tbuckley/cabot-search huggingface dataset:
Evidence for Multiple Genetic Forms with Similar Eyeless Phenotypes in the Blind Cavefish, Astyanax mexicanus
Authors: Thomas E. Dowling, David P. Martasian, William R. Jeffery
Journal: Molecular Biology and Evolution (2002)

A diverse group of animals has adapted to caves and lost their eyes and pigmentation, but little is known about how these animals and their striking phenotypes have evolved. The teleost Astyanax mexicanus consists of an eyed epigean form (surface fish) and at least 29 different populations of eyeless hypogean forms (cavefish). Current alternative hypotheses suggest that adaptation to cave environments may have occurred either once or multiple times during the evolutionary history of this species. If the latter is true, the unique phenotypes of different cave-dwelling populations may result from convergence of form, and different genetic changes and developmental processes may have similar morphological consequences. Here we report an analysis of variation in the mitochondrial NADH dehydrogenase 2 (ND2) gene among different surface fish and cavefish populations. The results identify a minimum of two genetically distinctive cavefish lineages with similar eyeless phenotypes. The distinction between these divergent forms is supported by differences in the number of rib-bearing thoracic vertebrae in their axial skeletons. The geographic distribution of ND2 haplotypes is consistent with roles for multiple founder events and introgressive hybridization in the evolution of cave-related phenotypes. The existence of multiple genetic lineages makes A. mexicanus an excellent model to study convergence and the genes and developmental pathways involved in the evolution of the eye and pigment degeneration.
Endothelial Cell Adhesion to the Extracellular Matrix Induces c-Src–Dependent VEGFR-3 Phosphorylation Without the Activation of the Receptor Intrinsic Kinase Activity
Authors: Federico Galvagni, Susanna Pennacchini, Ahmad Salameh, Marina Rocchigiani, Francesco Neri, Maurizio Orlandini, Felice Petraglia, Stefano Gotta, Gian Luca Sardone, Giacomo Matteucci, Georg C. Terstappen, Salvatore Oliviero
Journal: Circulation Research (2010)

Integrins cooperate with growth factor receptors to promote downstream signaling for cell proliferation and migration. However, the mechanism of receptor activation is still unknown.To analyze the mechanism of phosphorylation of the vascular endothelial growth factor receptor (VEGFR)-3 by cell adhesion.We show that VEGFR-3 phosphorylation, induced by cell attachment to the extracellular matrix, is independent from the intrinsic kinase activity of the receptor, as evidenced from phosphorylation cell adhesion experiments with a mutant kinase dead receptor or in the presence of the specific kinase inhibitor MAZ 51. Cell adhesion experiments in the presence of the c-Src inhibitor PP2 or in fibroblast triple knockout for c-Src, Yes, and Fyn (SYF) demonstrate that VEGFR-3 phosphorylation, induced by extracellular matrix, is mediated by c-Src. Kinase assays in vitro with recombinant c-Src show that VEGFR-3 is a direct c-Src target and mass spectrometry analysis identified the sites phosphorylated by c-Src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated VEGFR-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins CRKI/II and SHC inducing activation of JNK.These data suggest that cell adhesion to extracellular matrix induces a downstream signaling using the tyrosine kinase receptor VEGFR-3 as scaffold.
THE ROLE OF THE ENDOCRINE GLANDS IN KETOSIS. II. KETONEMIA FOLLOWING INSULIN HYPOGLYCEMIA*
Authors: Thomas T. Amatruda, Joan W. Chase, Frank L. Engel
Journal: Journal of Clinical Investigation (1962)

The pituitary, adrenal, and other endocrine glands are generally assumed to play a critical, or even indispensable role in the development of ketosis.However, a previous study demonstrated that in the rat neither the hypophysis nor the adrenal Awas essential for ketosis during a pro- longed fast (1), although they did influence the magnitude of the ketonemia and recovery there- from as the fast was prolonged.In the present study we investigated the ability of the endocrine-deficient rat to develop ketosis acutely in response to insulin-induced hypoglycemia.In these studies "ketosis" is considered as any state "in which the liver produces aceto- acetic and /3-hydroxybutyric acids more rapidly than they can be burned by the tissues" (2).Quantitatively it may vary from the minimal but physiologically important elevations in fasting to the profound pathological ketosis of diabetic acido- sis.These studies were concerned with physiological rather than pathological ketosis, although in many respects the two differ only in degree.The sequence of events, hypoglycemia followed by ketosis, simulates the metabolic pattern of pro- longed fasting telescoped into a period of a few hours.
Induction of the calcineurin variant CnAβ1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization
Authors: Marina M. López-Olañeta, María Villalba, Jesús M. Gómez-Salinero, Luis J. Jiménez-Borreguero, Ross Breckenridge, Paula Ortiz-Sánchez, Pablo García-Pavía, Borja Ibáñez, Enrique Lara-Pezzi
Journal: Cardiovascular Research (2014)

Ventricular remodelling following myocardial infarction progressively leads to loss of contractile capacity and heart failure. Although calcineurin promotes maladaptive cardiac hypertrophy, we recently showed that the calcineurin splicing variant, CnAβ1, has beneficial effects on the infarcted heart. However, whether this variant limits necrosis or improves remodelling is still unknown, precluding translation to the clinical arena. Here, we explored the effects and therapeutic potential of CnAβ1 overexpression post-infarction.Double transgenic mice with inducible cardiomyocyte-specific overexpression of CnAβ1 underwent left coronary artery ligation followed by reperfusion. Echocardiographic analysis showed depressed cardiac function in all infarcted mice 3 days post-infarction. Induction of CnAβ1 overexpression 1 week after infarction improved function and reduced ventricular dilatation. CnAβ1-overexpressing mice showed shorter, thicker scars, and reduced infarct expansion, accompanied by reduced myocardial remodelling. CnAβ1 induced vascular endothelial growth factor (VEGF) expression in cardiomyocytes, which resulted in increased infarct vascularization. This paracrine angiogenic effect of CnAβ1 was mediated by activation of the Akt/mammalian target of rapamycin pathway and VEGF.Our results indicate that CnAβ1 exerts beneficial effects on the infarcted heart by promoting infarct vascularization and preventing infarct expansion. These findings emphasize the translational potential of CnAβ1 for gene-based therapies.
An exercise challenge protocol for epidemiological studies of asthma in children: comparison with histamine challenge
Authors: MM Haby, SD Anderson, JK Peat, CM Mellis, BG Toelle, AJ Woolcock
Journal: European Respiratory Journal (1994)

We investigated whether an exercise challenge protocol is suitable for measuring bronchial responsiveness in epidemiological studies of asthma in children, and determined its comparability with histamine challenge. The exercise challenge was 6 minutes of outdoor, free-range running at 85-90% of maximum heart rate, measured by heart rate monitor. Nose clips were worn. Distance run was measured to estimate oxygen consumption. Water content of the inspired air was < 10 mg H2O.l-1. Histamine challenge was by the rapid method. We used questionnaires to measure respiratory symptoms and skin prick tests to measure atopy. A total of 96 children aged 8-11 years were studied. Bronchial hyperresponsiveness (BHR) to exercise challenge was defined as a fall in forced expiratory volume in one second (FEV1) of 13% of greater. Eleven children had a positive response to exercise challenge and 11 to histamine challenge but 12 responded to one challenge and not to the other. The correlation coefficient between the two tests was 0.65 (p = 0.0001). Exercise challenge thus proved to be a practical epidemiological tool for objective measurements of bronchial responsiveness in children. In this sample, some children responded to one challenge and not to the other which suggests that the two challenges identify different abnormalities of the airways.
Cooperation of the Agonistic DR5 Antibody Apomab with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival
Authors: Hongkui Jin, Renhui Yang, Jed Ross, Sharon Fong, Richard Carano, Klara Totpal, David Lawrence, Zhong Zheng, Hartmut Koeppen, Howard Stern, Ralph Schwall, Avi Ashkenazi
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Apomab is a fully human monoclonal antibody that induces programmed cell death through the proapoptotic receptor DR5 in various cancer cells but not in normal cells. Several lung cancer cell lines express DR5 and exhibit apoptosis in response to apomab in vitro. Experimental Design: We investigated the efficacy of apomab and its interaction with chemotherapy in xenograft models based on human NCI-H460 non–small-cell lung carcinoma cells. In an established model of s.c. tumor xenografts, apomab or Taxol plus carboplatin chemotherapy delayed tumor progression, whereas combined treatment caused tumor regression and a substantially longer growth delay. To test apomab activity in a setting that may more closely mimic lung cancer pathology in patients, we developed a lung orthotopic model. Results: In this model, microcomputed tomography imaging showed that apomab, chemotherapy, or combination treatment significantly inhibited tumor growth compared with vehicle, whereas the combination caused greater inhibition in tumor growth relative to chemotherapy or apomab. Similarly, histologic analysis revealed that apomab, chemotherapy, or the combination significantly reduced tumor size compared with vehicle, whereas the combination induced significantly greater reduction in tumor size than did chemotherapy or apomab. Furthermore, combined treatment improved 105-day survival relative to vehicle (P = 0.0023) as well as to apomab (P = 0.0445) or chemotherapy (P = 0.0415). Conclusion: These results show a positive interaction of apomab with chemotherapy, evidenced by significant inhibition of tumor growth as well as improved survival, thus supporting further investigation of this therapeutic approach in lung cancer patients.
Bronchoscopy-guided radiofrequency ablation as a potential novel therapeutic tool
Authors: K. Tsushima, T. Koizumi, T. Tanabe, R. Nakagawa, S. Yoshikawa, M. Yasuo, K. Kubo
Journal: European Respiratory Journal (2007)

The aim of the current study was to assess the safety of bronchoscopy-guided radiofrequency ablation (RFA) and compare the effectiveness between new internal cooled-RFA and standard noncooled-RFA. Normal lungs from sheep were used (n=6). Internal cooled-RFA and standard noncooled-RFA were set to assess the most suitable RFA conditions, such as power output, flow rate and ablation time. Internal cooled-RFA was then applied under the most optimal conditions of power output and flow rate for 15, 30, 60 and 120 s, and two water temperatures either room temperature (RT) water or cold water. Criteria for the most appropriate conditions were set over 15 s of ablation time and 50 degrees C of the tip's temperature. Internal cooled-RFA had no complications. Standard noncooled-RFA was complicated with bronchial bleeding after RFA. On the basis of the histological findings, average temperature and average output, the most appropriate conditions of the cooled-RFA were a power output of 30 W and flow rate of 30 or 40 mL.min(-1). The cooled-RFA using cold water caused a smaller, more discrete, lesion compared with that using RT water. Bronchoscopy-guided internal cooled-radiofrequency ablation was an effective, safe and feasible procedure that could become a potential therapeutic tool in managing lung pathology.
Peptide Vaccine Given with a Toll-Like Receptor Agonist Is Effective for the Treatment and Prevention of Spontaneous Breast Tumors
Authors: Pilar Nava-Parada, Guido Forni, Keith L. Knutson, Larry R. Pease, Esteban Celis
Journal: Cancer Research (2007)

Abstract Our goal is to develop peptide vaccines that stimulate tumor antigen–specific T-cell responses against frequently found cancers. Previous work has shown that to generate effective T-cell responses, peptides have to be administered in combination with strong adjuvants such as Toll-like receptor agonists. However, most animal tumor model systems used to study peptide vaccines were not truly representative of malignant diseases in humans because they solely used transplantable tumor lines, and instead of true tumor antigens, they used highly immunogenic foreign proteins. Here, we describe a peptide vaccination strategy, which is highly effective in delaying or preventing the occurrence of spontaneous breast tumors. Transgenic female BALB-neuT mice that carry the activated rat HER-2/neu oncogene were vaccinated with a synthetic peptide from the rat HER-2/neu gene product, which represents an epitope for CTLs in combination with a Toll-like receptor agonist adjuvant. Our results show that to obtain tumor antigen-specific CTL responses and antitumor effects, the vaccine had to be administered repetitively, or the function of CD4/CD25 T regulatory cells had to be blocked with anti-CD25 antibody therapy. Mice that were vaccinated with this approach remained tumor-free or were able to control spontaneous tumor growth and exhibited long-lasting CTL responses, not only against the immunizing peptide but also against other peptides derived from rat HER-2/neu product (i.e., epitope spreading). These results suggest that similar strategies should be followed for conducting clinical studies in patients. [Cancer Res 2007;67(3):1326–34]
Hirudin and nitrates inhibit the thrombin-induced release of endothelin from the intact porcine aorta.
Authors: C M Boulanger, T F Lüscher
Journal: Circulation Research (1991)

In intact porcine aorta, endothelium-derived nitric oxide released on thrombin stimulation inhibits the concomitant production of endothelin. Experiments were designed to examine the effect of hirudin (which inactivates thrombin) and the nitrovasodilators nitroglycerin and 3-morpholinosydnonimine on the spontaneous and thrombin-stimulated release of endothelin in intact blood vessels. Endothelin was detected by radioimmunoassay in the incubating medium of intact porcine aortas with endothelium. The spontaneous release of endothelin was not affected by hirudin (0.1 micrograms/ml) but that induced by thrombin (4 units/ml) was prevented. Nitroglycerin (10(-5) M) and the active metabolite of molsidomine, 3-morpholinosydnonimine (10(-5) M), did not modify the basal production of endothelin from the intima of intact porcine aortas. However, the nitrates fully inhibited the release of the peptide induced by thrombin (4 units/ml). The inhibitory effects of both 3-morpholinosydnonimine and nitroglycerin on the thrombin-stimulated release of endothelin were abolished in the presence of an inhibitor of soluble guanylate cyclase, methylene blue (10(-5) M). Thus, the thrombin-stimulated release of endothelin is inhibited by inactivation of thrombin with hirudin or by agents that mimic the effect of endothelium-derived nitric oxide. In contrast, the spontaneous production of endothelin is not modulated by the drugs.
Cardiovascular Risk Factor Control Among Veterans With Diabetes
Authors: Nicholas L. Smith, Leway Chen, David H. Au, Mary McDonell, Stephan D. Fihn
Journal: Diabetes Care (2004)

OBJECTIVE—To describe the extent to which hyperglycemia, hypertension, and dyslipidemia are currently detected, treated, and controlled in U.S. veterans with diabetes with and without ischemic heart disease (IHD). RESEARCH DESIGN AND METHODS—A cohort of 3,769 veterans who self-reported diabetes and who received all health care from the Veterans Administration (VA) medical centers were selected from subjects enrolled in the Ambulatory Care Quality Improvement Project, a randomized health services intervention at seven VA primary care clinics. IHD was defined by a self-reported history of myocardial ischemia, infarction, or revascularization. Mean values of HbA1c, blood pressure, and cholesterol subfractions were collected from computerized laboratory databases. Medication data were collected from computerized pharmacy databases. RESULTS—Mean HbA1c and optimal control (HbA1c &amp;lt;7%) did not differ for those without and with IHD: 8.1 vs. 8.0%, and 26 vs. 24%, respectively. Veterans with IHD were more likely to have hypertension (73 vs. 64%), to be treated (88 vs. 78%), and to have optimal blood pressure control (19 vs. 10%) compared with veterans without IHD (all P values &amp;lt;0.01). Veterans with IHD were more likely to have dyslipidemia (81 vs. 53%), were equally likely to be treated (54 vs. 50%), and were more likely to have optimal LDL levels (30 vs. 16%) compared with veterans without IHD, all P values &amp;lt;0.01. CONCLUSIONS—Optimal cardiovascular risk factor control was the exception in this cohort of diabetic veterans attending primary care clinics. More aggressive management of cardiovascular risk factors in veterans with diabetes may be warranted, especially among those without prevalent IHD.
Changes in proliferative activity as cells move along undulating basement membranes in stratified squamous epithelium
Authors: W.J. HUME, C.S. POTTEN
Journal: British Journal of Dermatology (1980)

The filiform papillae of mouse tongue provide evidence for a flow of interphase basal cells along the basement membrane. This implies that they are aligned on that structure according to age. In addition there is a decrease in proliferative potential as the basal cells age. This is probably due at least in part to a fall in growth fraction. Such a method of basal cell replacement may exist in other stratified squamous epithelia characterized by undulating basement membranes.
A Decision Analysis of Alternative Treatment Strategies for Clinically Localized Prostate Cancer
Authors: Craig Fleming
Journal: JAMA (1993)

To model the impact of initial therapy on outcomes for men with localized (clinical stage A or B) prostatic carcinoma.A decision analysis modeling three strategies: radical prostatectomy, external-beam radiation therapy, and watchful waiting, with delayed hormonal therapy if metastatic disease develops. We modeled the main benefit of treatment as a reduction in the chance of death or disutility from metastatic disease. These benefits were offset in the model by the risks of treatment-related morbidity and mortality. The model was used to analyze expected outcomes by tumor grade (well, moderately, and poorly differentiated) for men 60 to 75 years of age.Probabilities and rates for important clinical events, obtained through review of the literature for prostatic carcinoma and analysis of Medicare claims data.Several patterns emerged within the range of uncertainty about the risks and benefits of treatment for prostatic carcinoma. In patients with well-differentiated tumor grades, based on clinical staging, treatment at best offers limited benefit in terms of quality-adjusted life expectancy and may result in harm to the patient. Among patients with moderately or poorly differentiated tumors, if we use the most optimistic assumptions about treatment efficacy, then patients aged 60 to 65 years would benefit from either radical prostatectomy or external-beam radiation therapy, compared with watchful waiting. However, in most other cases, treatment offers less than a 1-year improvement in quality-adjusted life expectancy or decreases the quality-adjusted life expectancy compared with watchful waiting. Invasive treatment generally appears to be harmful for patients older than 70 years.Radical prostatectomy and radiation therapy may benefit selected groups of patients with localized prostate cancer, particularly younger patients with higher-grade tumors. However, our model shows that in most cases the potential benefits of therapy are small enough that the choice of therapy is sensitive to the patient's preferences for various outcomes and discounting. The choice of watchful waiting is a reasonable alternative to invasive treatment for many men with localized prostatic carcinoma.
Sleep disordered breathing and enlargement of the right heart after myocardial infarction
Authors: Stefan Buchner, Michael Eglseer, Kurt Debl, Andrea Hetzenecker, Andreas Luchner, Oliver Husser, Christian Stroszczynski, Okka W. Hamer, Claudia Fellner, Florian Zeman, Michael Pfeifer, Michael Arzt
Journal: European Respiratory Journal (2014)

Structural and functional integrity of the right heart is important in the prognosis after acute myocardial infarction (AMI). The objective of this study was to assess the impact of sleep disordered breathing (SDB) on structure and function of the right heart early after AMI. 54 patients underwent cardiovascular magnetic resonance 3–5 days and 12 weeks after AMI, and were stratified according to the presence of SDB, defined as an apnoea–hypopnoea index of ≥15 events·h −1 . 12 weeks after AMI, end-diastolic volume of the right ventricle had increased significantly in patients with SDB (n=27) versus those without (n=25) (mean± sd 14±23% versus 0±17%, p=0.020). Multivariable linear regression analysis accounting for age, sex, body mass index, smoking, left ventricular mass and left ventricular end-systolic volume showed that the apnoea–hypopnoea index was significantly associated with right ventricular end-diastolic volume (B-coefficient 0.315 (95% CI 0.013–0.617); p=0.041). From baseline to 12 weeks, right atrial diastolic area increased more in patients with SDB (2.9±3.7 cm 2 versus 1.0±2.4 cm 2 , p=0.038; when adjusted for left ventricular end systolic volume, p=0.166). SDB diagnosed shortly after AMI predicts an increase of right ventricular end-diastolic volume and possibly right atrial area within the following 12 weeks. Thus, SDB may contribute to enlargement of the right heart after AMI.
Successful Removal of a Solid Uterine Fibroma Weighing Seventy Pounds
Authors: T. S. Wells
Journal: BMJ (1878)

ON February 4th, I878, in consultation with Mr. Symonds of Oxford, I saw a single lady, thirty-six years of age.Her abdomen was enor- mously enlarged by a solid tumour, which extended upwards behind the lower ribs orn both sides, pressing them outwards, and passed downwards into the pelvis, filling up the hollow of the sacrum, and causing prolapse of the posterior wall of thc vagina.This sketch, al-
Long-term patient survival in ANCA-associated vasculitis
Authors: Oliver Flossmann, Annelies Berden, Kirsten de Groot, Chris Hagen, Lorraine Harper, Caroline Heijl, Peter Höglund, David Jayne, Raashid Luqmani, Alfred Mahr, Chetan Mukhtyar, Charles Pusey, Niels Rasmussen, Coen Stegeman, Michael Walsh, Kerstin Westman
Journal: Annals of the Rheumatic Diseases (2010)

The aim of the present study was to detect circulating tumor cells (CTCs) in the peripheral blood of patients with non-metastatic colon cancer and to evaluate whether there is a diurnal variation in the CTC counts. Furthermore, the study aimed to examine the correlation between CTCs and TNM stage, other paraclinical variables and prognosis.Blood samples were collected from 20 consecutive patients with colon cancer TNM stage I-III at four different perioperative time points. Detection of CTCs was performed using the immunological assay CellSearch®.CTCs were detected in 1 out of 60 preoperative blood samples, resulting in a detection rate of 1 in 20 patients (5%; 95% confidence interval = 0.1-25%). None of the postoperative blood samples had CTC levels above the cut-off value (≥ 2 CTCs/7.5 ml blood).The presence of CTCs in non-metastatic colon cancer is rare and barely detectable with the only commercially available assay for detection of CTCs, the CellSearch System.