tbuckley/cabot-search huggingface dataset:
Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients
Authors: M van der Heijden, G P van Nieuw Amerongen, P Koolwijk, V W M van Hinsbergh, A B J Groeneveld
Journal: Thorax (2008)

<h3>Background:</h3> Angiopoietin-2 and vascular endothelial growth factor (VEGF) may impair vascular barrier function while angiopoietin-1 may protect it. It was hypothesised that circulating angiopoietin-2 is associated with pulmonary permeability oedema and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) during septic or non-septic critical illness. <h3>Methods:</h3> Plasma levels of angiopoietin-1 and angiopoietin-2 were measured in mechanically ventilated patients (24 with sepsis, 88 without sepsis), together with the pulmonary leak index (PLI) for 67-gallium-labelled transferrin and extravascular lung water (EVLW) by transpulmonary thermal-dye dilution as measures of pulmonary permeability and oedema, respectively. ALI/ARDS was characterised by consensus criteria and the lung injury score (LIS). Plasma VEGF and von Willebrand factor (VWF) levels were assayed. <h3>Results:</h3> Angiopoietin-2, VWF, PLI, EVLW and LIS were higher in patients with sepsis than in those without sepsis and higher in patients with ALI/ARDS (n = 10/12 in sepsis, n = 19/8 in non-sepsis) than in those without. VEGF was also higher in patients with sepsis than in those without. Patients with high PLI, regardless of EVLW, had higher angiopoietin-2 levels than patients with normal PLI and EVLW. Angiopoietin-2 correlated with the PLI, LIS and VWF levels (minimum r = 0.34, p&lt;0.001) but not with EVLW. Angiopoietin-2 and VWF were predictive for ARDS in receiver operating characteristic curves (minimum area under the curve = 0.69, p = 0.006). Angiopoietin-1 and VEGF did not relate to the permeability oedema of ALI/ARDS. <h3>Conclusion:</h3> Circulating angiopoietin-2 is associated with pulmonary permeability oedema, occurrence and severity of ALI/ARDS in patients with and without sepsis. The correlation of angiopoietin-2 with VWF suggests activated endothelium as a common source.
Randomised, Phase 2 Study (OLIVIA) of Bevacizumab Plus mFOLFOX6 or Folfoxiri in Patients with Initially Unresectable Colorectal Cancer Liver Metastases
Authors: René Adam, John Bridgewater, Ian Chau, Pilar García Alfonso, Michel Rivoire, Susan Lasserre, Daniel Waterkamp, Thomas Gruenberger
Journal: Annals of Oncology (2013)
New MRI modalities for assessment of inflammatory bowel disease
Authors: J. Panes, E. Ricart, J. Rimola
Journal: Gut (2010)

Interest in the use of cross-sectional imaging for assessment of inflammatory bowel disease (IBD) is rapidly growing. Among the different available imaging techniques, MRI is experiencing the largest expansion as judged by the increasing number of publications and the number of units that recently implemented MRI for the study of abdominal inflammatory diseases. A very high soft tissue contrast, lack of ionising radiation, low incidence of adverse events related to the intravenous contrast employed and high diagnostic precision in the evaluation of luminal and extraluminal lesions justify this preference.1 2

Diffusion-weighted imaging (DWI) MR sequence is a functional imaging technique derived from the analysis of the displacement of tissue water molecules due to random thermally-driven motion over ultra-small distances (ie, Brownian motion of water molecules). By the acquisition of DWI, an apparent diffusion coefficient (ADC) map can be generated that provides quantitative information on diffusion. Restricted motion of tissue water molecules is depicted as high signal intensity on DWI sequences and has low ADC values.

DWI has been used mainly for the evaluation of central nervous system lesions, particularly acute ischaemic stroke, intracranial tumours and demyelinating disease.3 4 The main limitations for the use of DWI in the abdominopelvic area are the artefacts generated by respiratory movements. Recent technical improvements allow correction of motion artefacts and provide higher quality images of abdominal organs. At present, the main clinical application of DWI in the abdominopelvic area is the detection of …
Median mass aerodynamic diameter (MMAD) and fine particle fraction (FPF): Influence on lung deposition?
Authors: Cedric Van Holsbeke, Jonathan Marshall, Jan De Backer, Wim Vos
Journal: European Respiratory Journal (2014)

Rationale   The influence of particle size on lung deposition (LD) and efficacy with inhaled drugs is increasingly discussed, yet the role of the FPF is often overlooked. FPF is the fraction of the total drug dose    Methods   3D airway models of 6 asthma patients (mean FEV1 83%) were included. Total lung (TLD), central (C) and peripheral (P) airway deposition of a monodisperse model aerosol with MMAD of 1.5-4.5μm (geometric SD=1.20) and FPF of 10-40% delivered by a pMDI were assessed with FRI (inhalation volume: 3L; time: 3s; actuation start of inhalation).   Results   TLD as % of nominal dose for each permutation of model aerosol are shown in the table.  The C/P ratio for MMAD of 1.5, 3.0 and 4.5μm were 0.42, 0.69, and 1.39.   Conclusions   FPF had a large impact on TLD in vitro whereas MMAD had little effect, although MMAD had some influence on C and P deposition: both 1.5 and 3.0μm MMAD profiles deposited mainly in P (C/P 1.0). Many inhaled respiratory drugs need to reach both P and C airways but the optimal delivery between these for different classes of drugs is less understood. These data highlight the importance of FPF on TLD; beneficial drug effects often attributed to small particle size may really be a consequence of high FPF.  This study was funded by MundiPharma.
Central pyrogenic activity of muramyl dipeptide.
Authors: G Riveau, K Masek, M Parant, L Chedid
Journal: The Journal of Experimental Medicine (1980)

Fever can be elicited in the rabbit by the intravenous administration of relatively large doses of a synthetic immunoadjuvant, N-acetylmuramyl-L-alanyl-D-isoglutamine, or muramyl dipeptide (MDP). This response could be mediated by endogenous pyrogen because MDP has been shown to induce their production both in vivo and in vitro. The results reported here show that intracisternal injection of minute amounts of MDP could elevate fever without activating the release of endogenous pyrogen in the plasma or in the cerebrospinal fluid. Moreover, indomethacin inhibited hyperthermia produced by intracerebroventricular administration of MDP. Therefore, our findings argue in favor of a direct effect of the glycopeptide on the thermoregulatory centers besides its indirect effect through the production of leukocytic pyrogen. This molecule apparently represents the minimal requirement for the pyrogenicity of bacterial peptidoglycan because administration, even by the intracerebral route, of a mixture of muramic acid and of its dipeptide moiety did not elicit fever.
Impaired hematopoiesis in mice lacking the transcription factor Sp3
Authors: Pieter Fokko van Loo, Peter Bouwman, Kam-Wing Ling, Sabine Middendorp, Guntram Suske, Frank Grosveld, Elaine Dzierzak, Sjaak Philipsen, Rudolf W. Hendriks
Journal: Blood (2003)
Incidence and Risk of Congestive Heart Failure in Patients With Renal and Nonrenal Cell Carcinoma Treated With Sunitinib
Authors: Christopher J. Richards, Youjin Je, Fabio A.B. Schutz, Daniel Y.C. Heng, Susan M. Dallabrida, Javid J. Moslehi, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2011)

Sunitinib is a multitargeted receptor tyrosine kinase inhibitor approved for treatment of renal cell carcinoma (RCC) and GI stromal tumor. Congestive heart failure (CHF) is an important adverse effect that has been reported with sunitinib, but overall incidence and relative risk (RR) remain undefined. We performed an up-to-date meta-analysis to determine the risk of developing CHF in patients with both RCC and non-RCC tumors treated with sunitinib.Medline databases were searched for articles published between January 1966 and February 2011. Eligible studies were limited to phase II and III trials of sunitinib with adequate safety reporting in patients with cancer of any tumor type. Summary incidence, RR, and 95% CIs were calculated using random- or fixed-effects models based on the heterogeneity of included studies.A total of 6,935 patients were included. Overall incidence for all- and high-grade CHF in sunitinib-treated patients was 4.1% (95% CI, 1.5% to 10.6%) and 1.5% (95% CI, 0.8% to 3.0%), respectively. RR of all- and high-grade CHF in sunitinib-treated patients compared with placebo-treated patients was 1.81 (95% CI, 1.30 to 2.50; P < .001) and 3.30 (95% CI, 1.29 to 8.45; P = .01), respectively. On subgroup analysis, there was no difference observed in CHF incidence for patients with RCC versus non-RCC or in trials with or without cardiac monitoring. No evidence of publication bias was observed.Sunitinib use is associated with increased risk of CHF in patients with cancer.
Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance
Authors: Simone Post, Anke M. Smits, Alexandra J. van den Broek, Joost P.G. Sluijter, Imo E. Hoefer, Ben J. Janssen, Repke J. Snijder, Johannes J. Mager, Gerard Pasterkamp, Christine L. Mummery, Pieter A. Doevendans, Marie-José Goumans
Journal: Cardiovascular Research (2009)

Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to infarcted mouse myocardium. Stromal cell-derived factor-1α (SDF-1α) and the chemokine receptor CXCR4 are crucial for homing and negatively influenced by CD26. The aim of this study was to gain insight into the impaired homing of HHT1-MNCs. CXCR4 and CD26 expression on MNCs was determined by flow cytometry. Transwell migration to SDF-1α was used to analyse in vitro migration. Experimentally induced myocardial infarction in mice, followed by tail vein injection of MNCs, was applied to study homing in vivo. HHT1-MNCs expressed elevated levels of CXCR4, but this was counterbalanced by high levels of CD26, resulting in decreased migration towards an SDF-1α gradient in vitro. Migration was enhanced by inhibiting CD26 with Diprotin-A. While MNCs from healthy controls responded to transforming growth factor-beta stimulation by increasing CXCR4 and lowering CD26 expression levels, HHT1-MNCs did not react as efficiently: in particular, CD26 expression remained high. Inhibiting CD26 on MNCs increased the homing of human cells into the infarcted mouse heart. Interestingly, the defect in homing of HHT1-MNCs was restored by pre-incubating the HHT1-MNCs with Diprotin-A before injection into the tail vein. We show that a decreased homing of HHT1-MNCs is caused by an impaired ability of the cells to respond to SDF-1α. Our results suggest that modulating CD26 levels using inhibitors like Diprotin-A can restore homing in cases where increased expression of CD26 contributes to the underlying pathological mechanism.
Associations between Changes in Hemoglobin and Administered Erythropoiesis-Stimulating Agent and Survival in Hemodialysis Patients
Authors: Deborah L. Regidor, Joel D. Kopple, Csaba P. Kovesdy, Ryan D. Kilpatrick, Charles J. McAllister, Jason Aronovitz, Sander Greenland, Kamyar Kalantar-Zadeh
Journal: Journal of the American Society of Nephrology (2006)

Although treating anemia of chronic kidney disease by erythropoiesis-stimulating agents (ESA) may improve survival, most studies have examined associations between baseline hemoglobin values and survival and ignored variations in clinical and laboratory measures over time. It is not clear whether longitudinal changes in hemoglobin or administered ESA have meaningful associations with survival after adjustment for time-varying confounders. With the use of time-dependent Cox regression models, longitudinal associations were examined between survival and quarterly (13-wk averaged) hemoglobin values and administered ESA dose in a 2-yr (July 2001 to June 2003) cohort of 58,058 maintenance hemodialysis patients from a large dialysis organization (DaVita) in the United States. After time-dependent and multivariate adjustment for case mix, quarterly varying administered intravenous iron and ESA doses, iron markers, and nutritional status, hemoglobin levels between 12 and 13 g/dl were associated with the greatest survival. Among prevalent patients, the lower range of the recommended Kidney Disease Quality Outcomes Initiative hemoglobin target (11 to 11.5 g/dl) was associated with a higher death risk compared with the 11.5- to 12-g/dl range. A decrease or increase in hemoglobin over time was associated with higher or lower death risk, respectively, independent of baseline hemoglobin. Administration of any dose of ESA was associated with better survival, whereas among those who received ESA, requiring higher doses were surrogates of higher death risk. In this observational study, greater survival was associated with a baseline hemoglobin between 12 and 13 g/dl, treatment with ESA, and rising hemoglobin. Falling hemoglobin and requiring higher ESA doses were associated with decreased survival. Randomized clinical trials are required to examine these associations.
Gene expression variation in Down's syndrome mice allows prioritization of candidate genes
Authors: Marc Sultan, Ilaria Piccini, Daniela Balzereit, Ralf Herwig, Nidhi G Saran, Hans Lehrach, Roger H Reeves, Marie-Laure Yaspo
Journal: Genome biology (2007)

Down's syndrome (DS), or trisomy 21, is a complex developmental disorder that exhibits many clinical signs that vary in occurrence and severity among patients. The molecular mechanisms responsible for DS have thus far remained elusive. We argue here that normal variation in gene expression in the population contributes to the heterogeneous clinical picture of DS, and we estimated the amplitude of this variation in 50 mouse orthologs of chromosome 21 genes in brain regions of Ts65Dn (a mouse model of DS). We analyzed the RNAs of eight Ts65Dn and eight euploid mice by real-time polymerase chain reaction.In pooled RNAs, we confirmed that trisomic/euploid gene expression ratios were close to 1.5. However, we observed that inter-individual gene expression levels spanned a broad range of values. We identified three categories of genes: genes with expression levels consistently higher in Ts65Dn than in euploids (9, 17, and 7 genes in cerebellum, cortex, and midbrain, respectively); genes whose expression levels partially overlap between the two groups (10, 9, and 14 genes); and genes with intermingled expression, which cannot be used to differentiate trisomics from euploids (12, 5 and 9 genes). Of the genes in the first category, App, Cbr1, and Mrps6 exhibited tight regulation in the three tissues and are therefore attractive candidates for further research.This is the first analysis addressing inter-individual gene expression levels as a function of trisomy. We propose a strategy allowing discrimination between candidates for the constant features of DS and those genes that may contribute to the partially penetrant signs of DS.
Outcomes of the Bowel Cancer Screening Programme (BCSP) in England after the first 1 million tests
Authors: Richard F A Logan, Julietta Patnick, Claire Nickerson, Lynn Coleman, Matt D Rutter, Christian von Wagner
Journal: Gut (2011)

<h3>Introduction</h3> The Bowel Cancer Screening Programme in England began operating in 2006 with the aim of full roll out across England by December 2009. Subjects aged 60–69 are being invited to complete three guaiac faecal occult blood tests (6 windows) every 2 years. The programme aims to reduce mortality from colorectal cancer by 16% in those invited for screening. <h3>Methods</h3> All subjects eligible for screening in the National Health Service in England are included on one database, which is populated from National Health Service registration data covering about 98% of the population of England. This analysis is only of subjects invited to participate in the first (prevalent) round of screening. <h3>Results</h3> By October 2008 almost 2.1 million had been invited to participate, with tests being returned by 49.6% of men and 54.4% of women invited. Uptake ranged between 55–60% across the four provincial hubs which administer the programme but was lower in the London hub (40%). Of the 1.08 million returning tests 2.5% of men and 1.5% of women had an abnormal test. 17 518 (10 608 M, 6910 F) underwent investigation, with 98% having a colonoscopy as their first investigation. Cancer (n=1772) and higher risk adenomas (n=6543) were found in 11.6% and 43% of men and 7.8% and 29% of women investigated, respectively. 71% of cancers were ‘early’ (10% polyp cancer, 32% Dukes A, 30% Dukes B) and 77% were left-sided (29% rectal, 45% sigmoid) with only 14% being right-sided compared with expected figures of 67% and 24% for left and right side from UK cancer registration. <h3>Conclusion</h3> In this first round of screening in England uptake and fecal occult blood test positivity was in line with that from the pilot and the original European trials. Although there was the expected improvement in cancer stage at diagnosis, the proportion with left-sided cancers was higher than expected.
THE SELECTIVE ACTION OF SULFANILAMIDE ON THE PARASITES OF EXPERIMENTAL MALARIA IN MONKEYS IN VIVO AND IN VITRO
Authors: L. T. Coggeshall
Journal: The Journal of Experimental Medicine (1940)

It was found that with mixed malaria infections in the same experimental animal sulfanilamide eradicates a virulent P. knowlesi infection, leaving the animal with a milder chronic P. inui infection. Determinations of the metabolic activity of the two parasites in vitro showed that P. knowlesi consumed approximately six times more oxygen than P. inui. The addition of sulfanilamide in concentrations less than that necessary to effect a cure almost completely inhibited the respiration of P. knowlesi parasites in vitro, while the same concentrations of the drug against the same number of P. inui parasites had no apparent effect.
Discussing Palliative Care with Patients
Authors: B Lo, T Quill, J Tulsky
Journal: Annals of Internal Medicine (1999)

Palliative care focuses on relief of suffering, psychosocial support, and closure near the end of life. Even experienced physicians often struggle when initiating complex, emotionally laden discussions about palliative care with seriously ill patients and their families. We use two hypothetical case scenarios to illustrate how physicians can initiate these discussions and to emphasize and illustrate several communication techniques. Physicians can elicit a patient's concerns, goals, and values by using open-ended questions and following up on the patient's response before discussing specific clinical decisions. Physicians can acknowledge patients' emotions, explore the meaning of these emotions, and encourage patients to say more about difficult topics. Physicians should also screen for unaddressed spiritual and existential concerns. Some patients may make statements or ask questions that are difficult for physicians to respond to. We provide examples of responses that align the physician with patients' wishes without reinforcing unrealistic plans. Exploring such difficult issues may lessen feelings of aloneness even when the physician cannot "fix" the problem, and it raises new opportunities for patients to find comfort. In addition to addressing physical suffering, physicians can extend their caring by acknowledging and exploring psychosocial, existential, or spiritual suffering. As patients struggle to find closure in their lives, active listening and empathy have therapeutic value in and of themselves.
A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage
Authors: J.M. Findlay, M.R. Middleton, I. Tomlinson
Journal: Annals of Oncology (2014)

Recent advances in next generation sequencing reinforce the potential for DNA sequence markers to guide esophageal cancer management. We report the first systematic review and meta-analysis, identifying 94 markers of outcome and 41 of stage. Overall, evidence was poor. Meta-analyses demonstrated outcome associations for 6 tumor and 9 germline variants: priorities for prospective evaluation.IntroductionThere is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage.MethodsA systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study.ResultsFour thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutantTP53 andPIK3CA, copy number gain of ERBB2/HER2,CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms:ERCC1 rs3212986,ERCC2 rs1799793,TP53 rs1042522,MDM2 rs2279744,TYMS rs34743033,ABCB1 rs1045642 andMTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded.ConclusionsNumerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.
Use of recombinant granulocyte-macrophage colony-stimulating factor during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia (AML): final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the research and treatment of cancer (EORTC-LCG) and the Dutch Belgian Hemato-Oncology Cooperative Group (HOVON)
Authors: B. Lowenberg, S. Suciu, E. Archimbaud, G.J. Ossenkoppele, G.E.G. Verhoef, E. Vellenga, P. Wijermans, Z. Berneman, A.W. Dekker, P. Stryckmans, H.C. Schouten, U. Jehn, P. Muus, P. Sonneveld, M. Dardenne, R. Zittoun
Journal: Blood (1997)
Evolutionary Pathways in BRCA1-Associated Breast Tumors
Authors: Filipe C. Martins, Subhajyoti De, Vanessa Almendro, Mithat Gönen, So Yeon Park, Joanne L. Blum, William Herlihy, Gabrielle Ethington, Stuart J. Schnitt, Nadine Tung, Judy E. Garber, Katharina Fetten, Franziska Michor, Kornelia Polyak
Journal: Cancer Discovery (2012)

BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.