tbuckley/cabot-search huggingface dataset:
β-Catenin/POU5F1/SOX2 Transcription Factor Complex Mediates IGF-I Receptor Signaling and Predicts Poor Prognosis in Lung Adenocarcinoma
Authors: Chuan Xu, Dan Xie, Shi-Cang Yu, Xiao-Jun Yang, Li-Ru He, Jing Yang, Yi-Fang Ping, Bin Wang, Lang Yang, Sen-Lin Xu, Wei Cui, Qing-Liang Wang, Wen-Juan Fu, Qing Liu, Cheng Qian, You-Hong Cui, Jeremy N. Rich, Hsiang-Fu Kung, Xia Zhang, Xiu-Wu Bian
Journal: Cancer Research (2013)

Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma.
Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update
Authors: Michaela A Stoffer, Monika M Schoels, Josef S Smolen, Daniel Aletaha, Ferdinand C Breedveld, Gerd Burmester, Vivian Bykerk, Maxime Dougados, Paul Emery, Boulos Haraoui, Juan Gomez-Reino, Tore K Kvien, Peter Nash, Victoria Navarro-Compán, Marieke Scholte-Voshaar, Ronald van Vollenhoven, Désirée van der Heijde, Tanja A Stamm
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objective</h3> A systematic literature review (SLR; 2009–2014) to compare a target-oriented approach with routine management in the treatment of rheumatoid arthritis (RA) to allow an update of the treat-to-target recommendations. <h3>Methods</h3> Two SLRs focused on clinical trials employing a treatment approach targeting a specific clinical outcome were performed. In addition to testing clinical, functional and/or structural changes as endpoints, comorbidities, cardiovascular risk, work productivity and education as well as patient self-assessment were investigated. The searches covered MEDLINE, EMBASE, Cochrane databases and Clinicaltrial.gov for the period between 2009 and 2012 and separately for the period of 2012 to May of 2014. <h3>Results</h3> Of 8442 citations retrieved in the two SLRs, 176 articles underwent full-text review. According to predefined inclusion/exclusion criteria, six articles were included of which five showed superiority of a targeted treatment approach aiming at least at low-disease activity versus routine care; in addition, publications providing supportive evidence were also incorporated that aside from expanding the evidence provided by the above six publications allowed concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care. <h3>Conclusions</h3> The current study expands the evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care.
Incidence of ulcerative colitis in the Cardiff region 1968-1977.
Authors: T Morris, J Rhodes
Journal: Gut (1984)

The incidence of ulcerative colitis in South Glamorgan during the decade 1968-77 remained steady with a mean of 7.2/10(5)/year. The disease was slightly more common in women, male:female ratio 1:1.2. Ulcerative colitis was rare in childhood but showed two peaks of incidence in adults, in the third and fourth decades and in the eighth decade.
CYTOTOXIC POTENTIAL OF STIMULATED HUMAN LYMPHOCYTES
Authors: Göran Holm, Peter Perlmann
Journal: The Journal of Experimental Medicine (1967)

Viable and immunologically competent lymphocytes from unsensitized donors damage allogeneic tissue culture cells in the presence of phytohemagglutinin (PHA). This cytotoxicity is specific since syngeneic tissue culture cells are not at all or only slightly damaged under similar experimental conditions. In this investigation, the relation between the stimulation of human lymphocytes and their cytotoxicity was studied. Chang cells (human liver) served as target cells in all experiments. Cell damage was quantitated by measuring the release of isotope from target cells labeled with chromate-51Cr. The cytotoxicity of the lymphocytes was dependent on the concentration of PHA in the incubation medium. Cell damage was maximal at concentrations of 4–8 µl PHA/ml. Higher concentrations were inhibitory although aggregation was increased and no injury of the lymphocytes was noted. Stimulation of DNA and RNA synthesis in PHA-treated lymphocytes each followed dose response curves which were similar to that of cytotoxicity. In order to establish whether stimulation without mixed aggregation of lymphocytes and target cells would suffice for cytotoxicity, a series of nonagglutinating stimulants were investigated. Lymphocytes pretreated with a crude filtrate of Staphylococcus aureus for periods of 0.5–72 hr damaged Chang cells even in the absence of PHA. Lymphocytes from a tuberculin-positive donor were strongly cytotoxic after prestimulation with PPD while those from a negative donor were inactive. Moreover, strong cytotoxic effects were also obtained with lymphocytes which had been stimulated by preincubation with allogeneic lymphocytes in mixed culture. When two stimulants were applied at the same time, additive cytotoxic effects were seen. Addition of PHA to the lymphocyte/Chang cell mixtures potentiated the cytotoxicity of prestimulated lymphocytes. The cytotoxic potential of the lymphocytes was in all cases correlated to the degree of stimulation recorded as transformation into blast cells, and was independent both of the degree of aggregation and of the stimulating factor. These findings are compatible with the assumption that injury of the Chang cells reflected an immunologically nonspecific activity of lymphocytes enhanced by stimulation. The possible importance of this activity for a number of tissue-damaging immune reactions in vivo is pointed out.
Childhood Nutrition in Predicting Metabolic Syndrome in Adults
Authors: Paula Jääskeläinen, Costan G. Magnussen, Katja Pahkala, Vera Mikkilä, Mika Kähönen, Matthew A. Sabin, Mikael Fogelholm, Nina Hutri-Kähönen, Leena Taittonen, Risto Telama, Tomi Laitinen, Eero Jokinen, Terho Lehtimäki, Jorma S.A. Viikari, Olli T. Raitakari, Markus Juonala
Journal: Diabetes Care (2012)

Our aim was to study the associations of childhood lifestyle factors (the frequency of consumption of vegetables, fruit, fish, and meat, butter use on bread, and physical activity) with the metabolic syndrome (MetS) in adulthood.The study cohort consisted of 2,128 individuals, 3-18 years of age at the baseline, with a follow-up time of 27 years. We used the average of lifestyle factor measurements taken in 1980, 1983, and 1986 in the analyses. Childhood dietary factors and physical activity were assessed by self-reported questionnaires, and a harmonized definition of MetS was used as the adult outcome.Childhood vegetable consumption frequency was inversely associated with adult MetS (odds ratio [OR] 0.86 [95% CI 0.77-0.97], P = 0.02) in a multivariable analysis adjusted with age, sex, childhood metabolic risk factors (lipids, systolic blood pressure, insulin, BMI, and C-reactive protein), family history of type 2 diabetes and hypertension, and socioeconomic status. The association remained even after adjustment for adulthood vegetable consumption. Associations with the other childhood lifestyle factors were not found. Of the individual components of MetS, decreased frequency of childhood vegetable consumption predicted high blood pressure (0.88 [0.80-0.98], P = 0.01) and a high triglyceride value (0.88 [0.79-0.99], P = 0.03) after adjustment for the above-mentioned risk factors.Childhood vegetable consumption frequency is inversely associated with MetS in adulthood. Our findings suggest that a higher intake of vegetables in childhood may have a protective effect on MetS in adulthood.
Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice
Authors: Annie Mirsoian, Myriam N. Bouchlaka, Gail D. Sckisel, Mingyi Chen, Chien-Chun Steven Pai, Emanuel Maverakis, Richard G. Spencer, Kenneth W. Fishbein, Sana Siddiqui, Arta M. Monjazeb, Bronwen Martin, Stuart Maudsley, Charles Hesdorffer, Luigi Ferrucci, Dan L. Longo, Bruce R. Blazar, Robert H. Wiltrout, Dennis D. Taub, William J. Murphy
Journal: The Journal of Experimental Medicine (2014)

Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF+ macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT.
Response to Letter Regarding Article, “Cardiac Sodium Channel ( SCN5A ) Variants Associated with Atrial Fibrillation”
Authors: Dawood Darbar, Gayle Kucera, Tanya Stubblefield, Alfred L. George, Dan M. Roden, Prince J. Kannankeril, Brian S. Donahue, Jonathan L. Haines
Journal: Circulation (2008)
The vitronectin receptor serves as an accessory molecule for the activation of a subset of gamma/delta T cells.
Authors: K Roberts, W M Yokoyama, P J Kehn, E M Shevach
Journal: The Journal of Experimental Medicine (1991)

Constitutive production of cytokines was observed in 3 of 12 gamma/delta T cell lines derived from murine epidermis and correlated with the expression of the C gamma 4, V delta 6 T cell receptor (TCR). After adaptation of one of the lines (T195/BW) to serum-free culture conditions, cessation of the "spontaneous" production of interleukin 4 (IL-4) was observed and IL-4 production could then by induced by the addition of RGD-containing extracellular matrix (ECM) proteins to the culture. The response to the ECM proteins could be completely inhibited by a mAb to the murine vitronectin receptor (VNR). However, the induction of IL-4 production could also be inhibited by anti-CD3 and by an anti-clonotypic mAb to the TCR-gamma/delta of T195/BW. As TCR-gamma/delta loss mutants of T195/BW also failed to respond to ECM proteins, these data demonstrate that engagement of the VNR by its ligand is necessary, but not sufficient, for the induction of IL-4 production. Furthermore, the VNR is expressed by many other T cell clones (both gamma/delta and alpha/beta), none of which produce lymphokines constitutively. Taken together, these observations strongly favor the view that not only is coexpression of the VNR and TCR required for the induction of IL-4 production, but that the TCR must also be engaged by its ligand, most likely a cell surface antigen expressed by the hybridoma itself.
First group of CCGs for commissioning GPs' services is announced
Authors: A. O'Dowd
Journal: BMJ (2015)

The first group of GP led clinical commissioning groups (CCGs) have been given new powers to take on commissioning of GP contracts and services in England.

Doctors’ leaders, however, have expressed some concerns about no resources being attached to the additional role and a perceived conflict of interest among the GPs involved.

On 18 February NHS England announced that it was approving the first set of CCGs to take on responsibility for commissioning most GP services in their area from April this year. In total, 64 CCGs across the country have …
Frequencies of mitogen-reactive B cells in the mouse. II. Frequencies of B cells producing antibodies which lyse sheep or horse erythrocytes, and trinitrophenylated or nitrodophenylated sheep erythrocytes
Authors: J Andersson, A Coutinho, F Melchers
Journal: The Journal of Experimental Medicine (1977)

The B-cell mitogens LPS and lipoprotein stimulate 20-35 percent of all B cells in the spleen of 6- to 8-wk old C3H/Tif mice, as determined by limiting dilution analysis of precursors. Each reactive cell grows to a clone of IgM-secreting PFC, enumerated in a hemolytic plaque assay detecting all IgM secreting cells, regardless of v-region specificity. We have used these mitogens to reveal the total repertoire of Ig specificities produced by these mitogen-reactive B cells. We have determined in plaque assays with six different target erythrocytes the number of spleen cells limiting to one the number of mitogen-reactive B cells detected as specific IgM-secreting clones in each of these plaque assays. By this method, the absolute frequencies of precursor B cells with defined v-gene specificities could be calculated, for at least, one third of all B cells. The frequencies of specific IgM-plaque-forming B-cell clones within the total pool of mitogen-reactive B cells was 1 in 10 for NIP(12),-SRC, 1 in 50 for TNP(12)- SRC, 1 in 100 for NIP(1)-SRC, 1 in 160 for TNP(3)- SRC, 1 in 500 for HRC, and 1 in 1,000 for SRC. These frequencies were the same in the LPS- and in the lipoprotein-reactive B-cell population for TNP(30)- SRC and SRC.
Prodrugs of Peptides and Proteins for Improved Formulation and Delivery
Authors: R Oliyai, V J Stella
Journal: The Annual Review of Pharmacology and Toxicology (1993)

Prodrugs of Peptides and Proteins for Improved Formulation and Delivery, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/pharmtox/33/1/annurev.pa.33.040193.002513-1.gif
Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence
Authors: F Citarda, G Tomaselli, R Capocaccia, S Barcherini, M Crespi, The Italian Multicentre Study Group
Journal: Gut (2001)

Colorectal cancer is one of the leading causes of death from cancer in Western countries. Removal of adenomas is based on the assumption that it could lead to a reduction in the incidence of colorectal cancer, as demonstrated by the National Polyp Study in the USA. A critical issue is whether the benefit observed in clinical trials can also be observed in standard clinical practice. To address the issue, a multicentre Italian collaborative study was organised.The study cohort comprised 1693 subjects of both sexes, aged 40-69 years, enrolled between 1980 and 1987 following a total colon examination (TCE) (that is, total colonoscopy or colonoscopy and double contrast barium enema), with removal of at least one adenoma larger than 5 mm in diameter. Exclusion criteria were genetic syndromes, previous adenomas or colorectal cancer, previous colonic resection, inflammatory bowel disease, or sessile adenomas more than 3 cm in diameter. Follow up ended in December 1996 by TCE or telephone interview, and review of the medical records, clinical files, or death certificates. Incidence ratios for colorectal cancer were compared with expected age and sex specific incidences in the Italian general population.Follow up data were obtained for 97.3% of cases for a total of 14 211 person/years. Mean follow up was 10.5 years. Six colorectal cancer cases (four in males, two in females) at various stages were ascertained (one at 29 months, two at five years, one at seven years, one at eight years, and one at 10 years from the index examination). The number of cancers expected in the reference population was 17.7 for an incidence ratio of 0.34 (confidence interval 0.23-0.63; p<0.01).Colonoscopic polypectomy substantially reduced the incidence of colorectal cancer in the cohort compared with that expected in the general population. These results are of particular relevance considering that those with adenomas are at increased risk of colorectal cancer and that this retrospective study was performed on data obtained in standard clinical practice. This observation strengthens the concept of effective population screening in view of the fact that adenomatous polyps are the most frequent neoplastic outcome of screening and their removal is associated with a decrease in the incidence of colorectal cancer.
A transforming growth factor beta-like immunosuppressive factor in immunoglobulin G-binding factor.
Authors: C Bouchard, A Galinha, E Tartour, W H Fridman, C Sautès
Journal: The Journal of Experimental Medicine (1995)

Immunoglobulin G-binding factors (IgG-BF), which are produced by cells of the immune system, inhibit antibody production. In this paper, we show that transforming growth factor-beta (TGF-beta) suppresses secondary in vitro anti-sheep red blood cell responses of mouse splenocytes and lipopolysaccharide- or anti-IgM-stimulated mouse B cell responses in a way similar to, and with the same kinetics as, rodent IgG-BF. Moreover, the immunosuppressive activity of IgG-BF was totally neutralized by polyclonal and monoclonal anti-TGF-beta antibodies and it eluted with TGF-beta by gel exclusion chromatography, suggesting that a TGF-beta-like immunosuppressive factor is present in IgG-BF. We also show that TGF-beta behaves as an IgG-BF since it binds to insolubilized IgG, but not to insolubilized F(ab')2 or bovine serum albumin. Altogether, the data support the concept of a biological role for TGF-beta in the IgG-mediated negative feedback of antibody responses.
Autophagy in Locomotor Muscles of Patients with Chronic Obstructive Pulmonary Disease
Authors: Yeting Guo, Harry R. Gosker, Annemie M. W. J. Schols, Sophia Kapchinsky, Jean Bourbeau, Marco Sandri, R. Thomas Jagoe, Richard Debigaré, François Maltais, Tanja Taivassalo, Sabah N. A. Hussain
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Locomotor muscle atrophy develops in patients with chronic obstructive pulmonary disease (COPD) partly because of increased protein degradation by the ubiquitin-proteasome system. It is not known if autophagy also contributes to protein degradation.To investigate whether autophagy is enhanced in locomotor muscles of stable patients with COPD, to quantify autophagy-related gene expression in these muscles, and to identify mechanisms of autophagy induction.Muscle biopsies were obtained from two cohorts of control subjects and patients with COPD and the numbers of autophagosomes in the vastus lateralis and tibialis anterior muscles, the levels of LC3B protein lipidation, and the expression of autophagy-related genes were measured in the vastus lateralis muscle. To investigate potential pathways that might induce the activation of autophagy, measures were taken of protein kinase B (AKT), mTORC1, and AMPK pathway activation, transcription factor regulation, proteasome activation, and oxidative stress.Autophagy is enhanced in the locomotor muscles of patients with COPD as shown by significantly higher numbers of autophagosomes in affected muscles as compared with control subjects. Autophagosome number inversely correlates with FEV1. In the vastus lateralis, LC3B protein lipidation is increased by COPD and the expression of autophagy-related gene expressions is up-regulated. LC3B lipidation inversely correlates with thigh cross-sectional area, FEV1, and FEV1/FVC ratio. Enhanced autophagy is associated with activation of the AMPK pathway and FOXO transcription factors, inhibition of the mTORC1 and AKT pathways, and the development of oxidative stress.Autophagy is significantly enhanced in locomotor muscles of stable patients with COPD. The degree of autophagy correlates with severity of muscle atrophy and lung function impairment.
A Unique Recent Origin of the Allotetraploid Species Arabidopsis suecica: Evidence from Nuclear DNA Markers
Authors: Mattias Jakobsson, Jenny Hagenblad, Simon Tavaré, Torbjörn Säll, Christer Halldén, Christina Lind-Halldén, Magnus Nordborg
Journal: Molecular Biology and Evolution (2006)

A coalescent-based method was used to investigate the origins of the allotetraploid Arabidopsis suecica, using 52 nuclear microsatellite loci typed in eight individuals of A. suecica and 14 individuals of its maternal parent Arabidopsis thaliana, and four short fragments of genomic DNA sequenced in a sample of four individuals of A. suecica and in both its parental species A. thaliana and Arabidopsis arenosa. All loci were variable in A. thaliana but only 24 of the 52 microsatellite loci and none of the four sequence fragments were variable in A. suecica. We explore a number of possible evolutionary scenarios for A. suecica and conclude that it is likely that A. suecica has a recent, unique origin between 12,000 and 300,000 years ago. The time estimates depend strongly on what is assumed about population growth and rates of mutation. When combined with what is known about the history of glaciations, our results suggest that A. suecica originated south of its present distribution in Sweden and Finland and then migrated north, perhaps in the wake of the retreating ice.
A Mixture Of Non-digestible Oligosaccharides Enhances The Tolerizing Capacity Of A Partial Whey Hydrolysate In A Mouse Model For Cow'S Milk Allergy
Authors: B.C.A.M. van Esch, S. de kivit, G.A. Hofman, L.E.M. Willemsen, J. Garssen, L.M.J. Knippels
Journal: Journal of Allergy and Clinical Immunology (2012)