tbuckley/cabot-search huggingface dataset:
Neonatal ghrelin programs development of hypothalamic feeding circuits
Authors: Sophie M. Steculorum, Gustav Collden, Berengere Coupe, Sophie Croizier, Sarah Lockie, Zane B. Andrews, Florian Jarosch, Sven Klussmann, Sebastien G. Bouret
Journal: Journal of Clinical Investigation (2015)

A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation.
Bronchial and skin reactivity in asthmatic patients with and without atopic dermatitis
Authors: L Brinkman, JA Raaijmakers, CA Bruijnzeel-Koomen, L Koenderman, JW Lammers
Journal: European Respiratory Journal (1997)

It is unclear whether the presence and severity of atopic dermatitis (AD) is predictive for the occurrence and severity of early and late asthmatic responses to inhaled allergens. The aim of this study was to compare the bronchial effects of allergen inhalation challenge in allergic asthma (AA) and atopic dermatitis. We therefore studied these responses in: nine patients with mild-to-moderate AA without AD; eight patients with mild-to-moderate AA and mild AD; eight patients with severe AD and mild AA; and eight patients with severe AD without AA. Allergen challenge was performed by inhaling doubling doses until the dose provoking a 20% fall in forced expiratory volume in one second (PC20) was reached. The late asthmatic reaction (LAR) was defined as a fall of &gt;20% in peak expiratory flow (PEF) between 3 and 8 h after the challenge. All but four of the patients with severe AD without AA developed an early asthmatic response (EAR). A LAR was seen in all patients with severe AD and mild AA, in four patients with mild AD and mild-to-moderate AA, and in three patients with mild-to-moderate AA without AD. The LAR was most pronounced in patients with a combination of mild AA and severe AD. This could be explained, in part, by a decreased skin sensitivity in these patients, which made the Cockcroft formula for prediction of PC20 allergen less accurate in such patients. We conclude that patients with severe atopic dermatitis and mild asthma are at risk for developing pronounced late asthmatic responses after allergen exposure. This suggests that eosinophils activated in atopic dermatitis also predispose to airway inflammation.
A study of the physical working capacity of Gaelic footballers and hurlers.
Authors: A. W. Watson
Journal: British Journal of Sports Medicine (1977)

The possible contribution of endurance fitness to performance in the Gelic games, football and hurling, has been investigated. Two groups of 15 players were compared. The first consisted of members of teams reaching interprovincial finals and the second were similar members of comparable but less successful teams. The measurements taken were: height and weight, skinfold thicknesses on the triceps, biceps, subscapular and suprailiac sites, and the physical working capacity at a heart rate of 170 beats per minute (PWC 170). The more successful players were found to be taller and heavier and to have a higher PWC 170. There was no difference in estimated percentage of fat. The difference in PWC 170 of the two groups remained after correction for the difference in body weight. A group of seven of the players who participated in two or more finals was studied longitudinally. In six of these subjects PWC 170 was higher at the time of these matches than before or after. These findings are discussed and it is suggested that endurance fitness is a factor contributing to performance in football and hurling.
Crucial Role of the Interleukin 1 Receptor Family Member T1/St2 in T Helper Cell Type 2–Mediated Lung Mucosal Immune Responses
Authors: Anthony J. Coyle, Clare Lloyd, Jane Tian, Trang Nguyen, Christina Erikkson, Lin Wang, Par Ottoson, Per Persson, Tracy Delaney, Sophie Lehar, Steve Lin, Louis Poisson, Christian Meisel, Thomas Kamradt, Torbjorn Bjerke, Douglas Levinson, Jose Carlos Gutierrez-Ramos
Journal: The Journal of Experimental Medicine (1999)

T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.
Domiciliary non-invasive ventilation for recurrent acidotic exacerbations of COPD: an economic analysis
Authors: J M Tuggey
Journal: Thorax (2003)

Patients with chronic obstructive pulmonary disease (COPD) pose a significant burden to healthcare providers with frequent exacerbations necessitating hospital admission. Randomised controlled data exist supporting the use of acute non-invasive ventilation (NIV) in patients with exacerbations of COPD with mild to moderate acidosis. The use of NIV is also described in chronic stable COPD, with evidence suggesting a reduction in hospital admissions and general practitioner care. We present economic data on the impact of domiciliary NIV on the need for admission to hospital and its attendant costs.A cost and consequences analysis of domiciliary NIV based on a before and after case note audit was performed in patients with recurrent acidotic exacerbations of COPD who tolerated and responded well to NIV. The primary outcome measure was the total cost incurred per patient per year from the perspective of the acute hospital. Effectiveness outcomes were total days in hospital and in intensive care.Thirteen patients were identified. Provision of a home NIV service resulted in a mean (95% CI) saving of pound sterling 8254 (pound sterling 4013 to pound sterling 12,495) (Euro 11,720; Euro 5698 to Euro 17,743) per patient per year. Total days in hospital fell from a mean (SD) of 78 (51) to 25 (25) (p=0.004), number of admissions from 5 (3) to 2 (2) (p=0.007), and ICU days fell from a total of 25 to 4 (p=0.24). Outpatient visits fell from a mean of 5 (3) to 4 (2) (p=0.14).This study suggests that domiciliary NIV for a highly selected group of COPD patients with recurrent admissions requiring NIV is effective at reducing admissions and minimises costs from the perspective of the acute hospital. Such evidence is important in obtaining financial support for providing such a service.
Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity
Authors: Yuki Kagoya, Akihide Yoshimi, Keisuke Kataoka, Masahiro Nakagawa, Keiki Kumano, Shunya Arai, Hiroshi Kobayashi, Taku Saito, Yoichiro Iwakura, Mineo Kurokawa
Journal: Journal of Clinical Investigation (2014)

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.
From Atomic Structures to Neuronal Functions of G Protein–Coupled Receptors
Authors: Krzysztof Palczewski, Tivadar Orban
Journal: Annual Review of Neuroscience (2013)

G protein-coupled receptors (GPCRs) are essential mediators of signal transduction, neurotransmission, ion channel regulation, and other cellular events. GPCRs are activated by diverse stimuli, including light, enzymatic processing of their N-termini, and binding of proteins, peptides, or small molecules such as neurotransmitters. GPCR dysfunction caused by receptor mutations and environmental challenges contributes to many neurological diseases. Moreover, modern genetic technology has helped identify a rich array of mono- and multigenic defects in humans and animal models that connect such receptor dysfunction with disease affecting neuronal function. The visual system is especially suited to investigate GPCR structure and function because advanced imaging techniques permit structural studies of photoreceptor neurons at both macro and molecular levels that, together with biochemical and physiological assessment in animal models, provide a more complete understanding of GPCR signaling.
Effect of orally administeredL-carnitine on blood ammonia andL-carnitine concentrations in portacaval-shunted rats
Authors: Timothy J. Hearn, Anton E. Coleman, James C.K. Lai, Owen W. Griffith, Arthur J.L. Cooper
Journal: Hepatology (1989)

L-Carnitine (16 mmoles per kg, injected intraperitoneally) is reported to protect mice against subsequent injection of ammonium acetate given at the unprotected LD100. The present studies in rats show a variable protective effect of L-carnitine (16 mmoles per kg) administered 1 hr prior to an LD100 dose of ammonium acetate. Survival ranged from 100% to 35%. In two experiments, protection was highly significant; in a third experiment, L-carnitine did not protect against death but did significantly prolong time to death. Although the cause of this variability is not known, the data establish the protective effect in rats of L-carnitine given 1 hr before ammonium acetate. D-Carnitine and deoxycarnitine, chemically related analogs unable to substitute for L-carnitine metabolically, are without protective effect. The protective effect of L-carnitine is short-lived and is, for example, completely lost if ammonium acetate is given 24 hr after L-carnitine administration. In contrast, the free carnitine content of brain rises slowly but continuously for at least 24 hr following a single dose of L-carnitine. The observation that protection from ammonia toxicity is not correlated with brain carnitine levels strongly suggests a major peripheral component to the protective effect. Chronically hyperammonemic (portacaval-shunted) rats were found to have significantly depressed total and free carnitine levels in blood compared to normal and sham-operated controls. The hypocarnitinemia, but not the hyperammonemia, was completely reversed in portacaval-shunted rats given drinking water containing 10 mM L-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)
Static lung compliance in chronic heart failure: relation with dyspnoea and exercise capacity.
Authors: S A Evans, L Watson, A J Cowley, I D Johnston, W J Kinnear
Journal: Thorax (1995)

The pathogenesis of dyspnoea in patients with chronic heart failure is poorly understood. Static lung compliance is reduced in chronic heart failure. The relation between static lung compliance and exercise capacity and dyspnoea in chronic heart failure has been investigated.Static lung compliance was calculated from expiratory pressure-volume curves in 18 patients with chronic heart failure (three women, mean age 62 years). Catheter mounted pressure transducers were used to measure changes in oesophageal pressure. Changes in lung volume were determined by integrating flow at the mouth, measured by a pneumotachograph. New York Heart Association (NYHA) class for dyspnoea was determined by a single observer. Patients underwent treadmill exercise to symptom limited maximum using staged and fixed rate protocols. Borg ratings for dyspnoea at submaximal exercise were measured.Static lung compliance, whether expressed as % total lung capacity (TLC)/cm H2O or % predicted TLC/cm H2O, was unrelated to NYHA class. Similarly, there was no relation between static lung compliance and exercise capacity with either protocol or with Borg ratings for dyspnoea at submaximal exercise, with the exception of that measured after 11 minutes of the staged protocol.Static lung compliance at rest has no relation with treadmill exercise capacity in chronic heart failure, and its relation with measures of dyspnoea is variable. No role for lung elasticity in determining the symptomatology of chronic heart failure was found.
Can MicroRNAs Improve the Management of Lung Cancer Patients? A Clinician's Perspective
Authors: Amanda Tufman, Fei Tian, Rudolf Maria Huber
Journal: Theranostics (2013)

The treatment of patients with lung cancer is increasingly individualised.Rather than treating lung cancer as a single disease, clinicians are often called upon to consider the precise histology and molecular biology of each tumour in addition to the individual characteristics of each patient.Paralleling advances in lung cancer management, advances in the detection of lung cancer are changing practice.Lung cancer screening promises to find disease at a curable stage; however, the high false positive rate in screening trials has clinical and fiscal ramifications which demand attention.Biomarkers able to stratify for the risk of cancer, prognosticate the course of disease, or predict the response to treatment are in increasing demand.This paper summarizes some of the clinical problems faced by those treating lung cancer patients, and examines how knowledge about the role of microRNAs in lung cancer biology may change patient management.
DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression
Authors: Mei-Yi Hsieh, Jia-Rong Fan, Han-Wen Chang, Hsiang-Chin Chen, Tang-Long Shen, Shu-Chun Teng, Yen-Hsiu Yeh, Tsai-Kun Li
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Human DNA topoisomerase III alpha (hTOP3α) is involved in DNA repair surveillance and cell-cycle checkpoints possibly through formatting complex with tumor suppressors. However, its role in cancer development remained unsolved. Experimental Design: Coimmunoprecipitation, sucrose gradient, chromatin immunoprecipitation (ChIP), real time PCR, and immunoblotting analyses were performed to determine interactions of hTOP3α with p53. Paired cell lines with different hTOP3α levels were generated via ectopic expression and short hairpin RNA (shRNA)-mediated knockdown approaches. Cellular tumorigenic properties were analyzed using cell counting, colony formation, senescence, soft agar assays, and mouse xenograft models. Results: The hTOP3α isozyme binds to p53 and cofractionizes with p53 in gradients differing from fractions containing hTOP3α and BLM. Knockdown of hTOP3α expression (sh-hTOP3α) caused a higher anchorage-independent growth of nontumorigenic RHEK-1 cells. Similarly, sh-hTOP3α and ectopic expression of hTOP3α in cancer cell lines caused increased and reduced tumorigenic abilities, respectively. Genetic and mutation experiments revealed that functional hTOP3α, p53, and p21 are required for this tumor-suppressive activity. Mechanism-wise, ChIP data revealed that hTOP3α binds to the p53 and p21 promoters and positively regulates their expression. Two proteins affect promoter recruitments of each other and collaborate in p21 expression. Moreover, sh-hTOP3α and sh-p53 in AGS cells caused a similar reduction in senescence and hTOP3α mRNA levels were lower in gastric and renal tumor samples. Conclusion: We concluded that hTOP3α interacts with p53, regulates p53 and p21 expression, and contributes to the p53-mediated tumor suppression. Clin Cancer Res; 20(6); 1489–501. ©2014 AACR.
Engagement of Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Induces Transforming Growth Factor β (TGF-β) Production by Murine CD4+ T Cells
Authors: Wanjun Chen, Wenwen Jin, Sharon M. Wahl
Journal: The Journal of Experimental Medicine (1998)

Evidence indicates that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) may negatively regulate T cell activation, but the basis for the inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. CD4(+) T helper type 1 (Th1), Th2, and Th0 clones all secrete TGF-beta after antibody cross-linking of CTLA-4, indicating that induction of TGF-beta by CTLA-4 signaling represents a ubiquitous feature of murine CD4(+) T cells. Stimulation of the CD3-T cell antigen receptor complex does not independently induce TGF-beta, but is required for optimal CTLA-4-mediated TGF-beta production. The consequences of cross-linking of CTLA-4, together with CD3 and CD28, include inhibition of T cell proliferation and interleukin (IL)-2 secretion, as well as suppression of both interferon gamma (Th1) and IL-4 (Th2). Moreover, addition of anti-TGF-beta partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-beta1 gene-deleted (TGF-beta1(-/-)) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our data demonstrate that engagement of CTLA-4 leads to CD4(+) T cell production of TGF-beta, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-beta, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4(+) T cell activation.
The impact of ozone depletion on skin cancer incidence in Korea
Authors: S.G. Lee, N.Y. Ko, S.W. Son, H.J. Bae, J.S. Ha, H.Y. Pak, Y.S. Shin
Journal: British Journal of Dermatology (2013)

Conflict of interest: none declared. Dear Editor, A worldwide depletion of the ozone layer has been observed over the past decade. Concern was heightened when evidence emerged that ozone losses (albeit smaller than those over Antarctica) were also taking place in the Arctic and over heavily populated mid‐latitudes in both the northern and southern hemispheres. The damage to the ozone layer has therefore increased human exposure to ultraviolet (UV) B radiation, and subsequently increased the morbidity of non‐melanoma skin cancer.1 Until now no study has been completed estimating skin cancer incidence caused by ozone depletion in Asia. In this report, we used a simple function based on National Health Insurance databases to estimate increases in skin cancer morbidity because of ozone depletion in Korea. Measurements of solar radiation reaching each location were obtained from a UVB model 501 radiometer (Solar Light Company, Glenside, PA, U.S.A.) at National Weather Service stations located in five administrative districts. These meters measured the minimum erythemal dose (MED). The erythemally weighted UVB irradiance data measured every 10 min from January 1, 2010 to December 31, 2010 were analysed. We calculated the number of patients diagnosed with non‐melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) for the same time period using National Health Insurance databases. Population information for the five administrative districts was obtained from the 2010 Population and Housing Census data.2 Quantitative assessment of the skin cancer risks associated with a given or predicted level of ozone depletion involves two main stages. The first is the estimation of the resulting changes in the biologically effective UV dose received by the population, which is sometimes referred to as the radiation amplification factor (RAF). The absorption spectrum of ozone and the increased carcinogenic impact of UV radiation around 300 nm results in an approximate RAF value of 1.6%.3 The second involves the use of dose‐response models to estimate the change in cancer incidence that can be expected from the change in UV dose, often called the biological amplification factor (BAF). The overall increase in incidence per percentage of ozone depletion is then represented by the amplification factor (AF). ...
Chronic Ethanol Consumption Impairs Receptor–Mediated Endocytosis of Formaldehyde–Treated Albumin by Isolated Rat Liver Endothelial Cells
Authors: Geoffrey M. Thiele, Jacqueline A. Miller, Lynell W. Klassen, Dean J. Tuma
Journal: Hepatology (1999)

Receptor–mediated endocytosis (RME) by a scavenger receptor on sinusoidal liver endothelial cells (LECs) for formaldehyde–treated bovine serum albumin (f–Alb) has previously been shown to be impaired following chronic ethanol consumption. These studies were initially performed by in situ perfusion, making it difficult to determine the point in the process at which RME is affected. Therefore, it was the purpose of this study to use isolated LECs to begin elucidating at what point in the process chronic ethanol consumption affects RME. Initial studies showed that degradation at the single–cell level were similarly decreased at levels that had been observed for in situ studies, suggesting that the ethanol effects can be repeated using isolated LECs, making them useful for in vitro studies. Binding studies with 125 I–formaldehyde-treated bovine serum albumin ( 125 I-f–Alb) demonstrated there was a slight, but significantly different, decrease in binding by LECs from ethanol–fed rats when compared with pair–fed or chow–fed rats. However, the affinity of these receptors was not different between these groups. In contrast, a defect in the initial stages of receptor–ligand internalization was indicated as less surface–bound ligand was internalized and subsequently degraded in cells from the ethanol–treated animals as compared with controls. Additionally, once the data were adjusted for the amount of ligand internalized, the degradation of the internalized ligand was only slightly impaired. These results indicate that chronic ethanol feeding impairs the process of RME by the liver; the major cause of this impairment appears to be caused by a decreased ability of these cells to internalize all of the surface–bound ligand, with a minimal defect in postinternalization events.