tbuckley/cabot-search huggingface dataset:
Subepithelial vascular patterns in bronchial dysplasias using a high magnification bronchovideoscope
Authors: K Shibuya
Journal: Thorax (2002)

<b>Background:</b> We have developed a method of high magnification bronchovideoscopy that enables improved observation of subepithelial vascular patterns of the bronchial mucosa. A study was undertaken to investigate the value of high magnification bronchovideoscopy in the detailed examination of dysplasia in the bronchial mucosa of patients with abnormal mucosal fluorescence. <b>Methods:</b> Thirty one patients with sputum cytology specimens suspicious or positive for malignancy were entered into the study. Conventional white light examination was first performed under local anaesthesia and fluorescence bronchoscopy was also carried out using a light induced fluorescence endoscopy (LIFE) lung system. A high magnification bronchovideoscope (XBF 200HM2) was then used to examine the microvascular network in the bronchial mucosa at sites of normal and abnormal fluorescence and the images obtained were compared with pathological diagnoses from bronchial biopsy specimens. Vascular area ratios were calculated using image analysing apparatus. <b>Results:</b> Vascular networks with regular patterns were observed at 20 of 22 abnormal fluorescence sites in biopsy specimens from patients with bronchitis. However, vascular networks with increased vessel growth and complex networks of tortuous vessels of various sizes were observed in 15 of 21 abnormal fluorescence sites in dysplasia specimens. There was a significant difference between bronchitis and dysplasia specimens (OR=25, 95% CI 5.5 to 113, p&lt;0.0001). Mean vascular area ratios from 16 normal bronchial epithelium specimens with normal fluorescence, and 22 bronchitis and 21 dysplasia specimens with abnormal fluorescence were 0.054 (95% CI 0.039 to 0.07), 0.095 (95% CI 0.072 to 0.118), and 0.173 (95% CI 0.143 to 0.203), respectively. The results indicate a statistically significant increase in vascular area in the three groups (p&lt;0.0001). <b>Conclusion:</b> Areas of increased vessel growth and complex networks of tortuous vessels in the bronchial mucosa detected using a high magnification bronchovideoscope at sites of abnormal fluorescence may enable discrimination between bronchitis and dysplasia.
Deficient guanine nucleotide regulatory unit activity in cultured fibroblast membranes from patients with pseudohypoparathyroidism type I. A cause of impaired synthesis of 3',5'-cyclic AMP by intact and broken cells
Authors: Michael A. Levine, Charles Eil, Robert W. Downs, Allen M. Spiegel
Journal: Journal of Clinical Investigation (1983)

Deficient activity of the guanine nucleotide regulatory protein (G unit), an integral component of the membrane-bound adenylate cyclase complex, has been implicated as the biochemical lesion in many patients with pseudohypoparathyroidism (PHP) type I. In addition to renal resistance to parathyroid hormone in this disorder, there is decreased responsiveness of diverse tissues to hormones that act via 3',5'-cyclic AMP (cAMP). To assess whether a deficiency of G units could account for impaired adenylate cyclase activity, we studied cAMP production in intact cultured fibroblasts and fibroblast plasma membranes from five patients with PHP in response to several activators of adenylate cyclase.
<i>Ex vivo</i> and <i>In vivo</i> Delivery of Anti-Tissue Factor Short Interfering RNA Inhibits Mouse Pulmonary Metastasis of B16 Melanoma Cells
Authors: Mohammed Amarzguioui, Qian Peng, Merete T. Wiiger, Vlada Vasovic, Eshrat Babaie, Torgeir Holen, Jahn M. Nesland, Hans Prydz
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The coagulation trigger tissue factor has been implicated in tumor growth, angiogenesis, and metastasis. In this study, we explore the effects of ex vivo and in vivo delivery of short interfering RNA (siRNA) targeting tissue factor on B16 melanoma colonization of the lung in a murine model for metastasis. The purposes of this work are to establish a noncytotoxic in vivo model for investigation of tissue factor function and provide preclinical assessment of the therapeutic potential of tissue factor siRNA for prevention of metastasis. Experimental Design and Results: C57BL/6 mice were evaluated for pulmonary metastases following tail vein injection of B16 cells transfected with either active or inactive siRNA. Mice receiving cells transfected with active siRNA had significantly lower numbers of pulmonary tumors compared with mice injected with control cells (transfected with inactive siRNA). The average time point at which the mice started to exhibit tumor-associated stress was also increased significantly from 22 days for the control group to 27 days for the experimental group (P = 0.01). In a therapeutically more relevant model, where the siRNA was delivered i.p. and the cells (untransfected) by tail vein injection, an inhibitory effect on metastasis was observed when the siRNA treatment was initiated either before or at the time of cell injection. Conclusions: The results suggest that tissue factor has a crucial function in promoting lung tumor metastasis of blood-borne tumor cells in the early stages of the tumor take process and further suggest that treatment with tissue factor siRNA may become a viable clinical strategy for prevention of tumor metastasis.
Consideration of RNA Secondary Structure Significantly Improves Likelihood-Based Estimates of Phylogeny: Examples from the Bilateria
Authors: M. J Telford
Journal: Molecular Biology and Evolution (2005)

Sequences from ribosomal RNA (rRNA) genes have made a huge contribution to our current understanding of metazoan phylogeny and indeed the phylogeny of all of life. That said, some parts of this rRNA-based phylogeny remain unresolved. One approach to increase the resolution of these trees would be to use more appropriate models of sequence evolution in phylogenetic analysis.
Sexual Disturbances During Clozapine and Haloperidol Treatment for Schizophrenia
Authors: M Hummer, G Kemmler, M Kurz, I Kurzthaler, H Oberbauer, W W Fleischhacker
Journal: American Journal of Psychiatry (1999)

The aim of this study was to evaluate the frequency and course of sexual disturbances associated with clozapine and haloperidol and their potential influence on compliance with medication regimens in patients with schizophrenia.The authors prospectively investigated 153 patients with schizophrenia who received clozapine (N = 100) or haloperidol (N = 53) in a drug monitoring program.The frequency of sexual disturbances was lower in female patients than in male patients. There was no statistically significant difference between the patients taking haloperidol and those taking clozapine in the frequency of these disturbances. Clozapine plasma levels had a significant effect on diminished sexual desire and functional disturbances in male patients. Functional disturbances and diminished sexual desire did not have any influence on compliance in patients taking either haloperidol or clozapine.There was no statistically significant difference between haloperidol and clozapine in regard to their propensity to induce sexual side effects.
RETRACTED: <i>mda-9</i>/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB
Authors: Habib Boukerche, Zao-zhong Su, Luni Emdad, Devanand Sarkar, Paul B. Fisher
Journal: Cancer Research (2007)

Abstract mda-9/Syntenin is a scaffolding PDZ domain-containing protein overexpressed in multiple human cancers that functions as a positive regulator of melanoma metastasis. Using a normal immortal human melanocyte cell line and weakly and highly metastatic human melanoma cell lines, we presently show that mda-9/syntenin initiates a signaling cascade that activates nuclear factor-κB (NF-κB) in human melanoma cells. As a consequence of elevated mda-9/syntenin expression, tumor cell growth and motility, fundamental components of tumor cell invasion and metastatic spread of melanoma cells, are enhanced through focal adhesion kinase (FAK)–induced and p38 mitogen-activated protein kinase (MAPK)–induced activation of NF-κB. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin, NF-κB, using an adenovirus expressing a mutant superrepressor of IκBα, or FAK, and using a dominant-negative mutant of FAK (FRNK), blocks melanoma cell migration, anchorage-independent growth, and invasion. Downstream signaling changes mediated by mda-9/syntenin, which include activation of FAK, p38 MAPK, and NF-κB, promote induction of membrane-type matrix metalloproteinase-1 that then activates pro-MMP-2–promoting migration and extracellular matrix invasion of melanoma cells. These results highlight the importance of mda-9/syntenin as a key component of melanoma metastasis providing a rational molecular target for potentially intervening in the metastatic process. [Cancer Res 2007;67(4):1812–22]
Visceral adipocytes: old actors in obesity and new protagonists in Crohn's disease?
Authors: Alessandra Zulian, Raffaella Cancello, Giancarlo Micheletto, Davide Gentilini, Luisa Gilardini, Piergiorgio Danelli, Cecilia Invitti
Journal: Gut (2011)

Crohn's disease (CD) is a chronic inflammatory bowel disease characterised by a peculiar accumulation of mesenteric adipose tissue covering the inflamed intestinal wall.The authors characterised different adipose tissue compartments of patients with CD using morphological and molecular techniques and compared them to those of subjects with obesity (OB) and healthy subjects with normal weight (N). Adipose tissue samples were taken from subcutaneous adipose tissue, omental visceral adipose tissue (VAT) and healthy mesenteric depot (hMES), as well as from fat wrapping the affected (unhealthy) intestinal tracts (uhMES). Microarray analyses, validated by real-time quantitative PCR technique, were performed in whole adipose tissue and in isolated adipocytes.The morphology of subcutaneous adipose tissue was similar in subjects with CD and those with N. In patients with CD, VAT adipocytes were smaller than those derived from uhMES and hMES and were smaller than VAT adipocytes of subjects with N. The molecular profiles of CD, VAT and uhMES were characterised by upregulation of genes related to inflammation and downregulation of those involved in lipid metabolism. Adipocytes isolated from VAT of subjects with CD and those with OB exhibited similar upregulation of genes involved in inflammation and immunity. VAT adipocytes of patients with CD compared to those of patients with OB also showed a greater upregulation of several anti-inflammatory genes.In patients with CD, VAT distant from uhMES is affected by inflammation and displays features similar to those of VAT of patients with severe OB. The small diameter of VAT adipocytes of CD, together with their high expression of anti-inflammatory genes, suggests a potentially protective role for this tissue. VAT adipocytes may play an important role in the pathophysiology and/or activity of CD.
Lifetime Risks of Common Cancers Among Retinoblastoma Survivors
Authors: Olivia Fletcher, Douglas Easton, Kristin Anderson, Clare Gilham, Marcelle Jay, Julian Peto
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Compared with the general population, carriers of germline mutations in RB1 who survive retinoblastoma (i.e., hereditary retinoblastoma survivors) are at increased risk of early-onset second cancers, particularly sarcomas, brain tumors, and melanoma. However, their risks for the epithelial cancers that commonly occur after age 50 years are not known. Methods: We used hospital records to identify British retinoblastoma survivors born between 1873 and 1950, a period when few British retinoblastoma patients received high-dose radiotherapy. Cancers and deaths were identified by linkage with national registration records. All statistical tests were two-sided. Results: We could trace the cancer histories of 144 survivors of hereditary retinoblastoma. From age 25 to age 84, there were 58 subsequent cancers, for a cumulative cancer incidence of 68.8% (95% confidence interval [CI] = 48.0% to 87.4%) and a cumulative cancer mortality of 56.3% (95% CI = 40.5% to 73.3%). Only eight of the 58 cancers were of bone or soft tissue, in marked contrast to findings from contemporary studies of American patients treated with external beam radiotherapy, among whom most second tumors are sarcomas. Compared with the general population, hereditary retinoblastoma survivors had higher mortality from lung cancer (standardized mortality ratio [SMR] = 7.01, 95% CI = 3.83 to 11.76), bladder cancer (SMR = 26.31, 95% CI = 8.54 to 61.41), and all other epithelial cancers combined (SMR = 3.29, 95% CI = 1.64 to 5.89). The overall standardized mortality ratio for epithelial cancer was inversely proportional to the approximate square of age (exponent of age = −2.1, 95% CI = −3.6 to −0.7), declining from 11.32 (95% CI = 4.15 to 24.64) at age 25–44 to 2.83 (95% CI = 1.04 to 6.16) at age 65–84. Conclusions: Survivors of hereditary retinoblastoma who are not exposed to high-dose radiotherapy have a high lifetime risk of developing a late-onset epithelial cancer. Most of the excess cancer risks in hereditary retinoblastoma survivors might be preventable by limiting exposures to DNA damaging agents (radiotherapy, tobacco, and UV light).
Mutations in the Human Muscle LIM Protein Gene in Families With Hypertrophic Cardiomyopathy
Authors: Christian Geier, Andreas Perrot, Cemil Özcelik, Priska Binner, Damian Counsell, Katrin Hoffmann, Bernhard Pilz, Yvonne Martiniak, Katja Gehmlich, Peter F.M. van der Ven, Dieter O. Fürst, Arnold Vornwald, Eberhard von Hodenberg, Peter Nürnberg, Thomas Scheffold, Rainer Dietz, Karl Josef Osterziel
Journal: Circulation (2003)

Background— Muscle LIM protein (MLP) is an essential nuclear regulator of myogenic differentiation. Additionally, it may act as an integrator of protein assembly of the actin-based cytoskeleton. MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans. Methods and Results— We analyzed 1100 unrelated individuals (400 patients with DCM, 200 patients with HCM, and 500 controls) for mutations in the human CRP3 gene that encodes MLP. We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls. All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with α-actinin and with certain muscle-specific transcription factors. Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to α-actinin. All 3 index patients were characterized by typical asymmetrical septal hypertrophy. Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP. Conclusion— Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM.
Nomogram to Predict Cycle-One Serious Drug-Related Toxicity in Phase I Oncology Trials
Authors: David M. Hyman, Anne A. Eaton, Mrinal M. Gounder, Gary L. Smith, Erika G. Pamer, Martee L. Hensley, David R. Spriggs, Percy Ivy, Alexia Iasonos
Journal: Journal of Clinical Oncology (2014)

All patients in phase I trials do not have equivalent susceptibility to serious drug-related toxicity (SDRT). Our goal was to develop a nomogram to predict the risk of cycle-one SDRT to better select appropriate patients for phase I trials.The prospectively maintained database of patients with solid tumor enrolled onto Cancer Therapeutics Evaluation Program-sponsored phase I trials activated between 2000 and 2010 was used. SDRT was defined as a grade ≥ 4 hematologic or grade ≥ 3 nonhematologic toxicity attributed, at least possibly, to study drug(s). Logistic regression was used to test the association of candidate factors to cycle-one SDRT. A final model, or nomogram, was chosen based on both clinical and statistical significance and validated internally using a bootstrapping technique and externally in an independent data set.Data from 3,104 patients enrolled onto 127 trials were analyzed to build the nomogram. In a model with multiple covariates, Eastern Cooperative Oncology Group performance status, WBC count, creatinine clearance, albumin, AST, number of study drugs, biologic study drug (yes v no), and dose (relative to maximum administered) were significant predictors of cycle-one SDRT. All significant factors except dose were included in the final nomogram. The model was validated both internally (bootstrap-adjusted concordance index, 0.60) and externally (concordance index, 0.64).This nomogram can be used to accurately predict a patient's risk for SDRT at the time of enrollment. Excluding patients at high risk for SDRT should improve the safety and efficiency of phase I trials.
Vitamin D and bone mineral content after intestinal bypass operation for obesity.
Authors: H Rickers, C Christiansen, I Balslev, H Foltved, P Rodbro, M S Christensen
Journal: Gut (1983)

Twenty-three obese subjects who had undergone intestinal bypass operation (end-to-side jejunostomy) were studied with respect to vitamin D and other indices of calcium metabolism. Group 1 (11 patients) was examined before and one year after operation. Group 2 (12 patients, bypass operated two to seven years earlier was investigated twice with an interval of one year. The two groups were comparable. Bone mineral content and alkaline phosphatases were unchanged during the study in both groups. Bone phosphorus/hydroxyproline ratio was high postoperatively indicating a high degree of bone mineralisation. Serum calcium declined rapidly in group 1 to a constant level, which was maintained in group 2. The serum levels of iPTH and 1,25(OH)2D did not change within each group, but combining the two groups demonstrated an increase/decrease in iPTH/1,25(OH)2D over the years. The findings suggest that factors other than 1,25(OH)2D and iPTH are involved in calcium metabolism in such patients. The findings do not justify routine administration to such patients of high potency vitamin D derivatives, f.ex. 1 alpha-OH-D3.
Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease
Authors: Paul Albert, Alvar Agusti, Lisa Edwards, Ruth Tal-Singer, Julie Yates, Per Bakke, Bartolome R Celli, Harvey O Coxson, Courtney Crim, David A Lomas, William MacNee, Bruce Miller, Stephen Rennard, Edwin K Silverman, Jørgen Vestbo, Emiel Wouters, Peter Calverley
Journal: Thorax (2012)

Bronchodilator responsiveness is a potential phenotypic characteristic of chronic obstructive pulmonary disease (COPD). We studied whether change in lung function after a bronchodilator is abnormal in COPD, whether stable responder subgroups can be identified, and whether these subgroups experience different clinical outcomes.1831 patients with COPD, 285 smoking (SC) and 228 non-smoking (NSC) controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. Spirometric reversibility to 400 μg inhaled salbutamol was assessed on four occasions over 1 year.Forced expiratory volume in 1 s (FEV(1)) increase after salbutamol was similar in SC (mean 0.14 litres (SD 0.15)) and COPD (0.12 litres (0.15)) and was significantly greater than NSC (0.08 litres (0.14)). Reversibility status varied with repeated testing in parallel with the day-to-day variation in pre-bronchodilator FEV(1), which was similar in control subjects and patients with COPD. Absolute FEV(1) change decreased by Global initiative for chronic Obstructive Lung Disease (GOLD) stage in patients with COPD (GOLD II, mean 0.16 litres (SD 0.17); III, 0.10 litres (0.13); IV, 0.05 litres (0.08) as did chances of being classified as reversible. CT-defined emphysema was weakly related to the absolute change in FEV(1) post salbutamol. Consistently reversible patients (n=227) did not differ in mortality, hospitalisation or exacerbation experience from irreversible patients when allowing for differences in baseline FEV(1).Reversibility only assessed with salbutamol and defined by FEV(1) criteria. The COPD population was older than the control populations.Post-salbutamol FEV(1) change is similar in patients with COPD and smoking controls but is influenced by baseline lung function and the presence of emphysema. Bronchodilator reversibility status varies temporally and does not distinguish clinically relevant outcomes, making it an unreliable phenotype.
Fully defined in situ cross-linkable alginate and hyaluronic acid hydrogels for myocardial tissue engineering
Authors: Julia Dahlmann, Andreas Krause, Lena Möller, George Kensah, Markus Möwes, Astrid Diekmann, Ulrich Martin, Andreas Kirschning, Ina Gruh, Gerald Dräger
Journal: Biomaterials (2012)
Does Training Spare Insulin Secretion and Diminish Glucose Levels in Real Life?
Authors: Flemming Dela, Kári J Mikines, Michael von Linstow, Henrik Galbo
Journal: Diabetes Care (1992)

Compared with untrained subjects, in trained subjects the increased insulin sensitivity and decreased glucose induced insulin secretion will tend to promote health by decreasing glucose levels and insulin secretion, whereas the increased food intake will tend to increase these variables. To evaluate the net effect of training, we administered oral glucose loads making up identical fractions of daily carbohydrate intake (i.e., same relative glucose loads) to 8 athletes and 7 sedentary subjects (age: 25 ± 1 vs. 24 ± 1 yr [mean ± SE] [NS]; body weight: 76.0 ± 1.3 vs. 79.3 ± 2.3 kg [NS]; maximal oxygen uptake: 76 ± 2 vs. 48 ± 1 ml O2 · kg−1 · min−1 [2P &amp;lt; 0.05], respectively). Furthermore, 24 h plasma concentration profiles of glucose, C-peptide, and insulin were determined during ordinary living conditions. Daily carbohydrate intake was higher (2P &amp;lt; 0.05) in athletes compared with sedentary subjects (678 ± 34 vs. 294 ± 18 g · day−1, respectively). In response to same relative oral glucose loads, glucose and C-peptide responses were similar in athletes compared to sedentary subjects. Twenty-four hour integrated glucose and C-peptide concentrations did not differ between athletes and sedentary subjects (7.4 ± 0.2 vs. 7.3 ± 0.6 mol · L−1 · 1440 min [2P &amp;gt; 0.05] and 923 ± 99 vs. 1047 ± 175 pM · ml−1 · 1440 min [2P &amp;gt; 0.05], respectively), and insulin concentrations tended to be lower in athletes compared with sedentary subjects (124 ± 13 vs. 175 ± 38 pM · ml−1 · 1440 min [2P &amp;gt; 0.05]). It is concluded that, during training, adaptations in pancreas and insulin sensitive tissues allow the necessary increase in food intake without harmful hyperglycemia and overloading of (β-cells, but sparing of insulin secretion and reductions in glucose levels are only relative to food intake. However, training may be wholesome by increasing hepatic insulin extraction and thereby decreasing arterialinsulin levels.