tbuckley/cabot-search huggingface dataset:
Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels
Authors: Steffan T. Nawrocki, Jennifer S. Carew, Leslie Douglas, John L. Cleveland, Robin Humphreys, Janet A. Houghton
Journal: Cancer Research (2007)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumab-induced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21(+/+) cells but not in the HCT116 p21(-/-) cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab.
Identification of a Poor-Prognosis<i>BRAF</i>-Mutant–Like Population of Patients With Colon Cancer
Authors: Vlad Popovici, Eva Budinska, Sabine Tejpar, Scott Weinrich, Heather Estrella, Graeme Hodgson, Eric Van Cutsem, Tao Xie, Fred T. Bosman, Arnaud D. Roth, Mauro Delorenzi
Journal: Journal of Clinical Oncology (2012)

Purpose Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications. Materials and Methods A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T&gt;A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression–based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors. Results A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class. Conclusion A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.
Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI)
Authors: Pieter Dewint, Bettina E Hansen, Elke Verhey, Bas Oldenburg, Daniel W Hommes, Marieke Pierik, Cyriel I J Ponsioen, Hendrik M van Dullemen, Maurice Russel, Ad A van Bodegraven, C Janneke van der Woude
Journal: Gut (2013)

<h3>Objective</h3> To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohn9s disease (CD). <h3>Design</h3> Randomised, double-blind, placebo controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80 mg week 0, 2), patients received 40 mg every other week together with ciprofloxacin 500 mg or placebo twice daily for 12 weeks. After 12 weeks, adalimumab was continued. Follow-up was 24 weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohn9s Disease Activity Index, Crohn9s Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ). <h3>Results</h3> Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed. <h3>Conclusions</h3> Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained. <h3>Trial registration</h3> ClinicalTrials.gov Identifier: NCT00736983.
Health consequences associated with frequent wheezing in adolescents without asthma diagnosis
Authors: K. Yeatts, K. Johnston Davis, D. Peden, C. Shy
Journal: European Respiratory Journal (2003)

Using questions from the International Study of Asthma and Allergies in Childhood, this study evaluated the association between undiagnosed frequent wheezing and health consequences in adolescents. The North Carolina School Asthma Survey provided self-reported questionnaire data on respiratory health from 122,829 children aged 12–14 yrs. The frequency of health consequences were compared among undiagnosed frequent wheezers, diagnosed asthmatics, and children with no wheezing symptoms or diagnosed asthma. The odds of wheezing-related sleep disturbances, limited activities, and missed school were higher among undiagnosed frequent wheezers, relative to diagnosed asthmatics. The frequency of emergency room visits and hospitalisations did not differ substantially between the undiagnosed wheezing and diagnosed asthma groups, though the undiagnosed group was less likely to have visited a physician for wheezing in the past year. Children with frequent wheezing symptoms but no asthma diagnosis experience substantial illness-related morbidity similar to that of diagnosed asthmatics. Undiagnosed frequent wheezers require more recognition from primary care physicians and need active disease management to reduce health consequences.
Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients
Authors: S.J. Seong, M. Lim, S.K. Sohn, J.H. Moon, S.-J. Oh, B.S. Kim, H.M. Ryoo, J.S. Chung, Y.D. Joo, S.M. Bang, C.W. Jung, D.H. Kim, S.Y. Park, S.S. Yoon, I. Kim, H.G. Lee, J.H. Won, Y.H. Min, J.W. Cheong, J.S. Park, K.S. Eom, M.S. Hyun, M.K. Kim, H. Kim, M.R. Park, J. Park, C.S. Kim, H.J. Kim, Y.K. Kim, E.K. Park, D.Y. Zang, D.Y. Jo, H.W. Lee, Y.-R. Yoon
Journal: Annals of Oncology (2012)

BackgroundThis study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML).Patients and methodsIn total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy.ResultsThe CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR.ConclusionsThe results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.
Panel of Reactive T Cells as a Measurement of Primed Cellular Alloimmunity in Kidney Transplant Candidates
Authors: Emilio D. Poggio, Michael Clemente, Donald E. Hricik, Peter S. Heeger
Journal: Journal of the American Society of Nephrology (2005)

Pretransplantation panel reactive antibody (PRA) testing assesses posttransplantation risk for antibody-mediated graft injury. It was postulated analogously that screening for effector/memory alloreactive T cells by "panel of reactive T cells" (PRT) using IFN-γ enzyme-linked immunosorbent spot assays would evaluate independently cellular alloimmunity in transplant candidates. Peripheral blood lymphocytes from 41 hemodialysis patients who were awaiting first renal transplants were tested against a panel of allogeneic stimulator cells. Positive assays were defined arbitrarily as >25 spots/300,000 peripheral blood lymphocytes, and positive PRT was defined as when the responder reacted to 40 or 75% (PRT-75) of the stimulators. Seventeen percent of patients were PRT-75+, whereas 32% were PRA+. Twelve percent of the cohort was PRT-75+/PRA−, and only 5% of the patients were PRA+/PRT-75+, indicating that T cell alloreactivity did not routinely imply B cell sensitization and vice versa. PRT-75+ patients were more likely to be younger (<55 yr) and black. In contrast, a positive PRA was significantly associated with female gender but not race or age. Pretransplantation screening of cellular alloimmunity by enzyme-linked immunosorbent spot–based PRT detects a subset of hemodialysis patients who differ from those that are PRA+. Preliminary correlations with posttransplantation outcome in seven recipients suggest that PRT screening has the potential to aid in risk assessment in renal transplant candidates.
Potassium and magnesium depletion in patients with cirrhosis on maintenance diuretic regimens.
Authors: P G Wheeler, T Smith, C Golindano, A N Alam, S P Wilkinson, C J Edmonds, R Williams
Journal: Gut (1977)

Total body potassium (40K) and leucocyte potassium measurements were carried out on 19 patients with stable but decompensated cirrhosis maintained on diuretics for previous ascites. Of 13 patients receiving spironolactone alone none had a total body potassium below the expected lower limit of normal, whereas, of six receiving additional frusemide, two had low values. The results for leucocyte potassium were in agreement and simultaneous measurements of leucocyte magnesium showed a close correlation, those with intracellular potassium depletion also having magnesium depletion. One such patient was treated with magnesium supplements without effect on the potassium, although intracellular magnesium was improved. It is concluded that spironolactone alone is the treatment of choice in the maintenance management of such patients; that additional potassium would be unnecessary; and that additional frusemide should be avoided if possible.
Bryan Nicholas Brooke John Callander Lucy Margaret Elsom Ralph Harding Farrow Monica Madeline Mary Meynell Fisher Lilian Frances Jones Robert Noel Hall Michael James Hunter Susan Nicholls (nee Parish) Louis Jonah Opit Ralph Schram
Authors: G. Slaney, A. Riddell, J. Epsom, N. Farrow, C. Fisher, P. Powley, H. Brown, H P L Falla, C. Nicholls, R. Collins, M. Forsythe, E. Schram, J D Roche
Journal: BMJ (1998)
Association Between a High-Risk Autism Locus on 5p14 and Social Communication Spectrum Phenotypes in the General Population
Authors: Beate St. Pourcain, Kai Wang, Joseph T. Glessner, Jean Golding, Colin Steer, Susan M. Ring, David H. Skuse, Struan F.A. Grant, Hakon Hakonarson, George Davey Smith
Journal: American Journal of Psychiatry (2010)

Objective: Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum. Method: Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout. Results: Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple sub-threshold social, communicative, and cognitive impairments. Conclusions: Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.
Iodine-123 Metaiodobenzylguanidine Scintigraphy Scoring Allows Prediction of Outcome in Patients With Stage 4 Neuroblastoma: Results of the Cologne Interscore Comparison Study
Authors: Boris Decarolis, Christina Schneider, Barbara Hero, Thorsten Simon, Ruth Volland, Frederik Roels, Markus Dietlein, Frank Berthold, Matthias Schmidt
Journal: Journal of Clinical Oncology (2013)

Purpose Radioiodinated metaiodobenzylguanidine ( 123 I-mIBG) scintigraphy is an established imaging method in neuroblastoma. Semiquantitative scoring systems have been developed to assess the extent of disease and response to chemotherapy. We present the results of the comparison between the SIOPEN [International Society of Pediatric Oncology Europe Neuroblastoma Group] score and the modified Curie score. Patients and Methods We retrospectively analyzed 147 mIBG scans of 58 patients older than 1 year of age with stage 4 neuroblastoma from German Neuroblastoma Trial NB97 that were assessed according to the SIOPEN and the Curie scoring method. mIBG examinations were performed at diagnosis and after four and six cycles of chemotherapy. Results Scoring results were highly correlated between both methods, and interobserver reliability was excellent. A Curie score ≤ 2 and a SIOPEN score ≤ 4 (best cutoff) at diagnosis were correlated to significantly better event-free and overall survival compared with higher scores. After four cycles of chemotherapy, overall survival was significantly better for mIBG-negative patients compared with those with any residual mIBG-positive metastases. After six cycles of chemotherapy, there was no difference in survival between mIBG-negative patients and patients with residual mIBG-positive metastases. Patients without mIBG-positive metastases after four and six cycles of chemotherapy had a better overall survival, but late clearance of mIBG-positive metastases did not improve outcome. Conclusion Higher mIBG scores at diagnosis and occurrence of any residual mIBG-positive metastases after four cycles of chemotherapy predicted unfavorable outcome for patients with stage 4 neuroblastoma. Later clearance of metastases did not improve prognosis. The Curie and the SIOPEN score were equally reliable and predictive.
A possible role for Epstein-Barr virus in the pathogenesis of pleural effusion
Authors: S. F. T. Thijsen, R. Luderer, J. M. H. van Gorp, S. J. G. Oudejans, A. W. J. Bossink
Journal: European Respiratory Journal (2005)

A high percentage of pleural effusions remain unexplained despite an intensive diagnostic workup. Epstein-Barr virus (EBV) infections occur worldwide and affect the majority of the population. The present study investigated the prevalence and clinical relevance of EBV in pleural effusions. A prospective study was performed in which 60 consecutive patients with pleural effusion were enrolled. Real-time quantitative EBV-PCR was performed on pleural fluid and serum. Pleural fluid was further evaluated using standard biochemical, cytological and microbiological procedures. Demographic data, medical history and medication were recorded. A total of 24 (40%), from 60 pleural fluids tested, were positive in the EBV-PCR. Median EBV-DNA levels for positive samples was 454 genome equivalents (geq).mL-1 (range 36-163,446 geq.mL-1). A total of 20 (59%) out of 34 unexplained pleural effusions were EBV-PCR positive. Serological analysis of all patients with a positive PCR revealed a previous infection. Patients with a positive EBV-PCR on pleural fluid were more likely to have a positive EBV-PCR on serum than patients with a negative PCR on pleural fluid. Epstein-Barr virus reactivation in pleural fluid is a frequent event and the absence of an alternative diagnosis to explain the nature of the effusion in the majority of cases suggests an aetiological role for Epstein-Barr virus in the development of pleural effusion.
Delivery of Cardiolipins to the Salmonella Outer Membrane Is Necessary for Survival within Host Tissues and Virulence
Authors: Zachary D. Dalebroux, Mauna B. Edrozo, Richard A. Pfuetzner, Susanne Ressl, Bridget R. Kulasekara, Marie-Pierre Blanc, Samuel I. Miller
Journal: Cell Host & Microbe (2015)
THE MEDICAL SICKNESS SOCIETY
Authors: F. d. H. Hall
Journal: BMJ (1910)

<h3>Objective</h3> There is a pressing need to develop reliable molecular biomarkers in osteoarthritis. The aim of the study was to identify novel serum biomarkers for osteoarthritis using a metabolomics approach. <h3>Methods</h3> A two-stage study design was utilised. 123 knee osteoarthritis cases and 299 controls were selected from the TwinsUK cohort as a discovery sample. 76 knee osteoarthritis cases and 100 controls from the Chingford Study were used as replication. Knee osteoarthritis was defined as either radiographic, medically diagnosed or total knee joint replacement due to primary osteoarthritis. All the subjects were unrelated white women. Their serum samples were assessed for targeted metabolite profiling by electrospray ionisation tandem mass spectrometry using the AbsoluteIDQ kit. 163 serum metabolites were assessed and their concentrations obtained. The ratios of metabolite concentrations as proxies for enzymatic reaction rates were calculated and tested for the association with knee osteoarthritis. Significance was assessed after adjustment for multiple testing (Bonferroni method) and potential confounders. <h3>Results</h3> In the discovery stage, the authors identified 14 ratios significantly associated with knee osteoarthritis with p≤1.9×10<sup>−6</sup>. Two of these 14 ratios were successfully confirmed in the replication stage—the ratios of valine to histidine and xleucine to histidine, with p=0.002. The significance remained after adjustment for age and body mass index. <h3>Conclusion</h3> This is the first serum-based metabolomic study of osteoarthritis in humans. The branched-chain amino acids to histidine ratio has potential clinical use as an osteoarthritis biomarker and shows the clinical potential of metabolomics.
Epidemiology and Mechanisms of De Novo and Persistent Hypertension in the Postpartum Period
Authors: Arvind Goel, Manish R. Maski, Surichhya Bajracharya, Julia B. Wenger, Dongsheng Zhang, Saira Salahuddin, Sajid S. Shahul, Ravi Thadhani, Ellen W. Seely, S. Ananth Karumanchi, Sarosh Rana
Journal: Circulation (2015)

Background— The pathophysiology of hypertension in the immediate postpartum period is unclear. Methods and Results— We studied 988 consecutive women admitted to a tertiary medical center for cesarean section of a singleton pregnancy. The angiogenic factors soluble fms-like tyrosine kinase 1 and placental growth factor, both biomarkers associated with preeclampsia, were measured on antepartum blood samples. We then performed multivariable analyses to determine factors associated with the risk of developing postpartum hypertension. Of the 988 women, 184 women (18.6%) developed postpartum hypertension. Of the 184 women, 77 developed de novo hypertension in the postpartum period, and the remainder had a hypertensive disorder of pregnancy in the antepartum period. A higher body mass index and history of diabetes mellitus were associated with the development of postpartum hypertension. The antepartum ratio of soluble fms-like tyrosine kinase 1 to placental growth factor positively correlated with blood pressures in the postpartum period (highest postpartum systolic blood pressure [ r =0.29, P &lt;0.001] and diastolic blood pressure [ r =0.28, P &lt;0.001]). Moreover, the highest tertile of the antepartum ratio of soluble fms-like tyrosine kinase 1 to placental growth factor was independently associated with postpartum hypertension (de novo hypertensive group: odds ratio, 2.25; 95% confidence interval, 1.19–4.25; P =0.01; in the persistent hypertensive group: odds ratio, 2.61; 95% confidence interval, 1.12–6.05; P =0.02) in multivariable analysis. Women developing postpartum hypertension had longer hospitalizations than those who remained normotensive (6.5±3.5 versus 5.7±3.4 days; P &lt;0.001). Conclusions— Hypertension in the postpartum period is relatively common and is associated with prolonged hospitalization. Women with postpartum hypertension have clinical risk factors and an antepartum plasma angiogenic profile similar to those found in women with preeclampsia. These data suggest that women with postpartum hypertension may represent a group of women with subclinical or unresolved preeclampsia.