tbuckley/cabot-search huggingface dataset:
Blockage of Epidermal Growth Factor Receptor-Phosphatidylinositol 3-Kinase-AKT Signaling Increases Radiosensitivity of K-<i>RAS</i> Mutated Human Tumor Cells <i>In vitro</i> by Affecting DNA Repair
Authors: Mahmoud Toulany, Ulla Kasten-Pisula, Ingo Brammer, Shaomeng Wang, Jianyong Chen, Klaus Dittmann, Michael Baumann, Ekkehard Dikomey, H. Peter Rodemann
Journal: Clinical Cancer Research (2006)

Abstract Purpose: It is known that blockage of epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K) activity enhances radiation sensitivity of human tumor cells presenting a K-RAS mutation. In the present study, we investigated whether impaired repair of DNA double-strand breaks (DSB) is responsible for the radiosensitizing effect of EGFR and PI3K inhibition in K-RAS mutated (K-RASmt) cells. Experimental Design: The effect of the EGFR tyrosine kinase inhibitor BIBX1382BS (BIBX) on cellular radiosensitivity was determined in K-RASmt (A549) and K-RASwt (FaDu) cell lines by clonogenic survival assay. Radiation-induced phosphorylation of H2AX (Ser139), ATM (Ser1981), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs; Thr2609) was analyzed by immunoblotting. Twenty-four hours after irradiation, residual DSBs were quantified by identification of γH2AX foci and frequency of micronuclei. Results: BIBX reduced clonogenic survival of K-RASmt-A549 cells, but not of K-RASwt-FaDu cells, after single-dose irradiation. Analysis of the radiation-induced H2AX phosphorylation revealed that BIBX, as well as the PI3K inhibitor LY294002, leads to a marked reduction of P-H2AX in K-RASmt-A549 and MDA-MB-231 cells, but not in K-RASwt-FaDu and HH4ded cells. Likewise, radiation-induced autophosphorylation of DNA-PKcs at Thr2609 was only blocked in A549 cells by these two inhibitors and AKT1 small interfering RNA transfection. However, neither in K-RASmt nor in K-RASwt cells the inhibitors did affect radiation-induced ATM phosphorylation. As a consequence of inhibitor treatment, a significant enhancement of both residual DSBs and frequency of micronuclei was apparent only in A549 but not in FaDu cells following radiation. Conclusion: Targeting of the EGFR-dependent PI3K-AKT pathway in K-RAS-mutated A549 cells significantly affects postradiation survival by affecting the activation of DNA-PKcs, resulting in a decreased DSB repair capacity.
Imaging strategies for detection of urgent conditions in patients with acute abdominal pain: diagnostic accuracy study
Authors: W. Lameris, A. van Randen, H W. van Es, J. P M van Heesewijk, B. van Ramshorst, W. H Bouma, W. ten Hove, M. S van Leeuwen, E. M van Keulen, M. G W Dijkgraaf, P. M M Bossuyt, M. A Boermeester, J. Stoker
Journal: BMJ (2009)

To identify an optimal imaging strategy for the accurate detection of urgent conditions in patients with acute abdominal pain.Fully paired multicentre diagnostic accuracy study with prospective data collection.Emergency departments of two university hospitals and four large teaching hospitals in the Netherlands.1021 patients with non-traumatic abdominal pain of >2 hours' and <5 days' duration. Exclusion criteria were discharge from the emergency department with no imaging considered warranted by the treating physician, pregnancy, and haemorrhagic shock.All patients had plain radiographs (upright chest and supine abdominal), ultrasonography, and computed tomography (CT) after clinical and laboratory examination. A panel of experienced physicians assigned a final diagnosis after six months and classified the condition as urgent or non-urgent.Sensitivity and specificity for urgent conditions, percentage of missed cases and false positives, and exposure to radiation for single imaging strategies, conditional imaging strategies (CT after initial ultrasonography), and strategies driven by body mass index and age or by location of pain.661 (65%) patients had a final diagnosis classified as urgent. The initial clinical diagnosis resulted in many false positive urgent diagnoses, which were significantly reduced after ultrasonography or CT. CT detected more urgent diagnoses than did ultrasonography: sensitivity was 89% (95% confidence interval 87% to 92%) for CT and 70% (67% to 74%) for ultrasonography (P<0.001). A conditional strategy with CT only after negative or inconclusive ultrasonography yielded the highest sensitivity, missing only 6% of urgent cases. With this strategy, only 49% (46% to 52%) of patients would have CT. Alternative strategies guided by body mass index, age, or location of the pain would all result in a loss of sensitivity.Although CT is the most sensitive imaging investigation for detecting urgent conditions in patients with abdominal pain, using ultrasonography first and CT only in those with negative or inconclusive ultrasonography results in the best sensitivity and lowers exposure to radiation.
The Translocation t(4;14) Can Be Present Only in Minor Subclones in Multiple Myeloma
Authors: Benjamin Hébraud, Denis Caillot, Jill Corre, Gérald Marit, Cyrille Hulin, Xavier Leleu, Laurence Lodé, Marc Wetterwald, Mamoun Dib, Philippe Rodon, Laurent Voillat, Bruno Royer, Eric Voog, Olivier Fitoussi, Anne-Marie Stoppa, Laurent Garderet, Brigitte Kolb, Michel Maigre, Nadine Boullanger, Olivier Allangba, Lionel Karlin, Nicolas Daguindau, Laurence Legros, Claudine Sohn, Marie-Véronique Joubert, Pascal Lenain, Thierry Facon, Michel Attal, Philippe Moreau, Hervé Avet-Loiseau
Journal: Clinical Cancer Research (2013)

Although the translocation t(4;14) is supposed to be a primary event in multiple myeloma, we have been surprised to observe that in large relapse series of patients, the t(4;14) can be observed only in subpopulations of plasma cells, in contrast to what is seen at diagnosis. This observation raised the question of possible subclones harboring the translocation that would be observable only at the time of relapse.To address this issue, we analyzed by FISH a cohort of 306 patients for whom we had at least two samples obtained at different disease phases.We observed a "gain" of the t(4;14) in 14 patients, and conversely, a "loss" of the translocation in 11 patients. Two hypotheses were raised: either an acquisition of the translocation during evolution or the existence of small t(4;14)-positive subclones at the time of diagnosis. To address this question, we had the opportunity to analyze two patients at the time of diagnosis by RT-PCR (reverse transcription-polymerase chain reaction) to look for the chimeric Eμ-MMSET transcript, and one patient positive at diagnosis, but negative at relapse. The samples were positive, supporting the second hypothesis. Furthermore, the IGH sequences of two patients who "lose" the t(4;14) were identical at diagnosis and relapse, confirming the existence of a common ancestral clone.Thus, the conclusion of this study is that the t(4;14) is not a primary event in multiple myeloma and that it can be present in silent subclones at diagnosis, but also at relapse.
p300 Acetyltransferase Regulates Androgen Receptor Degradation and PTEN-Deficient Prostate Tumorigenesis
Authors: Jian Zhong, Liya Ding, Laura R. Bohrer, Yunqian Pan, Ping Liu, Jun Zhang, Thomas J. Sebo, R. Jeffrey Karnes, Donald J. Tindall, Jan van Deursen, Haojie Huang
Journal: Cancer Research (2014)

Abstract Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion–induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference–mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss. Cancer Res; 74(6); 1870–80. ©2014 AACR.
RAPID ASSESSMENT OF ACUTE CORONARY SYNDROME IN THE EMERGENCY ROOM: THE ADDED VALUE OF HEART TYPE FATTY ACID BINDING PROTEIN THE FAME-ER (FATTY ACID BINDING PROTEIN IN MYOCARDIAL INFARCTION EVALUATION IN THE EMERGENCY ROOM) STUDY
Authors: Marieke S. Dekker, Arend Mosterd, Nicolaas P.A. Zuithoff, Peter W.H.M. Verheggen, Evelyn A. de Vrey, Thierry X. Wildbergh, Jan F.C. Glatz, Arno W. Hoes
Journal: Journal of the American College of Cardiology (2011)
Fasting Until Noon Triggers Increased Postprandial Hyperglycemia and Impaired Insulin Response After Lunch and Dinner in Individuals With Type 2 Diabetes: A Randomized Clinical Trial
Authors: Daniela Jakubowicz, Julio Wainstein, Bo Ahren, Zohar Landau, Yosefa Bar-Dayan, Oren Froy
Journal: Diabetes Care (2015)

OBJECTIVE Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner. RESEARCH DESIGN AND METHODS In a crossover design, 22 patients with diabetes with a mean diabetes duration of 8.4 ± 0.7 years, age 56.9 ± 1.0 years, BMI 28.2 ± 0.6 kg/m2, and HbA1c 7.7 ± 0.1% (61 ± 0.8 mmol/mol) were randomly assigned to two test days: one day with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB). Postprandial plasma glucose, insulin, C-peptide, free fatty acids (FFA), glucagon, and intact glucagon-like peptide-1 (iGLP-1) were assessed. RESULTS Compared with YesB, lunch area under the curves for 0–180 min (AUC0–180) for plasma glucose, FFA, and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and iGLP-1 were 17% and 19% lower, respectively, on the NoB day (P &amp;lt; 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P &amp;lt; 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day. CONCLUSIONS Skipping breakfast increases PPHG after lunch and dinner in association with lower iGLP-1 and impaired insulin response. This study shows a long-term influence of breakfast on glucose regulation that persists throughout the day. Breakfast consumption could be a successful strategy for reduction of PPHG in type 2 diabetes.
A Nephritogenic Peptide Induces Intermolecular Epitope Spreading on Collagen IV in Experimental Autoimmune Glomerulonephritis
Authors: Lanlin Chen, Thomas Hellmark, Vadim Pedchenko, Billy G. Hudson, Charles D. Pusey, Jay W. Fox, W. Kline Bolton
Journal: Journal of the American Society of Nephrology (2006)

This group previously identified a peptide p13 of alpha3(IV)NC1 domain of type IV collagen that induces experimental autoimmune glomerulonephritis (EAG) in rats with generation of antibodies to sites on alpha3(IV)NC1 external to the peptide as a result of intramolecular epitope spreading. It was hypothesized that intermolecular epitope spreading to other collagen IV chains also was induced. Rats were immunized with nephritogenic peptide that was derived from the amino terminal part of rat alpha3(IV)NC1 domain, and serum and kidney eluate were examined for antibodies to both native and recombinant NC1 domains of collagen IV. Peptide induced EAG with proteinuria and decreased renal function and glomerular basement membrane IgG deposits. Sera from these rats were examined by ELISA, which revealed reactivity not only to immunizing peptide but also to human and rat alpha3(IV)NC1 and to human alpha4(IV)NC1 domains. Kidney eluate that was depleted of alpha3(IV)NC1 antibodies still reacted to alpha4(IV)NC1, and alpha3(IV)NC1 column-bound antibody reacted with alpha3(IV)NC1. There was minimal reactivity to other collagen chains. Eluate that was adsorbed to NC1 hexamer from rat glomerular basement membrane lost all reactivity to glomerular constituents, and the eluted antibodies reacted to alpha3(IV)NC1 and alpha4(IV)NC1 domains. These studies show that a T cell epitope of alpha3(IV)NC1 induces EAG, intramolecular epitope spreading along alpha3(IV)NC1, and intermolecular epitope spreading to alpha4(IV)NC1 domain with minimal or no reactivity to other collagen chains or glomerular constituents. This is the first demonstration in EAG of intermolecular epitope spreading and identification of the spread epitopes.
Time course for development of psoralen plus ultraviolet A erythema following oral administration of 5-methoxypsoralen
Authors: L. Berroeta, S. Attili, A. Wong, I. Man, R.S. Dawe, J. Ferguson, S.H. Ibbotson
Journal: British Journal of Dermatology (2009)

Conflicts of interest: none declared. Sir, Psoralen photochemotherapy (psoralen plus ultraviolet A radiation, PUVA) is an effective therapy for psoriasis and other dermatoses. Determination of the minimal phototoxic dose (MPD) prior to PUVA treatment is advisable as suggested by the British Photodermatology Group guidelines.1, 2 8‐Methoxypsoralen (8‐MOP) is widely used as the standard oral psoralen for PUVA. However, its use is limited by side‐effects including nausea, vomiting, pruritus and erythema. 5‐MOP is commonly used in those patients who develop gastrointestinal adverse reactions as it seems to be better tolerated. Ibbotson and Farr3 showed that peak erythema after oral 8‐MOP occurs at or beyond 96 h in 75% of subjects. Behrens‐Williams et al.4 and Grundmann‐Kollmann et al.5 demonstrated similar findings with bath, and cream and gel formulations of 8‐MOP. More recent studies by Man et al.6, 7 showed that MPD determination at 72 h underestimates the phototoxic response of PUVA, as peak PUVA erythema after 8‐MOP and 4,5′,8‐trimethylpsoralen occurs at 96–120 h.
Whole Body UVA Irradiation Lowers Systemic Blood Pressure by Release of Nitric Oxide From Intracutaneous Photolabile Nitric Oxide Derivates
Authors: Christian Opländer, Christine M. Volkmar, Adnana Paunel-Görgülü, Ernst E. van Faassen, Christian Heiss, Malte Kelm, Daniel Halmer, Manfred Mürtz, Norbert Pallua, Christoph V. Suschek
Journal: Circulation Research (2009)

Rationale: Human skin contains photolabile nitric oxide derivates like nitrite and S -nitroso thiols, which after UVA irradiation, decompose and lead to the formation of vasoactive NO. Objective: Here, we investigated whether whole body UVA irradiation influences the blood pressure of healthy volunteers because of cutaneous nonenzymatic NO formation. Methods and Results: As detected by chemoluminescence detection or by electron paramagnetic resonance spectroscopy in vitro with human skin specimens, UVA illumination (25 J/cm 2 ) significantly increased the intradermal levels of free NO. In addition, UVA enhanced dermal S -nitrosothiols 2.3-fold, and the subfraction of dermal S -nitrosoalbumin 2.9-fold. In vivo, in healthy volunteers creamed with a skin cream containing isotopically labeled 15 N-nitrite, whole body UVA irradiation (20 J/cm 2 ) induced significant levels of 15 N-labeled S -nitrosothiols in the blood plasma of light exposed subjects, as detected by cavity leak out spectroscopy. Furthermore, whole body UVA irradiation caused a rapid, significant decrease, lasting up to 60 minutes, in systolic and diastolic blood pressure of healthy volunteers by 11±2% at 30 minutes after UVA exposure. The decrease in blood pressure strongly correlated ( R 2 =0.74) with enhanced plasma concentration of nitrosated species, as detected by a chemiluminescence assay, with increased forearm blood flow (+26±7%), with increased flow mediated vasodilation of the brachial artery (+68±22%), and with decreased forearm vascular resistance (−28±7%). Conclusions: UVA irradiation of human skin caused a significant drop in blood pressure even at moderate UVA doses. The effects were attributed to UVA induced release of NO from cutaneous photolabile NO derivates.
Cytomegalovirus Pneumonitis Is a Risk for Bronchiolitis Obliterans Syndrome in Lung Transplantation
Authors: Laurie D. Snyder, C. Ashley Finlen-Copeland, W. Jackson Turbyfill, David Howell, Daniel A. Willner, Scott M. Palmer
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Cytomegalovirus pneumonitis is one of the most prevalent opportunistic infections after lung transplantation. Early studies reported that cytomegalovirus pneumonitis was a risk factor for chronic allograft dysfunction. More recently, in the era of routine prophylaxis and ganciclovir treatment, the adverse impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome has been challenged.Objectives: We hypothesized that cytomegalovirus pneumonitis contributes to adverse outcomes in the current antiviral era. We sought to define the impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome and survival in a large single-center cohort (n = 231) of consecutive patients undergoing lung transplantation from 2000 to 2004, all receiving short-course ganciclovir prophylaxis.Methods: Transbronchial biopsies were performed at defined intervals with prospective cytomegalovirus immunostaining on every biopsy (n = 1,887). Cox proportional hazards models were used to assess the relationship between treated cytomegalovirus pneumonitis and clinical outcomes.Measurements and Main Results: Forty-nine (21%) recipients developed cytomegalovirus pneumonitis a median of 106 days after transplantation. Treated cytomegalovirus pneumonitis within the first 6 months after transplantation significantly increased the risk for bronchiolitis obliterans syndrome (P = 0.001; hazard ratio, 2.19; 95% confidence interval, 1.36–3.51) and post-transplantation death (P = 0.02; hazard ratio, 1.89; 95% confidence interval, 1.11–3.23). This risk persisted when cytomegalovirus pneumonitis was considered as a time-dependent predictor as well as in multivariable models controlling for other risk factors.Conclusions: Cytomegalovirus pneumonitis affects more than 20% of lung transplant recipients. Despite treatment, it increases the risk for bronchiolitis obliterans syndrome and death. More effective preventive strategies for cytomegalovirus pneumonitis are needed to improve long-term outcomes after lung transplantation.
International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods
Authors: MI Asher, U Keil, HR Anderson, R Beasley, J Crane, F Martinez, EA Mitchell, N Pearce, B Sibbald, AW Stewart, al. et
Journal: European Respiratory Journal (1995)

The aetiology of asthma and allergic disease remains poorly understood, despite considerable research. The International Study of Asthma and Allergies in Childhood (ISAAC), was founded to maximize the value of epidemiological research into asthma and allergic disease, by establishing a standardized methodology and facilitating international collaboration. Its specific aims are: 1) to describe the prevalence and severity of asthma, rhinitis and eczema in children living in different centres, and to make comparisons within and between countries; 2) to obtain baseline measures for assessment of future trends in the prevalence and severity of these diseases; and 3) to provide a framework for further aetiological research into genetic, lifestyle, environmental, and medical care factors affecting these diseases. The ISAAC design comprises three phases. Phase 1 uses core questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations. Phase 2 will investigate possible aetiological factors, particularly those suggested by the findings of Phase 1. Phase 3 will be a repetition of Phase 1 to assess trends in prevalence.
GW25-e0444 Pentraxin-3 is associated with long-term adverse cardiovascular events in patients with chronic heart failure.
Authors: Liu Haibo, Wang Chunming, Yu Wangjun, Liu Yanhong, Fang Yu, Bao Yingchun, Zhang Limei, Cao Yong, Ge Junbo
Journal: Journal of the American College of Cardiology (2014)
Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome
Authors: Nicholas Hearle, Valérie Schumacher, Fred H. Menko, Sylviane Olschwang, Lisa A. Boardman, Johan J.P. Gille, Josbert J. Keller, Anne Marie Westerman, Rodney J. Scott, Wendy Lim, Jill D. Trimbath, Francis M. Giardiello, Stephen B. Gruber, G. Johan A. Offerhaus, Felix W.M. de Rooij, J.H. Paul Wilson, Anika Hansmann, Gabriela Möslein, Brigitte Royer-Pokora, Tilman Vogel, Robin K.S. Phillips, Allan D. Spigelman, Richard S. Houlston
Journal: Clinical Cancer Research (2006)

Abstract Background: Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited. Experimental Design: We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations. Results: Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference χ2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk. Conclusions: The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome.
Guidelines on pulmonary embolism
Authors: C. W H DAVIES;, A. MILLER
Journal: Thorax (1998)

The new guidelines for the practical approach to management of pulmonary embolism (PE) are clearly welcome to help all clinicians dealing with such patients.1 I would, however, like to take issue with the statement advising the administration of hydrocortisone in conjunction with streptokinase to reduce the risk of allergic complications.

Allergic reactions are a well recognised adverse effect of intravenous streptokinase treatment and are probably due to immediate hypersensitivity reactions mediated by IgE antibodies to streptokinase.2 The incidence …