tbuckley/cabot-search huggingface dataset:
A new endoscopic standardized grading system for macroscopic central airway complications following lung transplantion: The MDS classification
Authors: Hervé Dutau, Thomas Vandemoortele, Sophe Laroumagne, Philippe Astoul, Pascal Thomas, Martine Reynaud-Gaubert, Jean-Michel Vergnon
Journal: European Respiratory Journal (2013)

Background   Anastomotic complications, after lung transplantation, include stenosis, dehiscence, granulation tissue, bronchomalacia and fistula. They have already been included in classifications. None has been universally accepted.   Objective   The French Bronchoscopy Group (GELF) was mandated to develop an endoscopic classification, in order to describe the macroscopic aspect of the bronchial anastomoses, and downhill airways.   Methods   A classification taking into account the three major items of the description of bronchial anastomoses was elaborated. The first parameter is the Macroscopic evaluation (M), the second, the Diameter (D), and the third, the Sutures (S) of the anastomosis. Each parameter can be classified from 0 to 3. It was then submitted to experts from 9 French centers responsible for lung transplant for their opinion, using of a questionnaire.   Results   Two rounds were necessary to allow for a consensus: the MDS classification.  -  M:   o M0 : Scar tissue  o M1 : Protruding cartilage  o M2 : Inflammation/granulomas  o M3 : Ischemia/Necrosis  -  D :   o D0 : Normal to a fixed reduction   o D1 : Expiratory reduction (malacia) > 50%  o D2 : Fixed reduction from 33 to 66%  o D3 : Fixed reduction > 66%  -  S :   o S0 : Absence of dehiscence  o S1 : Limited dehiscence (  o S2 : Extensive dehiscence (from 25 to 50%)  o S3 : Very extensive dehiscence (more than 50%)  NB:  - For M and D: Extent of abnormalities can be graded; a, b, c, d.  - For S : a : anteriorly; b : other localizations   Conclusion   The MDS classification could represent a standardized, universally acceptable system, to describe the central airway complications after lung transplant.
Intracoronary Infusion of Allogeneic Mesenchymal Precursor Cells Directly After Experimental Acute Myocardial Infarction Reduces Infarct Size, Abrogates Adverse Remodeling, and Improves Cardiac Function
Authors: Jaco H. Houtgraaf, Renate de Jong, Kushan Kazemi, Daphne de Groot, Tycho I.G. van der Spoel, Fatih Arslan, Imo Hoefer, Gerard Pasterkamp, Silviu Itescu, Felix Zijlstra, Marcel L. Geleijnse, Patrick W. Serruys, Henricus J. Duckers
Journal: Circulation Research (2013)

Rationale: Mesenchymal precursor cells (MPCs) are a specific Stro-3+ subpopulation of mesenchymal stem cells isolated from bone marrow. MPCs exert extensive cardioprotective effects, and are considered to be immune privileged. Objective: This study assessed the safety, feasibility, and efficacy of intracoronary delivery of allogeneic MPCs directly after acute myocardial infarction in sheep. Methods and Results: Initially, intracoronary delivery conditions were optimized in 20 sheep. These conditions were applied in a randomized study of 68 sheep with an anterior acute myocardial infarction. Coronary flow was monitored during MPC infusion, and cardiac function was assessed using invasive hemodynamics and echocardiography at baseline and during 8 weeks follow-up. Coronary flow remained within thrombolysis in myocardial infarction III definitions in all sheep during MPC infusion. Global left ventricular ejection fraction as measured by pressure–volume loop analysis deteriorated in controls to 40.7±2.6% after 8 weeks. In contrast, MPC treatment improved cardiac function to 52.8±0.7%. Echocardiography revealed significant improvement of both global and regional cardiac functions. Infarct size decreased by 40% in treated sheep, whereas infarct and border zone thickness were enhanced. Left ventricular adverse remodeling was abrogated by MPC therapy, resulting in a marked reduction of left ventricular volumes. Blood vessel density increased by &gt;50% in the infarct and border areas. Compensatory cardiomyocyte hypertrophy was reduced in border and remote segments, accompanied by reduced collagen deposition and apoptosis. No microinfarctions in remote myocardial segments or histological abnormalities in unrelated organs were found. Conclusions: Intracoronary infusion of allogeneic MPCs is safe, feasible, and markedly effective in a large animal model of acute myocardial infarction.
Myeloid derived suppressor and dendritic cell subsets are related to clinical outcome in prostate cancer patients treated with prostate GVAX and ipilimumab
Authors: Saskia JAM Santegoets, Anita GM Stam, Sinéad M Lougheed, Helen Gall, Karin Jooss, Natalie Sacks, Kristen Hege, Israel Lowy, Rik J Scheper, Winald R Gerritsen, Alfons JM van den Eertwegh, Tanja D de Gruijl
Journal: Journal for ImmunoTherapy of Cancer (2014)

Cancer-related disturbances in myeloid lineage development, marked by high levels of myeloid-derived suppressor cells (MDSC) and impaired dendritic cell (DC) development, are associated with poor clinical outcome due to immune escape and therapy resistance. Redressing this balance may therefore be of clinical benefit. Here we investigated the effects of combined Prostate GVAX/ipilimumab immunotherapy on myeloid subsets in peripheral blood of castration-resistant prostate cancer (CRPC) patients as well as the putative predictive value of baseline and on-treatment myeloid parameters on clinical outcome.Patients with CRPC (n = 28) received thirteen intradermal administrations of Prostate GVAX, consisting of two allogeneic GM-CSF-transduced and irradiated prostate cancer cell lines (LN-CaP and PC3) and six infusions of escalating doses of anti-CTLA4/ipilimumab. Frequencies and activation status of peripheral blood DC (PBDC) and MDSC were determined before, during and after treatment by flowcytometric analysis and related to clinical benefit.Significant treatment-induced activation of conventional and plasmacytoid DC subsets (cDC and pDC) was observed, which in the case of BDCA1/CD1c(+) cDC1 and MDC8(+)/6-sulfoLacNAc(+) inflammatory cDC3 was associated with significantly prolonged overall survival (OS), but also with the development of autoimmune-related adverse events. High pre-treatment levels of CD14(+)HLA-DR(-)monocytic MDSC (mMDSC) were associated with reduced OS. Unsupervised clustering of these myeloid biomarkers revealed particular survival advantage in a group of patients with high treatment-induced PBDC activation and low pretreatment frequencies of suppressive mMDSC in conjunction with our previously identified lymphoid biomarker of high pretreatment CD4(+)CTLA4(+) T cell frequencies.Our data demonstrate that DC and MDSC subsets are affected by prostate GVAX/ipilimumab therapy and that myeloid profiling may contribute to the identification of patients with possible clinical benefit of Prostate GVAX/ipilimumab treatment.
“B” for Bad, Beneficial, or Both? Lung Lymphoid Neogenesis in Chronic Obstructive Pulmonary Disease
Authors: Jeffrey L. Curtis, Christine M. Freeman, Gary B. Huffnagle
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

cysteinyl leukotrienes and their receptors (14, 15), and overexpression of PgD 2 (16).Thus, it is intriguing that the current study, although confirming the presence of a Th2 signature, does demonstrate a hint at other distinctive features of AERD.Although excessive granulocyte-macrophage colony-stimulating factor and MCP-1 may support a more robust Th2 process, the dearth of tissue plasminogen activator is quite intriguing, suggesting a role for the procoagulation pathway and fibrin deposition that perhaps drives some of the aggressive remodeling that defines this disorder.Activation of the coagulation pathway might also be consistent with recent studies demonstrating a role for platelet-associated inflammation in AERD (17), which is another area of research largely unexplored in these diseases and inviting further research.
Commensal bacteria drive endogenous transformation and tumour stem cell marker expression through a bystander effect
Authors: Xingmin Wang, Yonghong Yang, Mark M Huycke
Journal: Gut (2014)

<h3>Objective</h3> Commensal bacteria and innate immunity play a major role in the development of colorectal cancer (CRC). We propose that selected commensals polarise colon macrophages to produce endogenous mutagens that initiate chromosomal instability (CIN), lead to expression of progenitor and tumour stem cell markers, and drive CRC through a bystander effect. <h3>Design</h3> Primary murine colon epithelial cells were repetitively exposed to <i>Enterococcus faecalis</i>-infected macrophages, or purified <i>trans</i>-4-hydroxy-2-nonenal (4-HNE)—an endogenous mutagen and spindle poison produced by macrophages. CIN, gene expression, growth as allografts in immunodeficient mice were examined for clones and expression of markers confirmed using interleukin (IL) 10 knockout mice colonised by <i>E. faecalis</i>. <h3>Results</h3> Primary colon epithelial cells exposed to polarised macrophages or 4-hydroxy-2-nonenal developed CIN and were transformed after 10 weekly treatments. In immunodeficient mice, 8 of 25 transformed clones grew as poorly differentiated carcinomas with 3 tumours invading skin and/or muscle. All tumours stained for cytokeratins confirming their epithelial cell origin. Gene expression profiling of clones showed alterations in 3 to 7 cancer driver genes per clone. Clones also strongly expressed stem/progenitor cell markers Ly6A and Ly6E. Although not differentially expressed in clones, murine allografts positively stained for the tumour stem cell marker doublecortin-like kinase 1. Doublecortin-like kinase 1 and Ly6A/E were expressed by epithelial cells in colon biopsies for areas of inflamed and dysplastic tissue from <i>E. faecalis</i>-colonised IL-10 knockout mice. <h3>Conclusions</h3> These results validate a novel mechanism for CRC that involves endogenous CIN and cellular transformation arising through a microbiome-driven bystander effect.
Promoter Analysis of MADS-Box Genes in Eudicots Through Phylogenetic Footprinting
Authors: Stefanie De Bodt, Guenter Theissen, Yves Van de Peer
Journal: Molecular Biology and Evolution (2006)

The MIKC MADS-box gene family has been shaped by extensive gene duplications giving rise to subfamilies of genes with distinct functions and expression patterns. However, within these subfamilies the functional assignment is not that clear-cut, and considerable functional redundancy exists. One way to investigate the diversity in regulation present in these subfamilies is promoter sequence analysis. With the advent of genome sequencing projects, we are now able to exert a comparative analysis of Arabidopsis and poplar promoters of MADS-box genes belonging to the same subfamily. Based on the principle of phylogenetic footprinting, sequences conserved between the promoters of homologous genes are thought to be functional. Here, we have investigated the evolution of MADS-box genes at the promoter level and show that many genes have diverged in their regulatory sequences after duplication and/or speciation. Furthermore, using phylogenetic footprinting, a distinction can be made between redundancy, neo/nonfunctionalization, and subfunctionalization.
Cutaneous findings in chronic lymphocytic leukaemia
Authors: K.L. Agnew, R. Ruchlemer, D. Catovsky, E. Matutes, C.B. Bunker
Journal: British Journal of Dermatology (2004)

Chronic lymphocytic leukaemia (CLL) is a malignancy characterized by clonal expansion of B lymphocytes with distinct morphology and immunophenotype. The dermatological literature relating to CLL is sparse. A global descriptive survey of a large number of CLL patients has not previously been published.To report the spectrum of dermatological conditions seen in a large series of CLL patients.Skin complications in patients with established CLL were identified retrospectively from clinical and photographic records, principally a database of over 750 consecutive cases. These events were classified, enumerated and compared.Forty patients with 125 skin manifestations were identified and studied. Forty-one manifestations had documented clinical or histological atypia. In 21 of these 41 complications there had been no prior immunosuppressive therapy. We observed that cutaneous malignancies frequently presented atypically both clinically and histologically. There were 18 patients with 56 instances of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), and clinical atypia was more common with SCC than with BCC. Other cutaneous findings included varicella zoster (n = 6), leukaemia cutis (n = 3), acute graft-versus-host disease (n = 5), cutaneous drug eruptions (n = 9), multiple warts (n = 3), herpes simplex (n = 3), cutaneous T-cell lymphoma (n = 2), eosinophilic folliculitis (n = 2), malignant melanoma (n = 2) and Merkel cell tumour (n = 2).We have identified a range of dermatological conditions in CLL patients, with a tendency to atypical presentations. The atypia was independent of prior chemotherapy.
Methylation of <i>O</i>6-Methylguanine DNA Methyltransferase and Loss of Heterozygosity on 19q and/or 17p Are Overlapping Features of Secondary Glioblastomas with Prolonged Survival
Authors: Marica Eoli, Francesca Menghi, Maria Grazia Bruzzone, Tiziana De Simone, Lorella Valletta, Bianca Pollo, Lorena Bissola, Antonio Silvani, Donatella Bianchessi, Ludovico D'Incerti, Graziella Filippini, Giovanni Broggi, Amerigo Boiardi, Gaetano Finocchiaro
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Recent data suggest that methylation of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT), by increasing the chemosensitivity of glioblastoma multiforme, is significantly associated with improved prognosis. Results in contradiction with these findings, however, are present in the literature and the clinical and genetic context framing MGMT methylation is poorly characterized. Experimental Design: To address these issues, we have investigated the MGMT methylation status, clinical and magnetic resonance imaging characteristics, and relevant genetic features (loss of heterozygosity on 17p and 19q, EGFR amplification, and p53 mutations) in a retrospective study on 86 patients affected by glioblastoma multiforme: 72 patients had a clinical history indicating de novo insurgence of the tumor and the remaining 14 were secondary glioblastoma multiforme. Results: MGMT methylation was detected by methylation-specific PCR in 41 of 86 cases (47.7%; Meth+). Progression-free survival and overall survival were significantly longer in Meth+ than in Meth− patients [10 versus 7 months (P = 0.003, log-rank test) and 18 versus 14 months (P = 0.0003, log-rank test), respectively]. Mixed-nodular enhancement at magnetic resonance imaging was significantly more frequent in Meth+ and secondary glioblastoma multiforme and ring enhancement in Meth− and primary glioblastoma multiforme (P &amp;lt; 0.005). MGMT methylation was more present in secondary glioblastoma multiforme (P = 0.006) and associated with loss of heterozygosity on 17p and/or 19q (P = 0.005). Conclusions: These observations suggest that MGMT methylation is part of a genetic signature of glioblastomas that developed from lower-grade gliomas.
Safety and tolerability of a novel chromatography‐based intravenous immunoglobulin when administered at a high infusion rate in patients with immune thrombocytopenic purpura
Authors: James B. Bussel, Kim Hanna
Journal: American Journal of Hematology (2006)

Abstract Intravenous immunoglobulin (IGIV) therapy is generally considered to be a safe and effective treatment for idiopathic thrombocytopenic purpura (ITP). The usual initial treatment dose is 1–2 g/kg body weight, which results in an extended infusion time, significantly impacting patients' day‐to‐day activities. Two crossover studies assessed the safety and tolerability of a novel IGIV preparation (IGIV‐C; Gamunex®, 10%) when infused at rates ranging from 0.08 mL/kg/min (the standard maximum licensed rate) to 0.14 mL/kg/min in patients with ITP. The first study included 28 patients and 3 infusion rates; 0.08, 0.11, and 0.14 mL/kg/min. The second study included 8 patients and 2 infusion rates; 0.08 and 0.14 mL/kg/min were evaluated. The incidence of infusion‐related adverse events was similar for all infusion rates. Headache was the most commonly reported infusion‐related adverse event. The incidence, combined for Studies 1 and 2, was 14.7% ( n = 34), 18.2% ( n = 22), and 19.4% ( n = 31) of patients, for each infusion rate of 0.08, 0.11, and 0.14 mL/kg/min, respectively. The majority were mild in severity. None of the other drug‐related, treatment‐emergent events were serious; most were mild, in spite of the higher rate of fluid loading over a shorter period of time for patients infused at 0.14 mL/kg/min. There were no clinically important changes in parameters that distinguished between infusion rates; there were no signs of hemolysis. The results suggest that IGIV‐C infused at rates up to 0.14 mL/kg/min in patients with ITP is well tolerated. Am. J. Hematol., 2007. © 2006 Wiley‐Liss, Inc.
Pharmacogenomic Predictor of Sensitivity to Preoperative Chemotherapy With Paclitaxel and Fluorouracil, Doxorubicin, and Cyclophosphamide in Breast Cancer
Authors: Kenneth R. Hess, Keith Anderson, W. Fraser Symmans, Vicente Valero, Nuhad Ibrahim, Jaime A. Mejia, Daniel Booser, Richard L. Theriault, Aman U. Buzdar, Peter J. Dempsey, Roman Rouzier, Nour Sneige, Jeffrey S. Ross, Tatiana Vidaurre, Henry L. Gómez, Gabriel N. Hortobagyi, Lajos Pusztai
Journal: Journal of Clinical Oncology (2006)

We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases.One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases.Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant.A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).
Clinical trials comparing norepinephrine with vasopressin in patients with septic shock: a meta-analysis
Authors: Fei-Hu Zhou, Qing Song
Journal: Military Medical Research (2014)

The effect of norepinephrine in patients with septic shock remains controversial. We conducted a meta-analysis to compare the mortality rates and benefits of norepinephrine and vasopressin.PubMed, EMBASE, and the Cochrane Library database were searched from database inception to December 2013. We selected randomized controlled trials in adults with septic shock and compared norepinephrine with vasopressin. After assessing the heterogeneity of treatment effects across trials using the I (2) statistic, we used a fixed effects model (P ≥ 0.1) and expressed the results as risk ratios (RRs) for dichotomous outcomes or as standardized mean differences (SMDs) for continuous data with 95% confidence intervals (CIs). Meta-analysis was conducted using Review Manager 5.1 software.Seven trials (n = 2323) met the inclusion criteria. Overall, the mortality rate in these seven trials was 36.2% (840/2323). There was no difference in mortality following the use of norepinephrine or vasopressin (RR 1.07; 95%CI 0.97-1.20; P = 0.19). Compared to norepinephrine, vasopressin had no significant effect on heart rate (HR) (SMD 0.21; 95%CI -0.08-0.50; P = 0.15), mean arterial pressure (MAP) (SMD 0.15; 95%CI -0.15-0.44; P = 0.33), cardiac index (CI) (SMD -0.10; 95%CI -0.64-0.44; P = 0.73), systemic vascular resistance index (SVRI) (SMD 0.15; 95%CI -0.39-0.70; P = 0.58), oxygen delivery (DO2) (SMD -0.06; 95%CI -0.62-0.49; P = 0.82), oxygen consumption (VO2) (SMD 0.03; 95%CI -0.52-0.59; P = 0.91) or lactic acid (SMD 0.07; 95%CI -0.23-0.36; P = 0.66). No significant heterogeneity was found in these comparisons (P ≥ 0.1).There is not sufficient evidence to prove conclusively that norepinephrine is superior to vasopressin in terms of mortality and hemodynamics. The effects of norepinephrine and vasopressin on patients with septic shock require further study in large randomized controlled trials.
Characterization of the methylation patterns of <i>MS4A2</i> in atopic cases and controls
Authors: M. A. R. Ferreira, N. A. Oates, J. Van Vliet, Z. Z. Zhao, M. Ehrich, N. G. Martin, G. W. Montgomery, E. Whitelaw, D. L. Duffy
Journal: Allergy (2009)

It is largely unknown whether epigenetic modifications of key genes may contribute to the reported maternal effects in atopy. The aim of this study was to characterize the methylation patterns of the membrane-spanning 4-domains, subfamily A, member 2 gene (MS4A2) (beta-chain of the IgE high-affinity receptor), a key gene in the allergic cascade.Mass spectrometry and bisulphite sequencing were used to measure the methylation of two potential substrates for epigenetic regulation of MS4A2, namely a predicted promoter and a CpG-rich AluSp repeat. Methylation was measured in DNA extracted from peripheral blood lymphocytes of 38 atopic cases and 37 controls. Cases were positive for atopy, asthma, bronchial hyper-responsiveness and had high IgE levels. Both parents of eight atopic cases were also tested.The AluSp element was highly methylated across all individuals (mean 0.92, range 0.87-0.94), a pattern inconsistent with classical imprinting. Variation in methylation at this locus was not associated with age, sex, daily steroid use or atopic status, and there were no differences in methylation between mothers and fathers of atopic cases. Bisulphite sequencing analysis of the promoter region showed that it was also not imprinted, and there was no evidence for allele-specific methylation, but we were unable to test for association with atopy status.Methylation levels at the AluSp repeat analysed in MS4A2 were inconsistent with classical imprinting mechanisms and did not associate with atopy status. The promoter region was less methylated but further analysis of this region in larger cohorts is warranted to investigate its role in allergic disease.