tbuckley/cabot-search huggingface dataset:
Deletion of Angiotensin II Type 2 Receptor Exaggerated Atherosclerosis in Apolipoprotein E–Null Mice
Authors: Masaru Iwai, Rui Chen, Zhen Li, Tetsuya Shiuchi, Jun Suzuki, Ayumi Ide, Masahiro Tsuda, Midori Okumura, Li-Juan Min, Masaki Mogi, Masatsugu Horiuchi
Journal: Circulation (2005)

Background— The role of angiotensin II (Ang II) type 2 (AT 2 ) receptor in atherosclerosis was explored with the use of AT 2 receptor/apolipoprotein E (ApoE)–double-knockout (AT 2 /ApoE-DKO) mice, with a focus on oxidative stress. Methods and Results— After treatment with a high-cholesterol diet (1.25% cholesterol) for 10 weeks, ApoE-knockout (KO) mice developed atherosclerotic lesions in the aorta. In AT 2 /ApoE-DKO mice receiving a high-cholesterol diet, the atherosclerotic changes were further exaggerated, without significant changes in plasma cholesterol level and blood pressure. In the atherosclerotic lesion, an increase in superoxide production, NADPH oxidase activity, and expression of p47 phox was observed. These changes were also greater in AT 2 /ApoE-DKO mice. An Ang II type 1 (AT 1 ) receptor blocker, valsartan, inhibited atherosclerotic lesion formation, superoxide production, NADPH oxidase activity, and p47 phox expression; these inhibitory effects were significantly weaker in AT 2 /ApoE-KO mice. We further examined the signaling mechanism of the AT 2 receptor–mediated antioxidative effect in cultured fetal vascular smooth muscle cells. NADPH oxidase activity and phosphorylation and translocation of p47 phox induced by Ang II were inhibited by valsartan but enhanced by an AT 2 receptor blocker, PD123319. Conclusions— These results suggest that AT 2 receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT 2 receptor stimulation by unbound Ang II.
Changes to NHS reforms will increase bureaucracy and treble the number of statutory organisations
Authors: A. O'Dowd
Journal: BMJ (2011)

The government’s changes to planned reforms of the NHS will create a more complicated and overly bureaucratic health service in which the number of statutory organisations will increase threefold to 521, MPs have heard.

Warnings that the recent amendments to the Health and Social Care Bill will make the NHS more complex and constrain doctor led commissioning groups came from several witnesses during a whole day evidence session on 28 June of the parliamentary Health and Social Care Bill Committee, which has been reconvened to scrutinise the changes to the bill.

The Department of Health last week published 180 amendments to the health bill to take into account the recommendations of the NHS Future Forum—the independent body set up by the government to review the planned reforms when they were “paused” in April.

MPs on the committee asked whether the new recommitted bill was now more complex and did it involve more reorganisation and more bureaucracy than its predecessor?

Clara Gerada, chair of the Royal College of General Practitioners (RCGP), giving evidence, said: “With the new bill, post pause, we have calculated that we have gone from 163 statutory organisations to a proposed 521 statutory organisations.

“We have clearly massively increased the bureaucracy within the new ‘post pause’ NHS. The current bill appears to be very incoherent. No matter what one felt about the pre-pause bill, it was coherent. This is now incoherent and is neither liberating nor controlling. It neither allows for GPs to be able …
CLEC-2 is required for development and maintenance of lymph nodes
Authors: Cécile Bénézech, Saba Nayar, Brenda A. Finney, David R. Withers, Kate Lowe, Guillaume E. Desanti, Clare L. Marriott, Steve P. Watson, Jorge H. Caamaño, Christopher D. Buckley, Francesca Barone
Journal: Blood (2014)
Free fatty acids act as endogenous ionophores, resulting in Na+ and Ca2+ influx and myocyte apoptosis
Authors: Kwang-Ming Fang, An-Sheng Lee, Ming-Jai Su, Chien-Liang Lin, Chung-Liang Chien, Mei-Lin Wu
Journal: Cardiovascular Research (2008)

Disturbances in lipid metabolism have been suggested to play an important role in myocardial damage. Marked accumulation of free fatty acids (FFAs), including arachidonic acid (AA), palmitic acid, oleic acid, and linoleic acid, occurs during post-ischaemia and reperfusion (post-I/R). Possible cellular mechanisms of AA/FFAs-induced mycoyte apoptosis were investigated. In neonatal rat ventricular myocytes, AA/FFAs activate a novel non-selective cation conductance (NSCC), resulting in both intracellular Ca2+ and Na+ overload. AA caused sustained cytosolic [Na+]cyt and [Ca2+]cyt overload, resulting in mitochondrial [Na+]m and [Ca2+]m overload, which induced caspase-3-mediated apoptosis. Similar apoptotic effects were seen using Na+ ionophore cocktail/Ca2+-free medium, which induced [Na+]cyt and [Na+]m, but not [Ca2+]cyt and [Ca2+]m overload. Electron microscopy showed that inhibition of [Na+]m overload prevented disruption of the mitochondrial membrane, showing that [Na+]m overload is an important upstream signal in AA- and FFA-induced myocyte apoptosis. AA and FFAs, which accumulate in the myocardium during post-I/R, may therefore act as naturally occurring endogenous ionophores and contribute to the myocyte death seen during post-I/R.
Transforming Growth Factor-β Promotes Survival of Mammary Carcinoma Cells through Induction of Antiapoptotic Transcription Factor DEC1
Authors: Shogo Ehata, Aki Hanyu, Makoto Hayashi, Hiroyuki Aburatani, Yukio Kato, Makoto Fujime, Masao Saitoh, Keiji Miyazawa, Takeshi Imamura, Kohei Miyazono
Journal: Cancer Research (2007)

Abstract Transforming growth factor-β (TGF-β) signaling facilitates tumor growth and metastasis in advanced cancer. In the present study, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stra13) as a downstream target of TGF-β signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC(A) and 4T1, the TGF-β type I receptor kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-β induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TGF-β type I receptor kinase inhibitors as well as by expression of dominant-negative TGF-β type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC(A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-β–promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC(A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-β–mediated cell survival and metastasis of cancer. [Cancer Res 2007;67(20):9694–703]
The B7 Family and Cancer Therapy: Costimulation and Coinhibition
Authors: Xingxing Zang, James P. Allison
Journal: Clinical Cancer Research (2007)

Abstract The activation and development of an adaptive immune response is initiated by the engagement of a T-cell antigen receptor by an antigenic peptide-MHC complex. The outcome of this engagement is determined by both positive and negative signals, costimulation and coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. The importance of costimulation and coinhibition of T cells in controlling immune responses is exploited by tumors as immune evasion pathways. Absence of the expression of costimulatory B7 molecules renders tumors invisible to the immune system, whereas enhanced expression of inhibitory B7 molecules protects them from effective T cell destruction. Therefore, the manipulation of these pathways is crucial for developing effective tumor immunotherapy. Translation of our basic knowledge of costimulation and coinhibition into early clinical trials has shown considerable promise.
Defective acid base regulation by the gall bladder epithelium and its significance for gall stone formation.
Authors: J N Plevris, I A Bouchier
Journal: Gut (1995)

Gall stone disease is a common cause of morbidity and cholecystectomy represents the most common elective abdominal operation in Western society. In the United Kingdom alone about 20% of the population may expect to develop cholelithiasis.' Initially most research had been focused on the biochemical changes that occur in bile during gall stone formation. Recent years have seen significant advances in our knowledge and it is now recognised that the gall bladder is not a passive reservoir but has several absorptive, secretory, and motor functions, which are integrated to produce concentrated bile. The interactions between gall bladder bile and mucosa are of paramount importance to maintain the fine balance between concentration and precipitation of the biliary constituents. The gall bladder mucosa has one of the highest rates of water absorption in the body and an 80-90% decrease in the initial volume of bile occurs within the gall bladder. This is achieved by the coupling of active sodium transport and passive water absorption resulting in isotonic fluid absorption.2 Fluid transport is subject to a variety of influences such as chronic inflammation or the presence of pharmacological agents (prostaglandins, prostacyclin, and various gastrointestinal peptides); fluid absorption is higher in daytime and is reversed to net secretion with feeding.3 Electrolyte transport has been extensively investigated; chloride is actively absorbed in exchange for bicarbonate, and potassium moves from the mucosa to the serosa according to electrochemical gradients.4 5 Calcium is also absorbed and its distribution across the gall bladder epithelium is of importance in the formation of gall stones.6
Carcinoembryonic Antigen in Histopathology: Immunoperoxidase Staining of Conventional Tissue Sections2
Authors: David M. Goldenberg, Robert M. Sharkey, F. James Primus
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Carcinoembryonic Antigen in Histopathology: Immunoperoxidase Staining of Conventional Tissue Sections Get access David M. Goldenberg, David M. Goldenberg Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert M. Sharkey, Robert M. Sharkey Search for other works by this author on: Oxford Academic PubMed Google Scholar F. James Primus F. James Primus Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 57, Issue 1, July 1976, Pages 11–22, https://doi.org/10.1093/jnci/57.1.11 Published: 01 July 1976 Article history Received: 22 September 1975 Accepted: 06 January 1976 Published: 01 July 1976
Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation
Authors: Yasodha Natkunam, Izidore S. Lossos, Behnaz Taidi, Shuchun Zhao, Xiao Qing Lu, Feying Ding, Anne Sofie Hammer, Teresa Marafioti, Gerald E. Byrne, Shoshana Levy, Roger A. Warnke, Ronald Levy
Journal: Blood (2005)
The relationship between cyclic adenosine 3',5'-monophosphate and biochemical events in rat skin after the induction of epidermal hyperplasia using hexadecane
Authors: ROBIN F. PETERS, ALAN M. WHITE
Journal: British Journal of Dermatology (1978)

Sequential changes in skin metabolism have been studied in a model system of epidermal hyperplasia and hyperkeratinization induced by the application of n-hexadecane to shaved rat skin. The epidermal accumulation of glycogen typical of the hyperplastic response has been correlated with an increase in glycogenesis and a decrease in glycogenolysis. DNA synthesis was increased by 6 h after the start of hexadecane treatment and reached a maximum after one day. The concentration of skin cyclic AMP fell immediately after hexadecane application and subsequently rose to give a prolonged increase. Use of the combined topical application of hexadecane and the anti-inflammatory drugs triamcinolone acetonide, hydrocortisone and indomethacin showed that the hexadecane-induced changes in DNA synthesis and glycogen metabolism were linked to the initial fall in cyclic AMP concentration. The significance of the biphasic change in cyclic AMP levels is discussed as a possible system of control for the development and maintenance of hyperplasia.
Accessory cells in murine Peyer's patch. I. Identification and enrichment of a functional dendritic cell.
Authors: D M Spalding, W J Koopman, J H Eldridge, J R McGhee, R M Steinman
Journal: The Journal of Experimental Medicine (1983)

Previous studies have suggested that in vitro and in vivo immune responses are defective in Peyer's patch (PP) as a result of a deficiency in accessory cell number or function. However, we report here that enzymatic dissociation of PP does release a cell population with accessory activity in oxidative mitogenesis, i.e., the proliferation of periodate-modified T cells. The accessory activity present in PP is quantitatively similar to that of spleen. Accessory function is mediated by a cell type(s) that has the following characteristics: low buoyant density, lack of adherence to plastic or glass surfaces, lack of Fc receptors, and presence of surface Ia and the 33D1 dendritic cell (DC)-specific determinants. This PP accessory cell was markedly enriched by a novel technique. PP cells formed large aggregates when cultured for 16 h with irradiated, periodate-treated spleen cells. From the clusters we obtained a low density cell population that was 60% Ia positive, 33D1 positive, non-T and non-B, Fc receptor-negative, and dendritic in morphology. The DC-enriched populations were 60-80-fold enriched in accessory function relative to unfractionated PP. We can now compare PP accessory cells with accessory cells from other organs, and try to determine how PP dendritic cells contribute to the unique functions of this lymphoid organ.
Smoking versus infection as the aetiology of bronchial mucous gland hypertrophy in chronic bronchitis
Authors: G. E. Megahed, G. A. Senna, M. H. Eissa, S. Z. Saleh, H. A. Eissa
Journal: Thorax (1967)

The smoking habits of 50 proved cases of chronic bronchitis were studied. Bronchoscopy was done and a bronchial biopsy was taken for histological examination. Bronchial lavage was obtained under sterile conditions for bacteriological studies. The degree of bronchial mucous gland hypertrophy was determined, and the presence or absence of infection, as shown by the presence of potential pathogens in the bronchial lavage, was noted. We think that tobacco smoking and its resulting irritation to the bronchi is the most important underlying cause of bronchial mucous gland hypertrophy because there is: (1) a significantly higher incidence of mucous gland hypertrophy in smokers than in non-smokers among the 50 chronic bronchitics studied; (2) a significantly higher accumulated lifetime tobacco consumption in patients exhibiting mucous gland hypertrophy than in those without hypertrophy of the bronchial mucous glands; (3) a significant association and correlation between the degree of mucous gland hypertrophy and the intensity of smoking; and (4) no difference in the comparative frequency of occurrence of bronchial mucous gland hypertrophy in subjects with and without demonstrable infection, as shown by the presence of potential pathogens in the bronchial lavage. We could not deny that infection might be having an initiating or potentiating effect.
Gene Expression Profiling Reveals Similarities between the<i>In vitro</i>and<i>In vivo</i>Responses of Immune Effector Cells to IFN-α
Authors: Jason M. Zimmerer, Gregory B. Lesinski, Amy S. Ruppert, Michael D. Radmacher, Carl Noble, Kari Kendra, Michael J. Walker, William E. Carson
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-α would be similar to the in vivo response to treatment with high-dose IFN-α. Experimental Design: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-α were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-α. Results: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-α in vitro for 18 hours (&amp;gt;2-fold, P &amp;lt; 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-α–treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-α-2b (20 MU/m2 i.v.) revealed significant up-regulation (&amp;gt;2-fold) of 21 genes (P &amp;lt; 0.001). Also, the gene expression profile of in vitro IFN-α–stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-α therapy. Conclusions: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-α and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-α may be a useful predictor of the in vivo response of immune cells to IFN-α immunotherapy.
A STUDY OF THE PASSIVE TRANSFER OF DELAYED HYPERSENSITIVITY TO DNP-POLY-<scp>L</scp>-LYSINE AND DNP-GL IN RESPONDER AND NONRESPONDER GUINEA PIGS
Authors: Ira Green, William E. Paul, Baruj Benacerraf
Journal: The Journal of Experimental Medicine (1967)

A study of the passive transfer of delayed hypersensitivity to DNP-poly-L-lysine and to DNP-GL was performed in Hartley guinea pigs. Delayed hypersensitivity to DNP-PLL and DNP-GL could be transferred successfully only by means of sensitized cells from genetic responder guinea pigs and in most cases, only into those guinea pigs genetically capable of responding to PLL. The inability to transfer delayed hypersensitivity to DNP-PLL or DNP-GL to genetic nonresponder guinea pigs is not the result of the early destruction of the transferred cells by an incompatible host, since it was shown that delayed hypersensitivity to ovalbumin could be successfully transferred from guinea pigs with the PLL gene into genetic nonresponder animals. The requirement of active participation of specific and genetically controlled host mechanisms in the successful passive transfer of delayed sensitivity to DNP-PLL and DNP-GL has been demonstrated.
Treatment and control of arterial hypertension in a rural community in Ecuador
Authors: Mariella Anselmi, Fausto Avanzini, Juan-Martin Moreíra, Gregorio Montalvo, Daniela Armani, Rosanna Prandi, Monica Marquez, Cynthia Caicedo, Fabio Colombo, Gianni Tognoni
Journal: The Lancet (2003)
Mechano-Electrochemical Properties Of Articular Cartilage: Their Inhomogeneities and Anisotropies
Authors: Van C. Mow, X. Edward Guo
Journal: Annual Review of Biomedical Engineering (2002)

In this chapter, the recent advances in cartilage biomechanics and electromechanics are reviewed and summarized. Our emphasis is on the new experimental techniques in cartilage mechanical testing, new experimental and theoretical findings in cartilage biomechanics and electromechanics, and emerging theories and computational modeling of articular cartilage. The charged nature and depth-dependent inhomogeneity in mechano-electrochemical properties of articular cartilage are examined, and their importance in the normal and/or pathological structure-function relationships with cartilage is discussed, along with their pathophysiological implications. Developments in theoretical and computational models of articular cartilage are summarized, and their application in cartilage biomechanics and biology is reviewed. Future directions in cartilage biomechanics and mechano-biology research are proposed.
Nocturnal saturation and glucose tolerance in children with cystic fibrosis
Authors: D. Suratwala, J. S. H. Chan, A. Kelly, L. J. Meltzer, P. R. Gallagher, J. Traylor, R. C. Rubenstein, C. L. Marcus
Journal: Thorax (2011)

<h3>Background</h3> Glucose intolerance is common in cystic fibrosis (CF), and is associated with worsening pulmonary function and nutritional status, and increased mortality. As sleep-disordered breathing is associated with disorders of glucose metabolism, it was hypothesised that recurrent episodes of hypoxaemia during sleep, and sleep disruption, would be associated with inflammation and glucose intolerance in CF. <h3>Methods</h3> 25 children (aged 14±4 (mean±SD) years) with CF underwent polysomnography, actigraphy, measurement of serum inflammatory markers and oral glucose tolerance testing. Blood glucose area under the curve (AUC), as a cumulative measure of glucose response, was determined. Polysomnography data were compared with retrospective data from 25 healthy controls. <h3>Results</h3> Forced expiratory volume in 1 s was 92±14% predicted. 24 subjects underwent glucose tolerance testing, of whom 29% had impaired glucose tolerance and 4% had diabetes. The mean nocturnal oxygen saturation correlated negatively with glucose AUC at 120 min (r=−0.49, p=0.015). Partial correlations and regression models including age, body mass index, nocturnal saturation and pulmonary function indicated that nocturnal saturation accounted for the majority of the predictive power for glucose AUC (R<sup>2</sup>=0.24, p=0.001). There were no meaningful relationships between sleep quality, inflammation and glucose tolerance. <h3>Conclusions</h3> Lower oxyhaemoglobin saturation is associated with worse glucose regulation in children with CF. Further studies are needed to determine whether lower saturation negatively impacts glucose regulation or, alternatively, whether abnormalities in glucose metabolism are an early sign of pulmonary dysfunction.
Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in <i>EGFR</i>-Mutant Lung Cancer
Authors: Erin M. Tricker, Chunxiao Xu, Sharmeen Uddin, Marzia Capelletti, Dalia Ercan, Atsuko Ogino, Christine A. Pratilas, Neal Rosen, Nathanael S. Gray, Kwok-Kin Wong, Pasi A. Jänne
Journal: Cancer Discovery (2015)

Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and EGFR inhibitor-resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFR(T790M), prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here, we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002-induced apoptosis, and inhibits the emergence of resistance in WZ4002-sensitive models known to acquire resistance via both T790M-dependent and T790M-independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial cotargeting of EGFR and MEK could significantly impede the development of acquired resistance in EGFR-mutant lung cancer.Patients with EGFR-mutant lung cancer develop acquired resistance to EGFR and mutant-selective EGFR tyrosine kinase inhibitors. Here, we show that cotargeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms in vitro and in vivo and may be a superior therapeutic regimen for these patients.