tbuckley/cabot-search huggingface dataset:
Targeted Deletion of <i>Prkar1a</i> Reveals a Role for Protein Kinase A in Mesenchymal-to-Epithelial Transition
Authors: Kiran S. Nadella, Georgette N. Jones, Anthony Trimboli, Constantine A. Stratakis, Gustavo Leone, Lawrence S. Kirschner
Journal: Cancer Research (2008)

Abstract Dysregulation of protein kinase A (PKA) activity, caused by loss of function mutations in PRKAR1A, is known to induce tumor formation in the inherited tumor syndrome Carney complex (CNC) and is also associated with sporadic tumors of the thyroid and adrenal. We have previously shown that Prkar1a+/− mice develop schwannomas reminiscent of those seen in CNC and that similar tumors are observed in tissue-specific knockouts (KO) of Prkar1a targeted to the neural crest. Within these tumors, we have previously described the presence of epithelial islands, although the nature of these structures was unclear. In this article, we report that these epithelial structures are derived from KO cells originating in the neural crest. Analysis of the mesenchymal marker vimentin revealed that this protein was markedly down-regulated not only from the epithelial islands, but also from the tumor as a whole, consistent with mesenchymal-to-epithelial transition (MET). In vitro, Prkar1a null primary mouse embryonic fibroblasts, which display constitutive PKA signaling, also showed evidence for MET, with a loss of vimentin and up-regulation of the epithelial marker E-cadherin. Reduction of vimentin protein occurred at the posttranslational level and was rescued by proteasomal inhibition. Finally, this down-regulation of vimentin was recapitulated in the adrenal nodules of CNC patients, confirming an unexpected and previously unrecognized role for PKA in MET. [Cancer Res 2008;68(8):2671–7]
Effects of Adding Linagliptin to Basal Insulin Regimen for Inadequately Controlled Type 2 Diabetes
Authors: Hannele Yki-Järvinen, Julio Rosenstock, Santiago Durán-Garcia, Sabine Pinnetti, Sudipta Bhattacharya, Sandra Thiemann, Sanjay Patel, Hans-Juergen Woerle
Journal: Diabetes Care (2013)

To evaluate the efficacy and long-term safety of linagliptin added to basal insulins in type 2 diabetes inadequately controlled on basal insulin with or without oral agents.A total of 1,261 patients (HbA1c ≥7.0% [53 mmol/mol] to ≤10.0% [86 mmol/mol]) on basal insulin alone or combined with metformin and/or pioglitazone were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo for ≥52 weeks. The basal insulin dose was kept unchanged for 24 weeks but could thereafter be titrated according to fasting plasma glucose levels at the investigators' discretion. The primary end point was the mean change in HbA1c from baseline to week 24. The safety analysis incorporated data up to a maximum of 110 weeks.At week 24, HbA1c changed from a baseline of 8.3% (67 mmol/mol) by -0.6% (-6.6 mmol/mol) and by 0.1% (1.1 mmol/mol) with linagliptin and placebo, respectively (treatment difference -0.65% [95% CI -0.74 to -0.55] [-7.1 mmol/mol]; P < 0.0001). Despite the option to uptitrate basal insulin, it was adjusted only slightly upward (week 52, linagliptin 2.6 IU/day, placebo 4.2 IU/day; P < 0.003), resulting in no further HbA1c improvements. Frequencies of hypoglycemia (week 24, linagliptin 22.0%, placebo 23.2%; treatment end, linagliptin 31.4%, placebo 32.9%) and adverse events (linagliptin 78.4%, placebo 81.4%) were similar between groups. Mean body weight remained unchanged (week 52, linagliptin -0.30 kg, placebo -0.04 kg).Linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight.
Serum Protein Changes in Caplan's Syndrome
Authors: J. A. L. Gorringe
Journal: Annals of the Rheumatic Diseases (1962)

1956> indicated that tuberculosis caused quite consistent changes in serum proteins, namely increased cx,and y-globulins and reduced albumin.That similar- changes occur in coal-workers' pneumoconiosis and silicosis associated with tuberculosis was confirmed to the nature of lung lesions on the basis of which they were at first included, and one because of doubt as to the diagnosis of rheumatoid arthritis.As a new electrophoretic technique was to be used (Gorringe, 1957), a group of twelve normal subjects was also studied to provide evidence as to the values to be expected for the various protein fractions in healthy individuals.
PROFIT AND LOSS IN INTERMITTENT HÆMODIALYSIS
Authors: D.B. Evans, J.R. Curtis, H.E. De Wardener, DavidN.S. Kerr, Walter Elliott, John Swinney, C.R. Blagg, F.M. Parsons, RobinA.J. Eady, D.A.K. Black
Journal: The Lancet (1965)
OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice
Authors: Jamal Zaini, Sita Andarini, Minoru Tahara, Yasuo Saijo, Naoto Ishii, Kazuyoshi Kawakami, Masaru Taniguchi, Kazuo Sugamura, Toshihiro Nukiwa, Toshiaki Kikuchi
Journal: Journal of Clinical Investigation (2007)

The exceptional immunostimulatory capacity of DCs makes them potential targets for investigation of cancer immunotherapeutics. We show here in mice that TNF-α–stimulated DC maturation was accompanied by increased expression of OX40 ligand (OX40L), the lack of which resulted in an inability of mature DCs to generate cellular antitumor immunity. Furthermore, intratumoral administration of DCs modified to express OX40L suppressed tumor growth through the generation of tumor-specific cytolytic T cell responses, which were mediated by CD4+ T cells and NKT cells. In the tumors treated with OX40L-expressing DCs, the NKT cell population significantly increased and exhibited a substantial level of IFN-γ production essential for antitumor immunity. Additional studies evaluating NKT cell activation status, in terms of IFN-γ production and CD69 expression, indicated that NKT cell activation by DCs presenting α-galactosylceramide in the context of CD1d was potentiated by OX40 expression on NKT cells. These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4+ T cells, in the induction of antitumor immunity in tumor-bearing mice.
H2-M3, A FULL-SERVICE CLASS I<scp>b</scp>HISTOCOMPATIBILITY ANTIGEN
Authors: Kirsten Fischer Lindahl, Derek E. Byers, Vikram M. Dabhi, Rolf Hovik, Elsy P. Jones, Geoffrey P. Smith, Chyung-Ru Wang, Hong Xiao, Masayasu Yoshino
Journal: Annual Review of Immunology (1997)

▪ Abstract H2-M3 is an MHC class Ib molecule of the mouse with a unique preference for N-formylated peptides, which may come from the N-termini of endogenous, mitochondrial proteins or foreign, bacterial proteins. The crystal structure of M3 revealed a hydrophobic peptide-binding groove with an occluded A pocket and the peptide shifted one residue relative to class Ia structures. The formyl group is held by a novel hydrogen bonding network, involving His9 on the bottom of the groove, and the side chain of the P1 methionine is lodged in the B pocket. M3 is a full-service histocompatibility (H) antigen, i.e. self-M3 can present endogenous peptides as minor H antigens and foreign, bacterial antigens in a defensive immune response to infection; and foreign M3 complexed with endogenous self-peptides can be recognized as an alloantigen. The hydrophobic groove of M3 may also allow it to present nonpeptide ligands in the manner of human CD1.
Dual Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Carotid Stenosis Evaluated Using Doppler Embolic Signal Detection
Authors: Hugh S. Markus, Dirk W. Droste, Manfred Kaps, Vincent Larrue, Kennedy R. Lees, Mario Siebler, E. Bernd Ringelstein
Journal: Circulation (2005)

Evidence for efficacy of dual antiplatelet therapy in stroke is limited. Symptomatic carotid stenosis patients are at high risk of early recurrent stroke. In this group, asymptomatic microembolic signals (MES), detected by transcranial Doppler ultrasound (TCD), are markers of future stroke and transient ischemic attack (TIA) risk. They offer a surrogate marker to evaluate antiplatelet therapy, but no multicenter study has evaluated the feasibility of this approach.Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) is a randomized, double-blind study in subjects with recently symptomatic > or =50% carotid stenosis. Patients were screened with TCD, and if MES were detected, they were randomized to clopidogrel and aspirin or aspirin monotherapy. Repeated TCD recordings were made on days 2 and 7. MES were detected in 110 of 230 patients by online analysis at baseline, of whom 107 were randomized. Intention-to-treat analysis revealed a significant reduction in the primary end point: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%; 95% CI, 13.8 to 58.0; P=0.0046). The secondary end point of MES frequency per hour was reduced (compared with baseline) by 61.4% (95% CI, 31.6 to 78.2; P=0.0013) in the dual-therapy group at day 7 and by 61.6% (95% CI, 34.9 to 77.4; P=0.0005) on day 2. There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis; 2 additional ipsilateral TIAs occurred before treatment started. MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without (mean+/-SD: 24.4+/-27.7 versus 8.9+/-11.5 per hour; P=0.0003).In patients with recently symptomatic carotid stenosis, combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization. Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies.
Homocysteine Levels, Paraoxonase 1 (PON1) Activity, and Cardiovascular Risk
Authors: Eddie Vos
Journal: JAMA (2008)

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Molecular Pathways: SWI/SNF (BAF) Complexes Are Frequently Mutated in Cancer—Mechanisms and Potential Therapeutic Insights
Authors: Xiaofeng Wang, Jeffrey R. Haswell, Charles W.M. Roberts
Journal: Clinical Cancer Research (2013)

Abstract SWI/SNF chromatin remodeling complexes are pleomorphic multisubunit cellular machines that utilize the energy of ATP hydrolysis to modulate chromatin structure. The complexes interact with transcription factors at promoters and enhancers to modulate gene expression and contribute to lineage specification, differentiation, and development. Initial clues to a role in tumor suppression for SWI/SNF complexes came over a decade ago when the gene encoding the SMARCB1/SNF5 core subunit was found specifically inactivated in nearly all pediatric rhabdoid tumors. In the last three years, cancer-genome sequencing efforts have revealed an unexpectedly high mutation rate of SWI/SNF subunit genes, which are collectively mutated in 20% of all human cancers and approach the frequency of p53 mutations. Here, we provide a background on these newly recognized tumor suppressor complexes, discuss mechanisms implicated in the tumor suppressor activity, and highlight findings that may lead to potential therapeutic targets for SWI/SNF-mutant cancers. Clin Cancer Res; 20(1); 21–27. ©2013 AACR.
Long-Term Effects of Spontaneous Breathing During Ventilatory Support in Patients with Acute Lung Injury
Authors: CHRISTIAN PUTENSEN, SABINE ZECH, HERMANN WRIGGE, JÖRG ZINSERLING, FRANK STÜBER, TILMANN VON SPIEGEL, NORBERT MUTZ
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Improved gas exchange has been observed during spontaneous breathing with airway pressure release ventilation (APRV) as compared with controlled mechanical ventilation. This study was designed to determine whether use of APRV with spontaneous breathing as a primary ventilatory support modality better prevents deterioration of cardiopulmonary function than does initial controlled mechanical ventilation in patients at risk for acute respiratory distress syndrome (ARDS). Thirty patients with multiple trauma were randomly assigned to either breathe spontaneously with APRV (APRV Group) (n = 15) or to receive pressure-controlled, time-cycled mechanical ventilation (PCV) for 72 h followed by weaning with APRV (PCV Group) (n = 15). Patients maintained spontaneous breathing during APRV with continuous infusion of sufentanil and midazolam (Ramsay sedation score [RSS] of 3). Absence of spontaneous breathing (PCV Group) was induced with sufentanil and midazolam (RSS of 5) and neuromuscular blockade. Primary use of APRV was associated with increases (p < 0.05) in respiratory system compliance (CRS), arterial oxygen tension (PaO2 ), cardiac index (CI), and oxygen delivery (Do 2), and with reductions (p < 0.05) in venous admixture (Q˙ va/Q˙ t), and oxygen extraction. In contrast, patients who received 72 h of PCV had lower CRS, PaO2 , CI, Do 2, and Q˙ va/Q˙ t values (p < 0.05) and required higher doses of sufentanil (p < 0.05), midazolam (p < 0.05), noradrenalin (p < 0.05), and dobutamine (p < 0.05). CRS, PaO2 , CI and Do 2 were lowest (p < 0.05) and Q˙ va/Q˙ t was highest (p < 0.05) during PCV. Primary use of APRV was consistently associated with a shorter duration of ventilatory support (APRV Group: 15 ± 2 d [mean ± SEM]; PCV Group: 21 ± 2 d) (p < 0.05) and length of intensive care unit (ICU) stay (APRV Group: 23 ± 2 d; PCV Group: 30 ± 2 d) (p < 0.05). These findings indicate that maintaining spontaneous breathing during APRV requires less sedation and improves cardiopulmonary function, presumably by recruiting nonventilated lung units, requiring a shorter duration of ventilatory support and ICU stay.
PWE-175 Cost-effectiveness Of Linaclotide (lin) Compared To Antidepressants (atds) In The Treatment Of Irritable Bowel Syndrome With Constipation (ibs-c) In Scotland
Authors: M Fisher, A Walker, M Falqués, M Rance, D Taylor, L Lindner
Journal: Gut (2014)

<h3>Introduction</h3> IBS-C is a chronic functional gastrointestinal disorder that has been shown to decrease quality of life (QoL) and work productivity, and increase activity impairment. LIN is indicated by the European Medicines Agency as the only treatment for IBS-C (covering all key symptoms) in adults and has received a positive recommendation from the Scottish Medicines Consortium. This study sought to determine the cost-effectiveness of LIN compared with ATDs for the treatment of adults with moderate to severe IBS-C who have previously received antispasmodics and/or laxatives. <h3>Methods</h3> A Markov model was created to estimate costs and quality-adjusted life years (QALYs) on 4-week cycles over a 5-year time horizon from the perspective of NHS Scotland. The comparator used was ATDs, reflecting Scottish current practice. Health states were based on treatment satisfaction (satisfied, moderately satisfied, not satisfied) and death. Transitions between states were based on satisfaction data from the LIN pivotal studies and the Scottish general all-cause mortality statistics. Treatment costs were calculated from the British National Formulary using the least-expensive ATD cost (amitriptyline hydrochloride 20 mg). NHS resource use for each state was collected from Scottish clinician interviews and combined with NHS Reference costs to obtain disease-related costs. QoL was based on the EQ-5D collected from the pivotal studies. Uncertainty was explored through extensive sensitivity analyses. <h3>Results</h3> The base case comparing LIN with ATDs over 5 years provided an incremental cost-effectiveness ratio (ICER) value (cost per QALY) of £7,370. Scenario analyses conducted to address structural uncertainty resulted in ICERs ranging from £1,204 to £10,899. Probabilistic sensitivity analysis was also conducted using 10,000 iterations to examine parameter uncertainty over the entire model. This analysis showed that there was an 83% probability that LIN was cost-effective at a willingness to pay an ICER of £20,000 when compared with ATDs. The mean probabilistic ICER was £4,606 (mean incremental costs £394 and mean incremental QALYs 0.085). <h3>Conclusion</h3> LIN is a cost-effective treatment for adults with moderate to severe IBS-C who have previously received antispasmodics and/or laxatives. The ICER in Scotland was calculated as £7,370 when compared with ATDs and was based on conservative assumptions. Results were robust to extensive sensitivity analyses. Study funded by Almirall UK. <h3>Disclosure of Interest</h3> M. Fisher Conflict with: former employee of WG Consulting, A. Walker Consultant for: WG Consulting, Conflict with: WG Consulting (Advisory Board meeting), M. Falqués Employee of: Almirall S. A., M. Rance Employee of: Almirall UK, D. Taylor Employee of: Ironwood Pharmaceuticals, L. Lindner Employee of: Almirall S. A.
Self-antigen–specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response
Authors: Gabrielle A. Rizzuto, Taha Merghoub, Daniel Hirschhorn-Cymerman, Cailian Liu, Alexander M. Lesokhin, Diana Sahawneh, Hong Zhong, Katherine S. Panageas, Miguel-Angel Perales, Grégoire Altan-Bonnet, Jedd D. Wolchok, Alan N. Houghton
Journal: The Journal of Experimental Medicine (2009)

A primary goal of cancer immunotherapy is to improve the naturally occurring, but weak, immune response to tumors. Ineffective responses to cancer vaccines may be caused, in part, by low numbers of self-reactive lymphocytes surviving negative selection. Here, we estimated the frequency of CD8+ T cells recognizing a self-antigen to be &amp;lt;0.0001% (∼1 in 1 million CD8+ T cells), which is so low as to preclude a strong immune response in some mice. Supplementing this repertoire with naive antigen-specific cells increased vaccine-elicited tumor immunity and autoimmunity, but a threshold was reached whereby the transfer of increased numbers of antigen-specific cells impaired functional benefit, most likely because of intraclonal competition in the irradiated host. We show that cells primed at precursor frequencies below this competitive threshold proliferate more, acquire polyfunctionality, and eradicate tumors more effectively. This work demonstrates the functional relevance of CD8+ T cell precursor frequency to tumor immunity and autoimmunity. Transferring optimized numbers of naive tumor-specific T cells, followed by in vivo activation, is a new approach that can be applied to human cancer immunotherapy. Further, precursor frequency as an isolated variable can be exploited to augment efficacy of clinical vaccine strategies designed to activate any antigen-specific CD8+ T cells.
VO2MAX, blood doping, and erythropoietin
Authors: M J Joyner
Journal: British Journal of Sports Medicine (2003)

Methods (legal and illegal) of increasing total body haemoglobin and thereby o2max are discussed

By the 1930s it was clear that champion endurance athletes had remarkably high maximal O2 uptake (o2max).1 In the 1950s, 1960s, and 1970s, classic studies were performed on the physiological determinants of o2max and on its key role in endurance performance.2–4 During this time there was much debate on O2 delivery versus O2 extraction as the “limiting factor” for o2max.5,6 Observations during this era clearly established the role of maximal cardiac output as a determinant of o2max, and very high maximal cardiac output values were seen in champion endurance athletes.2 In addition, the important role of blood volume and total body haemoglobin as determinants of o2max also emerged (fig 1).2,7–9 In an effort to better understand the physiological determinants of o2max, studies were then conducted that attempted to manipulate O2 delivery using a variety of approaches including altered concentrations of inspired O2, drugs that speed or slow the heart, and, as will be discussed here, techniques that altered total body haemoglobin and haemoglobin concentration.10,11

In general, by the 1970s it was clear that manoeuvres that increased total body haemoglobin increased o2max and manoeuvres that reduced total body haemoglobin reduced o2max. …
Amino acids and asthma: a case-control study
Authors: A. Fogarty, E. Broadfield, S. Lewis, N. Lawson, J. Britton
Journal: European Respiratory Journal (2004)

Amino acids contribute to various anti-oxidant and immunological activities relevant to asthma pathogenesis, raising the possibility that differences in amino acids may be involved in asthma aetiology. The authors hypothesised that cystine reduces the risk of asthma <i>via</i> glutathione metabolism. Methionine, glutamine, glutamic acid and glycine may have potential protective effects, whilst arginine, phenylalanine and tryptophan may have adverse effects in asthma. Fasting plasma levels of amino acids were compared in a case-control study. A total of 89 adults, aged 18–65 yrs, with asthma controlled by inhaled corticosteroids, were recruited from a volunteer database and local primary care registers, and compared with 89 controls individually matched for age, sex and primary care centre. Contrary to the primary hypothesis, cases had higher fasting plasma cystine levels than controls, and there was no difference between cases and controls in any of the other amino acids tested, with the exception of plasma glycine, which was associated with a strongly reduced risk of asthma (odds ratio for the highest tertile compared to lowest 0.30 (95% confidence interval (0.11–0.82)). This study negates the hypothesis that higher fasting plasma cystine levels have a protective effect on the risk of asthma, although the inverse correlation with plasma glycine deserves further investigation.
Menopause hormone replacement therapy and cancer risk: an Italian record linkage investigation
Authors: G. Corrao, A. Zambon, V. Conti, F. Nicotra, C. La Vecchia, C. Fornari, G. Cesana, P. Contiero, G. Tagliabue, R.E. Nappi, L. Merlino
Journal: Annals of Oncology (2007)