09). FEV1.0% predicted was significantly lower in the CPFE group than in the IP group(Table 2). Acute exacerbations of interstitial lung disease after surgery developed in three patients(6.3%), one of whom died, in the CPFE group and two patients(6.7%) in the IP group(p = 0.94).  Conclusions : Although IPF was more frequent in the CPFE group than in the IP group, the occurrence of acute exacerbations after surgery was not different between the two groups.
Mapping of the IgE and IgG4 sequential epitopes of milk allergens with a peptide microarray–based immunoassay
Authors: Inmaculada Cerecedo, Javier Zamora, Wayne G. Shreffler, Jing Lin, Ludmilla Bardina, Ma Carmen Dieguez, Julie Wang, Alfonso Muriel, Belén de la Hoz, Hugh A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2008)
Socioeconomic and Racial Disparities in Cancer Risk from Air Toxics in Maryland
Authors: Benjamin J. Apelberg, Timothy J. Buckley, Ronald H. White
Journal: Environmental Health Perspectives (2005)

We linked risk estimates from the U.S. Environmental Protection Agency's National Air Toxics Assessment (NATA) to racial and socioeconomic characteristics of census tracts in Maryland (2000 Census) to evaluate disparities in estimated cancer risk from exposure to air toxics by emission source category. In Maryland, the average estimated cancer risk across census tracts was highest from on-road sources (50% of total risk from nonbackground sources), followed by nonroad (25%), area (23%), and major sources (< 1%). Census tracts in the highest quartile defined by the fraction of African-American residents were three times more likely to be high risk (> 90th percentile of risk) than those in the lowest quartile (95% confidence interval, 2.0-5.0). Conversely, risk decreased as the proportion of whites increased (p < 0.001). Census tracts in the lowest quartile of socioeconomic position, as measured by various indicators, were 10-100 times more likely to be high risk than those in the highest quartile. We observed substantial risk disparities for on-road, area, and nonroad sources by socioeconomic measure and on-road and area sources by race. There was considerably less evidence of risk disparities from major source emissions. We found a statistically significant interaction between race and income, suggesting a stronger relationship between race and risk at lower incomes. This research demonstrates the utility of NATA for assessing regional environmental justice, identifies an environmental justice concern in Maryland, and suggests that on-road sources may be appropriate targets for policies intended to reduce the disproportionate environmental health burden among economically disadvantaged and minority populations.
Maternal genetic asthma predisposition affects signaling networks in lungs of neonatal offspring
Authors: Petra Nathan, Stefan Dehmel, Rabea Imker, Martin Irmler, Steffen Sass, Nikola Müller, Oliver Eickelberg, Susanne Krauss-Etschmann
Journal: European Respiratory Journal (2012)

Introduction:  Exposure-induced deregulation of microRNAs (miRs) during early critical developmental periods has been proposed to contribute to the propagation of asthma risk in later life.   Aim:   We asked if maternal genetic asthma predisposition is sufficient to affect pulmonary miR and also mRNA profiles in offspring that do not bear the genetic asthma risk. To address this question, we used female mice with a heterozygous deficiency for Tbx21 as they develop spontaneous airway remodeling and airway hyperreactivity (Finotto et al., Science, 2002; 295:336).   Methods:  Female C57BL/6J Tbx21+/- mice were mated with wild type (wt) males. Neonatal lungs from wt pups of dams with (Tbx21+/-, n=8) and without (wt, n=8) genetic asthma predisposition were removed within 24h after birth and total mRNA including small RNAs was extracted. RNA from individual animals was subjected to microRNA (ABI, TaqMan® Array microRNA cards) and mRNA (Affymetrix Mouse Gene ST 1.0® arrays) expression profiling. Counter-regulated miRNA-mRNA pairs were further analyzed for pathway enrichment using in silico tools (GePS, IPA).   Results:   After adjustment for gender differences 57 miRNAs and 2599 mRNAs were differentially regulated. Within these, 39 miRNAs paired to 1456 mRNA targets according to expression regulation. Enrichment analysis showed that developmentally important pathways (e.g. growth factor and BMP-signaling) are affected by exposure to maternal asthma predisposition even in the absence of genetic risk in the pups.   Conclusion:  These data show that maternal genetic asthma predisposition affects pulmonary miR and mRNA profiles during an early developmental stage and might therefore influence lung development.
Risk of Bacterial Meningitis in Children with Cochlear Implants
Authors: Jennita Reefhuis, Margaret A. Honein, Cynthia G. Whitney, Shadi Chamany, Eric A. Mann, Krista R. Biernath, Karen Broder, Susan Manning, Swati Avashia, Marcia Victor, Pamela Costa, Owen Devine, Ann Graham, Coleen Boyle
Journal: New England Journal of Medicine (2003)

In June 2002, the Food and Drug Administration received reports of bacterial meningitis in patients with cochlear implants for treatment of hearing loss. Implants that included a positioner (a wedge inserted next to the implanted electrode to facilitate transmission of the electrical signal by pushing the electrode against the medial wall of the cochlea) were voluntarily recalled in the United States in July 2002.We identified patients with meningitis and conducted a cohort study and a nested case-control investigation involving 4264 children who had received cochlear implants in the United States between January 1, 1997, and August 6, 2002, and who were less than six years of age when they received the implants. We calculated the incidence of meningitis in the cohort and assessed risk factors for meningitis among patients and among 199 controls, using data from interviews with parents and abstracted from medical records.We identified 26 children with bacterial meningitis. The incidence of meningitis caused by Streptococcus pneumoniae was 138.2 cases per 100,000 person-years--more than 30 times the incidence in a cohort of the same age in the general U.S. population. Postimplantation bacterial meningitis was strongly associated with the use of an implant with a positioner (odds ratio, 4.5 [95 percent confidence interval, 1.3 to 17.9], with adjustment for medical, surgical, and environmental factors) and with the joint presence of radiographic evidence of a malformation of the inner ear and a cerebrospinal fluid leak (adjusted odds ratio, 9.3 [95 percent confidence interval, 1.2 to 94.5]). The incidence of meningitis among patients who had received an implant with a positioner remained higher than the incidence among those whose implants did not have a positioner for the duration of follow-up (24 months from the time of implantation).Parents and health care providers should ensure that all children who receive cochlear implants are appropriately vaccinated and are then monitored and treated promptly for any bacterial infections after receiving the implant.
Acute effects of therapeutic irradiation for prostatic carcinoma on anorectal function
Authors: E K Yeoh, A Russo, R Botten, R Fraser, D Roos, M Penniment, M Borg, W M Sun
Journal: Gut (1998)

The incidence of anorectal symptoms after radiotherapy (RTH) for localised pelvic malignant disease is unclear. In addition, the effects of pelvic irradiation on both anorectal motility and sensory function are poorly defined. A prospective study was therefore performed on 35 patients (55-82 years of age) with localised prostatic carcinoma before and four to six weeks after RTH to assess its effects on anorectal function.Anorectal symptoms were assessed by questionnaire. Anorectal pressures at rest and in response to voluntary squeeze, rectal distension, and increases in intra-abdominal pressure were evaluated with perfused sleeve side hole manometry. Rectal sensation was tested during graded balloon distension. Rectal compliance was calculated by the pressure-volume relation obtained during the testing of rectal sensation. Ultrasound was used to determine anal sphincter structure and integrity.RTH had no effect on anal sphincter morphology. The frequency of defecation increased after RTH (7 (3-21) v 10 (3-56) bowel actions a week; p < 0.01). After RTH, 16 patients had faecal urgency and eight faecal incontinence, compared with five and one respectively before RTH (p < 0.01 for each). Basal and squeeze sleeve recorded pressures were reduced after RTH (54 (3) v 49 (3) mm Hg (p < 0.05) and 111 (8) v 102 (8) mm Hg (p < 0.01), before and after RTH respectively; means (SEM)). Rectal compliance was reduced after RTH (1.2 v 1.4 mm Hg/ml, p < 0.05). After RTH, threshold volumes for perception of rectal distension were lower in the 16 patients who either experienced faecal urgency for the first time (13 patients) or reported worsening of this symptom (three patients) compared with the remaining patients (34 (4) v 48 (5) ml respectively, p < 0.05).Faecal incontinence (23%) is a common problem four to six weeks after RTH for prostatic carcinoma and is associated with minor reductions in anal sphincter pressures. The high prevalence of faecal urgency in patients after RTH may be related to alterations in rectal perception of stool.
A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the BeSt study
Authors: K. Visser, Y. P. M. Goekoop-Ruiterman, J. K. de Vries-Bouwstra, H. K. Ronday, P. E. H. Seys, P. J. S. M. Kerstens, T. W. J. Huizinga, B. A. C. Dijkmans, C. F. Allaart
Journal: Annals of the Rheumatic Diseases (2010)

To develop a matrix model for the prediction of rapid radiographic progression (RRP) in subpopulations of patients with recent-onset rheumatoid arthritis (RA) receiving different dynamic treatment strategies.Data from 465 patients with recent-onset RA randomised to receive initial monotherapy or combination therapy were used. Predictors for RRP (increase in Sharp-van der Heijde score > or =5 after 1 year) were identified by multivariate logistic regression analysis. For subpopulations, the estimated risk of RRP per treatment group and the number needed to treat (NNT) were visualised in a matrix.The presence of autoantibodies, baseline C-reactive protein (CRP) level, erosion score and treatment group were significant independent predictors of RRP in the matrix. Combination therapy was associated with a markedly reduced risk of RRP. The positive and negative predictive values of the matrix were 62% and 91%, respectively. The NNT with initial combination therapy to prevent one patient from RRP with monotherapy was in the range 2-3, 3-7 and 7-25 for patients with a high, intermediate and low predicted risk, respectively.The matrix model visualises the risk of RRP for subpopulations of patients with recent-onset RA if treated dynamically with initial monotherapy or combination therapy. Rheumatologists might use the matrix for weighing their initial treatment choice.
COPD, end of life and Ceiling of Treatment: Table 1
Authors: D Robin Taylor
Journal: Thorax (2014)

An elderly patient with severe COPD and at least four previous admissions with acute on chronic respiratory failure was admitted under my care. During the final admission, an end-of-life conversation took place with the patient and his family, acknowledging that the patient was terminally ill. It was agreed that treatment would be limited to oxygen, fluids, lorazepam and morphine. This was documented, but at 3:00 next morning, when nursing staff noted the patient to be more breathless, the on-call registrar commenced non-invasive ventilation (NIV). The patient died 4 h later, incommunicado. The family lodged an informal complaint.

Death is inevitable. Death is sometimes preventable, but ultimately it is only postponed. This existential truth applies to us all. More immediately, the logic applies to patients with severe COPD just as it does to patients with disseminated malignancy. The only difference between these situations is that the trajectory towards end of life is less predictable in COPD; the distinction between preventable and inevitable death is more difficult to make. However in ‘frequent flyers’ with severe COPD, the distinction is crucial in deciding how to provide best possible care. Just because it is difficult does not mean that the challenge should be avoided. How we manage life-threatening exacerbations of COPD should be appropriate and we need to be prepared to adapt our approach as the patient nears the end of life. Such responsiveness will impact positively on the quality of care received by patients and perceived by families.

Many studies have highlighted the predictors for mortality for COPD. The underlying assumption is that by identifying these factors, we will focus our efforts on high-risk patients with a view to reducing mortality. The most reliable predictor of mortality is the frequency of exacerbations, and the most reliable predictor of exacerbations is the frequency of exacerbations …
Pulmonary deposition and clearance of aerosolized alpha-1-proteinase inhibitor administered to dogs and to sheep.
Authors: R M Smith, L D Traber, D L Traber, R G Spragg
Journal: Journal of Clinical Investigation (1989)

Augmentation of lung antiprotease levels may be an important therapeutic intervention in the prevention of pulmonary emphysema. We have administered aerosols of plasma-derived human alpha 1 proteinase inhibitor (A1PI) to the lungs of dogs and sheep to investigate (a) delivery of the protein to the distal air spaces of the lung; (b) maintenance of functional activity of the protein; and (c) flux of the protein across the components of the alveolar-capillary membrane. A1PI (26.4 mg/kg body weight) was administered as an aerosol to anesthetized animals; sheep were prepared for the chronic collection of lung lymph. Immunoperoxidase staining of lung tissue obtained 2 h after administration of A1PI demonstrated the presence of human A1PI on the surface of alveoli and distal bronchioles. Bronchoalveolar lavage fluid recovered at intervals after A1PI administration demonstrated time-dependent elevations of human A1PI levels with augmentation of lavage fluid antielastase activity in proportion to the content of human A1PI. Using radiolabeled A1PI as a tracer, we found that 32% of the aerosol was retained in the animals' lungs. Measurements of the rate of loss of A1PI from the lung and of the rate of appearance of human A1PI in plasma resulted in a calculated permeability of the alveolar-capillary membrane to A1PI of 3.49-6.39 X 10(-10) cm/s. Experiments using instrumented sheep allowed independent calculation of endothelial permeability to A1PI of 122-236 X 10(-10) cm/s and calculation of epithelial permeability of 4.70-4.81 X 10(-10) cm/s. Modeling of aerosol delivery of A1PI to humans using the results of these studies predicts that the ratio of plasma/alveolar levels of delivered A1PI will be 0.024, and that aerosolization of 175 mg A1PI/d will result in an A1PI alveolar fluid level of 1.0 mg/ml. Aerosol administration of A1PI may provide an efficient method of augmenting alveolar antiprotease levels.
Neutralizing antibody to interleukin 4 induces systemic protection and T helper type 1-associated immunity in murine candidiasis.
Authors: L Romani, A Mencacci, U Grohmann, S Mocci, P Mosci, P Puccetti, F Bistoni
Journal: The Journal of Experimental Medicine (1992)

An interleukin 4 (IL-4)-specific monoclonal antibody (mAb) was administered to mice infected systemically with the yeast Candida albicans, and the animals were monitored for mortality, development of delayed-type hypersensitivity, production of antibodies of different isotypes, release of IL-2, IL-4, IL-6, and interferon gamma (IFN-gamma) in vitro by splenic CD4+ lymphocytes, and levels of IL-4 and IFN-gamma mRNA in these cells. Neutralization of IL-4 by three weekly injections of mAb in several independent experiments resulted in an overall cure rate of 81% versus 0% of controls. Cure was associated with efficient clearance of the yeast from infected organs and histologic evidence of disease resolution, detection of strong T helper type 1 (Th1) responses, and establishment of long-lasting protective immunity. Soon after infection, and as a result of the first or second injection of mAb, there was a decrease in IL-4 mRNA in CD4+ cells, which was accompanied by an increase in the levels of IFN-gamma-specific transcripts. Our data thus indicate that the production of IL-4 by Th2 cells may limit Th1-associated protective immunity in murine candidiasis.
Dendritic Cells Recognize Tumor-Specific Glycosylation of Carcinoembryonic Antigen on Colorectal Cancer Cells through Dendritic Cell–Specific Intercellular Adhesion Molecule-3–Grabbing Nonintegrin
Authors: Klaas P.J.M. van Gisbergen, Corlien A. Aarnoudse, Gerrit A. Meijer, Teunis B.H. Geijtenbeek, Yvette van Kooyk
Journal: Cancer Research (2005)

Abstract Dendritic cells play a pivotal role in the induction of antitumor immune responses. Immature dendritic cells are located intratumorally within colorectal cancer and intimately interact with tumor cells, whereas mature dendritic cells are present peripheral to the tumor. The majority of colorectal cancers overexpress carcinoembryonic antigen (CEA), and malignant transformation changes the glycosylation of CEA on colon epithelial cells, resulting in higher levels of Lewisx and de novo expression of Lewisy on tumor-associated CEA. Dendritic cells express the C-type lectin dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN) that has high affinity for nonsialylated Lewis antigens, so we hypothesized that DC-SIGN is involved in recognition of colorectal cancer cells by dendritic cells. We show that immature dendritic cells within colorectal cancer express DC-SIGN and that immature dendritic cells but not mature dendritic cells interact with tumor cells. DC-SIGN mediates these interactions through binding of Lewisx and Lewisy carbohydrates on CEA of colorectal cancer cells. In contrast, DC-SIGN does not bind CEA expressed on normal colon epithelium that contains low levels of Lewis antigens. This indicates that dendritic cells may recognize colorectal cancer cells through binding of DC-SIGN to tumor-specific glycosylation on CEA. Similar to pathogens that target DC-SIGN to escape immunosurveillance, tumor cells may interact with DC-SIGN to suppress dendritic cell functions.