tbuckley/cabot-search huggingface dataset:
Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease
Authors: Aitana Sogorb-Esteve, María-Salud García-Ayllón, Juan Fortea, Raquel Sánchez-Valle, Alberto Lleó, José-Luis Molinuevo, Javier Sáez-Valero
Journal: Molecular Neurodegeneration (2016)

Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzheimer's disease (AD), particularly in both symptomatic and asymptomatic genetically determined AD, in order to evaluate their potential as early biomarkers.Western blotting, differential centrifugation and co-immunoprecipitation served to determine and characterize CSF-PS1 complexes. We also monitored the assembly of soluble PS1 into complexes in a cell model, and the participation of Aβ in the dynamics and robustness of the stable PS1 complexes.There was an age-dependent increase in CSF-PS1 levels in cognitively normal controls, the different complexes represented in similar proportions. The total levels of CSF-PS1, and in particular the proportion of the stable 100-150 kDa complexes, increased in subjects with autosomal dominant AD that carried PSEN1 mutations (eight symptomatic and six asymptomatic ADAD) and in Down syndrome individuals (ten demented and ten non-demented DS), compared with age-matched controls (n = 23), even prior to the appearance of symptoms of dementia. The proportion of stable CSF-PS1 complexes also increased in sporadic AD (n = 13) and mild-cognitive impaired subjects (n = 12), relative to age-matched controls (n = 17). Co-immunoprecipitation demonstrated the association of Aβ oligomers with soluble PS1 complexes, particularly the stable complexes.Our data suggest that CSF-PS1 complexes may be useful as an early biomarker for AD, reflecting the pathology at asymptomatic state.
Specific Chromosomal IG Translocations Have Different Prognosis In Chronic Lymphocytic Leukemia
Authors: Florence Nguyen-Khac, CLaude Lesty, Elise Chapiro, Aurore Grelier, Isabelle Luquet, Isabelle Radford-Weiss, Sandra Fertferrer, Evelyne Callet-Bauchu, Christine Lefebvre, Eric Lippert, Christine Terré, Lucienne Michaux, Marie-Agnes Collonge-Rame, Carole Barin, Francine Mugneret, Pascaline Talmant, Sylvie Taviaux, Stephanie Struski, Virginie Eclache, Carine Gervais, Benoit Quilichini, Nathalie Gachard, Steven Richebourg, Nicole Dastugue, Catherine Settegrana, Frederic Davi, Karim Maloum, Helene Merle-Beral
Journal: Blood (2010)
MAINTENANCE THERAPY FOR ADVANCED NON-SMALL CELL LUNG CANCER: HOW DOES MY PATIENT FEEL ABOUT IT?
Authors: A Sibille, L Peeters, B Anrys, O Christel, Christophe Dooms, Kristiaan Nackaerts, I Wauters, Johan Vansteenkiste
Journal: Journal of Thoracic Oncology (2012)
Uncoupling of mucosal gene regulation, mRNA splicing and adherent microbiota signatures in inflammatory bowel disease
Authors: Robert Häsler, Raheleh Sheibani-Tezerji, Anupam Sinha, Matthias Barann, Ateequr Rehman, Daniela Esser, Konrad Aden, Carolin Knecht, Berenice Brandt, Susanna Nikolaus, Sascha Schäuble, Christoph Kaleta, Andre Franke, Christoph Fretter, Werner Müller, Marc-Thorsten Hütt, Michael Krawczak, Stefan Schreiber, Philip Rosenstiel
Journal: Gut (2016)

Objective An inadequate host response to the intestinal microbiota likely contributes to the manifestation and progression of human inflammatory bowel disease (IBD). However, molecular approaches to unravelling the nature of the defective crosstalk and its consequences for intestinal metabolic and immunological networks are lacking. We assessed the mucosal transcript levels, splicing architecture and mucosa-attached microbial communities of patients with IBD to obtain a comprehensive view of the underlying, hitherto poorly characterised interactions, and how these are altered in IBD. Design Mucosal biopsies from Crohn's disease and patients with UC, disease controls and healthy individuals (n=63) were subjected to microbiome, transcriptome and splicing analysis, employing next-generation sequencing. The three data levels were integrated by different bioinformatic approaches, including systems biology-inspired network and pathway analysis. Results Microbiota, host transcript levels and host splicing patterns were influenced most strongly by tissue differences, followed by the effect of inflammation. Both factors point towards a substantial disease-related alteration of metabolic processes. We also observed a strong enrichment of splicing events in inflamed tissues, accompanied by an alteration of the mucosa-attached bacterial taxa. Finally, we noted a striking uncoupling of the three molecular entities when moving from healthy individuals via disease controls to patients with IBD. Conclusions Our results provide strong evidence that the interplay between microbiome and host transcriptome, which normally characterises a state of intestinal homeostasis, is drastically perturbed in Crohn's disease and UC. Consequently, integrating multiple OMICs levels appears to be a promising approach to further disentangle the complexity of IBD.
Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: First results of the PETACC-6 randomized phase III trial.
Authors: Hans-Joachim Schmoll, Karin Haustermans, Timothy Jay Price, Bernard Nordlinger, Ralf Hofheinz, Jean-Francois Daisne, Jozef Janssens, Baruch Brenner, Peter Schmidt, Hans Reinel, Stephan Hollerbach, Karel Caca, Florian W.B. Fauth, Carla Hannig, John Raymond Zalcberg, Niall C. Tebbutt, Murielle E. Mauer, Carlo G. M. Messina, Manfred P. Lutz, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2013)

3531 Background: The PETACC-6 trial investigates whether the addition of oxaliplatin to preoperative oral fluoropyrimidine-based chemoradiation (CRT) followed by postoperative adjuvant fluoropyrimidine-based chemotherapy (CT) improves disease-free survival (DFS) in locally advanced rectal cancer. We present results of the early secondary endpoints. Methods: Between 11/2008 and 09/2011, patients with rectal cancer within 12 cm from the anal verge, T3/4 and/or node-positive, with no evidence of metastatic disease and considered either resectable at the time of entry or expected to become resectable after preoperative CRT, were randomly assigned to receive 5 weeks of preoperative CRT (45 Gy in 25 fractions) with capecitabine (825 mg/m² twice daily), followed by 6 cycles of adjuvant CT with capecitabine (1000 mg/m 2 twice daily/days 1-15 every three weeks) (arm 1) or to receive the same regimen with the addition of oxaliplatin before (50 mg/m²/days 1, 8, 15, 22, 29) and after surgery (130 mg/m²/day 1, every three weeks) (arm 2). Additional RT before surgery (5.4 Gy/days 36-38) using the same fields or as a boost with capecitabine was an option. Primary endpoint is DFS. Results: 1094 patients were randomized (547 in each arm). 98% and 92% of patients, respectively, received at least 45 Gy of preoperative RT in arm 1 and arm 2. More than 90% of full dose concurrent CT was delivered in 91% and 63% of patients, respectively, in arm 1 and arm 2. Preoperative grade 3/4 toxicity occurred in 15.1% of patients in arm 1 vs. 36.7% in arm 2; 1 vs. 3 patients died before surgery. R0 resection rate was 92.0% in arm 1 and 86.3% in arm 2. The pCR rate (ypT0N0) was equal in both arms with 11.3% in arm 1 and 13.3% in arm 2 (p=0.31). The anal sphincter was preserved in 70% vs. 65% (p=0.09) in arm 1 and 2. Postoperative complications were not different between arms (38% vs. 41%; 5 vs. 4 patients died following surgery). Definitive numbers will be presented at the congress. Conclusions: The addition of oxaliplatin to preoperative fluoropyrimidine-based CRT led to decreased treatment compliance and increased toxicity, but did not improve surgical outcome. Clinical trial information: NCT00766155.
Abstract 15905: Incidence and Characteristics of Major Bleeding Among Rivaroxaban Users With Renal Disease and Non-valvular Atrial Fibrillation
Authors: Sally Tamayo, Manesh Patel, Zhong Yuan, Nicholas Sicignano, Kathleen Hopf, Frank Peacock
Journal: Circulation (2015)

Background: Patients with renal impairment (as compared to those without) who receive anticoagulants appear to be at increased risk of bleeding based on recent clinical trials. Rivaroxaban is a direct factor Xa inhibitor used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Purpose: To quantify the rates and better understand the pattern of major bleeding (MB) among NVAF patients with and without a coded diagnosis of renal disease (RD) who take rivaroxaban. Methods: Nearly 10 million electronic medical records from the Department of Defense healthcare system were evaluated to identify MB related hospitalizations among rivaroxaban users with NVAF over a 2 year period as part of an ongoing post-marketing study. A validated algorithm (Cunningham 2011) was used to identify MB. Renal disease (reflective of impaired renal function) was defined via diagnostic codes within 6 months prior to the bleeding date for MB cases, or the reporting quarter for non-MB patients. Rates of MB were quantified by renal disease status. Additional data were collected on patient characteristics and comorbidities, MB management, and outcomes. Results: Overall, 39,052 rivaroxaban users with NVAF were identified; 6,034 patients (15.5%) had RD. Patients with RD had a higher rate of MB than those without RD, 4.65 per 100 person-years versus 2.59 per 100 person-years, respectively. Patients with RD also had a greater prevalence of comorbidities and higher CHA 2 DS 2 -VASc scores. Key findings are presented in Table 1. Conclusion: In a post-marketing study of 39,052 rivaroxaban users with nonvalvular atrial fibrillation, patients with renal disease experienced a higher rate of MB than those without renal disease. This higher rate of MB may be partly due to the confounding effects of comorbidities in patients with RD, as reflected by their higher CHA 2 DS 2 -VASc scores, and is worthy of further investigation.
Comparative Study of Autologous Stem Cell Transplant (ASCT) in HIV-1 Positive (HIV+) on Haart and HIV-1 Negative (HIV−) Non Hodgkin Lymphoma (NHL) Patients.
Authors: David Serrano, Pascual Balsalobre, Rafael Carrion, Javier Anguita, Pilar Miralles, Juan Berenguer, Ismael Buño, Alfonso Gomez-Pineda, Rosario Varela, Eulogio Conde, Ildefonso Espigado, Lourdes Escola, Pascual Fernandez, Pedro Sanchez-Godoy, Javier Loscertales, Josep-Maria Ribera, Jose L. Diez-Martin
Journal: Blood (2006)
Efficacy and safety of erlotinib in >1200 East/South-East (E/SE) Asian patients (pts) with advanced non-small-cell lung cancer (NSCLC)
Authors: T. S. Mok, C. Zhou, S. Kim, Y. Wu, R. Perng
Journal: Journal of Clinical Oncology (2008)

19001 Background: The open-label, global phase IV TRUST study provided erlotinib for pts with advanced NSCLC. Methods: Eligible pts had stage IIIB/IV NSCLC and had either failed on or were unsuitable to receive chemo-/radiotherapy. Erlotinib 150mg/d p.o. was given until disease progression or unacceptable toxicity. Results: Data were available for 1223 pts from seven E/SE Asian countries/areas: mainland China (n=501), Taiwan (n=300), South Korea (n=201), Hong Kong (n=178), Thailand/Indonesia/Malaysia (n=43). Median age was 60y (range 22–87). Baseline characteristics (%): male/female 54/46; non-smoker/ever-smoker 55/45; ECOG PS 0/1/2/3/no data 16/65/14/4/<1; adenocarcinoma/squamous-cell/other 70/18/12; stage IIIB/IV/no data 20/79/<1; erlotinib 1st/2nd/3rd-line/other 9/57/34/<1; >99% pts were Asian. Tumor response data were available for 1097 pts: <1% had a CR, 26% had a PR and 52% had SD; disease control rate (CR+PR+SD) = 78%. Median PFS was 25.1wks (95% CI 23.9–28.9; n=1222), compared with 14.1wks in the overall TRUST population, and similar across treatment lines (1st-line 24.3 wks; 2nd-line 24.6 wks; 3rd-line 28.0 wks). A trend to higher PFS was observed in pts with PS 0/1 (n=989) vs 2 (n=177) (26.3 vs 20.7wks). Pts with a higher degree of rash also appeared to do better: those with gr 0/1 rash (n=609) had PFS of 19.0 wks vs 40.9 wks in pts with gr 2/3/4 rash (n=556; p<0.0001). OS data will be presented; current 1-yr survival rate = 60%. In safety analyses (n=1062), 17% had ≥1 erlotinib-related adverse event (AE; excluding 15 most frequent events pre-specified in the protocol); 3% reported ≥1 erlotinib-related serious AE (SAE); 13% had dose reductions and 3% discontinued erlotinib. Only 6 pts (1%) reported a respiratory SAE, including 1 pt with confirmed interstitial lung disease. As expected, 83% of pts had erlotinib-related rash, mostly gr 1/2. Conclusions: Erlotinib appears to be a particularly effective and well-tolerated treatment in this E/SE Asian subpopulation of the TRUST study, and may be considered for all suitable pts with advanced NSCLC. As selection bias may apply to the trial demography in this region, it is not possible to comment on the predictive value of baseline characteristics. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Pfizer, Roche AstraZeneca, Eli Lilly, Roche
Long-term outcomes of responders in a randomized, controlled phase II trial of aptamer AS1411 in AML.
Authors: D. Rizzieri, K. Stockerl-Goldstein, A. Wei, R. H. Herzig, F. Erlandsson, R. K. Stuart
Journal: Journal of Clinical Oncology (2010)

6557 Background: AS1411 is the most advanced aptamer in oncology clinical development. It targets nucleolin, a protein upregulated on the surface of cancer cells. Data from a phase II study of AS1411 in relapsed and refractory AML were reported at ASCO 2009. In this update, we report follow-up data for the responders in the study. Methods: This randomized, multicenter phase II trial compared AS1411 plus high-dose cytarabine (HiDAC) to HiDAC alone as treatment for relapsed (≤3 previous lines of therapy) or refractory AML. Patients in cohort I were randomized 2:1 to receive AS1411 10 mg/kg/day IV CI days 1-7 + HiDAC 1.5 g/m2 bid days 4-7 (AS1411-10), or HiDAC alone for 4 days (control). Following safety assessment, a second cohort was randomized to receive AS1411 40 mg/kg/day + HiDAC (AS1411-40) or HiDAC alone. Objectives were comparison of response rates (CR+CRp), safety and tolerability between groups. For this analysis, we collected data on post-remission therapy (PRT) and overall survival (OS) among responders. Results: 71 patients were randomized: 22 to AS1411-10, 26 to AS1411-40 and 23 to control. 67 patients were evaluable for safety (AS1411-10, 21; AS1411 40, 25; control, 21). Grade 3 and 4 toxicities were similar across all groups: febrile neutropenia, neutropenia, thrombocytopenia, and infections. Deaths within 28 days of treatment were: AS1411-10, 1/21; AS1411-40, 2/25; and control, 3/21. 59 patients were evaluable for response; AS1411-10, 21% (4CR/19); AS1411-40, 19% (2CR+2CRp/21); and control, 5% (1CRp/19). PRT and OS data for responding patients are tabulated. Conclusions: This phase II trial suggested that addition of AS1411 to cytarabine may enhance anti-leukemic activity and that the combination has an acceptable safety profile in patients with relapsed and refractory AML. Follow-up suggests substantial survival durations in some patients responding to AS1411 + cytarabine. A phase IIb study is now evaluating responses, duration of responses and survival in AML patients randomized to AS1411 + cytarabine or cytarabine alone. Group CR/CRp PRT OS (months) Control CRp None 6 AS1411-10 CR Clinical trial 12 CR HiDAC 12+ CR HSCT 18+ CR HSCT 20+ AS1411-40 CRp Allo SCT 3 CR DLIs, Depocyt 5 CRp - 14+ CR - - Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisoma Antisoma Antisoma Antisoma
Interviews with paediatric rheumatologists about psoriasis and psoriatic arthritis in children: how can specialties learn from each other?
Authors: E. Burden-Teh, K.S. Thomas, S. Rangaraj, R. Murphy
Journal: British Journal of Dermatology (2016)

Opportunities exist for cross-specialty learning between dermatology and other medical disciplines; to the benefit of patients, clinical decision making and professional development.The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) promotes the concept of 'psoriatic disease' to encompass psoriasis and psoriatic arthritis, and in their new disease management recommendations emphasise the importance of collaborative working between dermatologists and rheumatologists 1 .Whilst the group primarily focuses on adult disease we suggest that a similar model should exist for the paediatric population.Juvenile psoriatic arthritis (JPsA) is a separate disease to psoriatic arthritis in adults and is a distinct subset of juvenile idiopathic arthritis (JIA); an inflammatory arthritis with onset under the age of 16 years and unknown aetiology 2 .Diagnosis of cutaneous psoriasis and psoriatic nail disease are both core components of the diagnostic classification for JPsA 3 .However, recognition of psoriasis in children can be more challenging compared to adult disease as the signs are often more subtle 4 .
β-Myosin Heavy Chain Variant Val606Met Causes Very Mild Hypertrophic Cardiomyopathy in Mice, but Exacerbates HCM Phenotypes in Mice Carrying Other HCM Mutations
Authors: Robert Blankenburg, Katarzyna Hackert, Sebastian Wurster, René Deenen, J.G. Seidman, Christine E. Seidman, Martin J. Lohse, Joachim P. Schmitt
Journal: Circulation Research (2014)

Rationale : Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family. Objective : To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. Methods and Results : Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling. Conclusions : The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations.
Efficacy of bevacizumab in combination with irinotecan or oxaliplatin as second-line, third-line or later treatment in metastatic colorectal cancer (MCRC) patients
Authors: A. Lièvre, E. Samalin, P. Senesse, C. Boyer-Gestin, E. Mitry, C. Lepère, J. Bachet, J. Vaillant, M. Ychou, P. Rougier
Journal: Journal of Clinical Oncology (2007)

14558 Introduction: Bevacizumab (Bev) is efficient in MCRC patients (pts) as first-line treatment (L1) with 5FU±irinotecan, and with FOLFOX as second-line (L2). It has no efficacy in 3rd or later-line, alone or with 5FU. In Europe, Bev was approved by the EMEA (European Medicines Evaluation Agency) in 2005 and many patients could not received it in L1 before this date. This study evaluated the efficacy of Bev combined to polychemotherapy (CT) in L2, L3 or later-line in CT refractory pts. Methods: Between May 2005 and October 2006, 38 pts (median age: 54.5 years, range:25–82) received Bev combined with CT as L2 (n=18), L3 (n=6), L4 (n=7), L5 or later-line (n=7). Tumor response (OR) was assessed according to RECIST criteria by CT-scan. Results: Tumor sites: 28 colon and 10 rectum. Number of metastatic sites were 1, 2 and more in 16, 13 and 9 cases, mostly hepatic (89%) or pulmonary (42%). Bev (5mg/kg/2weeks) was combined with FOLFIRI (n=24) or FOLFOX (n=14); 299 cycles were administered, mean: 7.9 cycles/pt (range:2–14). OR rate was 42,1%, stabilization 42,1% and was not different according to the line or the CT regimen (table). Initial progressions were rare. Tolerance was acceptable (no perforation and no severe Hypertension). Conclusion: This study reports a significant activity of Bev at the dose of 5mg/kg combined with FOLFOX and/or FOLFIRI in CT refractory pts. These results warrant prospective studies of Bev combined with active CT in CT refractory pts who could not received Bev in the setting of the EMEA authorization. [Table: see text] No significant financial relationships to disclose.
Computerized Tomographic Pulmonary Angiography Compared with Ventilation-Perfusion Lung Scanning as Inital Diagnostic Modality for Patients with Suspected Pulmonary Embolism: A Randomized Controlled Trial.
Authors: David R. Anderson, Philip S. Wells, Susan Kahn, Marc Rodger, Michael J. Kovacs, Tim Morris, Susan Pleasance
Journal: Blood (2005)
Diverse Intestinal Bacteria Contain Putative Zwitterionic Capsular Polysaccharides with Anti-inflammatory Properties
Authors: C. Preston Neff, Matthew E. Rhodes, Kathleen L. Arnolds, Colm B. Collins, Jody Donnelly, Nichole Nusbacher, Paul Jedlicka, Jennifer M. Schneider, Martin D. McCarter, Michael Shaffer, Sarkis K. Mazmanian, Brent E. Palmer, Catherine A. Lozupone
Journal: Cell Host & Microbe (2016)
Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure
Authors: Steven T. Haller, Sivarajan Kumarasamy, David A. Folt, Leah M. Wuescher, Stanislaw Stepkowski, Manish Karamchandani, Harshal Waghulde, Blair Mell, Muhammad Chaudhry, Kyle Maxwell, Siddhi Upadhyaya, Christopher A. Drummond, Jiang Tian, Wanda E. Filipiak, Thomas L. Saunders, Joseph I. Shapiro, Bina Joe, Christopher J. Cooper
Journal: Kidney International (2016)