tbuckley/cabot-search huggingface dataset:
Interactive plasticity of alveolar macrophages and microbiota in lung transplant recipient
Authors: Eric Bernasconi, Angela Koutsokera, Dominique Dumas, Celine Pattaroni, Boubou Camara, Benjamin J. Marsland, Christian Benden, Christophe Pison, John-David Aubert, Laurent P. Nicod
Journal: European Respiratory Journal (2014)

Introduction:  The lung microbiota has distinct constituents depending on local inflammatory status. As yet, the direct implications of the lung microbiota in disease development is unknown. We hypothesized that the lung microbiota directly influences macrophage functionality and consequently long-term graft survival.   Methods:  DNA and total RNA were isolated from bronchoalveolar lavages from 58 patients at 0.5-4 (short-term) or 6-24 (long-term) months post-transplantation. Expression of a set of genes involved in prototypic macrophage functions was quantified using RT-qPCR. Microbiota composition at phylum level was determined using 16S rDNA amplification.   Results:  A subset of samples displayed macrophage polarization, either with inflammation and immunoregulation (Polar1, 20.7%) or remodeling (Polar2, 10.3%) predominance. Compared to Polar2, Polar1 were most often enriched in either Firmicutes, Proteobacteria or Actinobacteria, were more frequently associated with infection (83.3% vs. 20.0%) and had higher neutrophil counts as an indication of inflammation (62.5% vs. 8.7%). In contrast, Polar2 displayed a 42.3-111.6-fold increase in expression of pro-remodeling genes (TIMP1, PDGF, fibronectin) and higher Bacteroidetes percentage (median 53.4% vs. 2.1%). While Polar1 originated from similar numbers of short- and long-term transplant recipients, Polar2 were almost exclusively from the latter group (94.1%).   Conclusions:  Alveolar macrophage polarization in conjunction with microbiota composition reflects dynamic changes in lung transplant recipients. Longitudinal follow-up of patients with polarized samples will elucidate whether these conditions may predict a negative outcome for graft survival.
Knockout of p21-activated kinase-1 attenuates exercise-induced cardiac remodelling through altered calcineurin signalling
Authors: Robert T. Davis, Jillian N. Simon, Megan Utter, Paul Mungai, Manuel G. Alvarez, Shamim A.K. Chowdhury, Ahlke Heydemann, Yunbo Ke, Beata M. Wolska, R. John Solaro
Journal: Cardiovascular Research (2015)

Despite its known cardiovascular benefits, the intracellular signalling mechanisms underlying physiological cardiac growth remain poorly understood. Therefore, the purpose of this study was to investigate a novel role of p21-activated kinase-1 (Pak1) in the regulation of exercise-induced cardiac hypertrophy.Wild-type (WT) and Pak1 KO mice were subjected to 6 weeks of treadmill endurance exercise training (ex-training). Cardiac function was assessed via echocardiography, in situ haemodynamics, and the pCa-force relations in skinned fibre preparations at baseline and at the end of the training regimen. Post-translational modifications to the sarcomeric proteins and expression levels of calcium-regulating proteins were also assessed following ex-training. Heart weight/tibia length and echocardiography data revealed that there was marked hypertrophy following ex-training in the WT mice, which was not evident in the KO mice. Additionally, following ex-training, WT mice demonstrated an increase in cardiac contractility, myofilament calcium sensitivity, and phosphorylation of cardiac myosin-binding protein C, cardiac TnT, and tropomyosin compared with KO mice. With ex-training in WT mice, there were also increased protein levels of calcineurin and increased phosphorylation of phospholamban.Our data suggest that Pak1 is essential for adaptive physiological cardiac remodelling and support previous evidence that demonstrates Pak1 signalling is important for cardiac growth and survival.
Intragenic Hill-Robertson Interference Influences Selection Intensity on Synonymous Mutations in Drosophila
Authors: J. M. Comeron
Journal: Molecular Biology and Evolution (2005)

Natural selection influences synonymous mutations and synonymous codon usage in many eukaryotes to improve the efficiency of translation in highly expressed genes. Recent studies of gene composition in eukaryotes have shown that codon usage also varies independently of expression levels, both among genes and at the intragenic level. Here, we investigate rates of evolution (Ks) and intensity of selection (γs) on synonymous mutations in two groups of genes that differ greatly in the length of their exons, but with equivalent levels of gene expression and rates of crossing-over in Drosophila melanogaster. We estimate γs using patterns of divergence and polymorphism in 50 Drosophila genes (100 kb of coding sequence) to take into account possible variation in mutation trends across the genome, among genes or among codons. We show that genes with long exons exhibit higher Ks and reduced γs compared to genes with short exons. We also show that Ks and γs vary significantly across long exons, with higher Ks and reduced γs in the central region compared to flanking regions of the same exons, hence indicating that the difference between genes with short and long exons can be mostly attributed to the central region of these long exons. Although amino acid composition can also play a significant role when estimating Ks and γs, our analyses show that the differences in Ks and γs between genes with short and long exons and across long exons cannot be explained by differences in protein composition. All these results are consistent with the Interference Selection (IS) model that proposes that the Hill-Robertson (HR) effect caused by many weakly selected mutations has detectable evolutionary consequences at the intragenic level in genomes with recombination. Under the IS model, exon size and exon-intron structure influence the effectiveness of selection, with long exons showing reduced effectiveness of selection when compared to small exons and the central region of long exons showing reduced intensity of selection compared to flanking coding regions. Finally, our results further stress the need to consider selection on synonymous mutations and its variation—among and across genes and exons—in studies of protein evolution.
Prognosis of acute respiratory distress syndrome in neutropenic cancer patients
Authors: Djamel Mokart, Thomas van Craenenbroeck, Jérôme Lambert, Julien Textoris, Jean-Paul Brun, Antoine Sannini, Laurent Chow-Chine, Smail Hamouda, Louis Fouché, Florence Ettori, Marion Faucher, Jean-Louis Blache
Journal: European Respiratory Journal (2011)

To date, no study has been specifically designed to identify determinants of death in neutropenic cancer patients presenting with acute respiratory distress syndrome (ARDS). The aim of this study was to identify early predictive factors of 28-day mortality in these patients. Factors associated with 28-day mortality during intensive care unit (ICU) stay were also described. 70 consecutive cancer patients with ARDS and neutropenia were prospectively analysed over a 6-yr period. Mortality at 28 days was 63%. Factors independently associated with good prognosis were: lobar ARDS (OR 0.10, 95% CI 0.02–0.48), use of initial antibiotic treatment active on difficult to treat bacteria (ticarcillin-resistant <i>Pseudomonas aeruginosa</i>, <i>Stenotrophomonas maltophilia</i> or extended-spectrum β-lactamase-producing strains) (OR 0.08, 95% CI 0.02–0.33) and first-line chemotherapy (OR 0.08, 95% CI 0.02–0.37). During the ICU stay, mortality was associated with the markers of organ dysfunctions, the absence of neutropenia recovery and the use of vasopressors. During the first 3 weeks, the conditional probability of discharge alive from ICU did not decrease. At ICU admission, first-line chemotherapy, lobar ARDS and antibiotic treatment active on difficult-to-treat bacteria were associated with survival. During ICU stay, mortality was associated with organ dysfunctions and use of vasopressors. Most survivors have an ICU stay of &gt;3 weeks.
Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection
Authors: Wai-Man Wong, Pui-Chee Wu, Man-Fung Yuen, Chi-Chung Cheng, Wing-Wai Yew, Poon-Chuen Wong, Cheuk-Ming Tam, Chi-Chiu Leung, Ching-Lung Lai
Journal: Hepatology (2000)

Liver toxicity is a common side effect of antituberculosis (anti-TB) drugs. We studied the differences in liver dysfunction observed during anti-TB treatment between hepatitis B virus carriers (HBV) and noncarriers. Three hundred twenty-four patients on anti-TB drugs were recruited and followed up for 1 year. Forty-three patients with HBV and 276 non-HBV patients were included for analysis. Liver function tests and viral markers were monitored monthly. Liver biopsy was requested whenever the alanine transaminase (ALT) was persistently abnormal. Eighty-six HBV carriers who were not given anti-TB drugs were chosen as a second control and evaluated prospectively. The incidence of liver dysfunction was significantly higher in HBV carriers given anti-TB drugs (34.9%) when compared to noncarriers (9.4%, P <.001) and with HBV carriers not given anti-TB drugs (8.1%, P <.001). For patients given anti-TB drugs, HBV carriers who developed liver dysfunction were younger (P =.011) and had more severe liver injury compared with noncarriers (P =.008). By multiple logistic regression analysis, age (P =.002) and hepatitis B infection (P <.001) were the only 2 significant risk factors for hepatotoxicity related to anti-TB therapy.
Implications for Altered Glutamate and GABA Metabolism in the Dorsolateral Prefrontal Cortex of Aged Schizophrenic Patients
Authors: Martin R Gluck, Rohan G Thomas, Kenneth L Davis, Vahram Haroutunian
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Pharmacological, clinical, and postmortem studies suggest altered γ-aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects. METHOD: Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal nonpsychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, α-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase. RESULTS: Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences. Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged. CONCLUSIONS: Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.
ON THE CHEMISTRY AND STAINING PROPERTIES OF CERTAIN DERIVATIVES OF THE METHYLENE BLUE GROUP WHEN COMBINED WITH EOSIN
Authors: Thomas M. Wilson
Journal: The Journal of Experimental Medicine (1907)

1. Eosinate of thionin gives very satisfactory staining for blood smears. It is easily prepared and dissolves readily in methylated spirits. 2. In the methods heretofore employed for making mixtures of eosin and methylene blue derivatives, the eosinates of methylene violet and methylene azure are present in very small quantities or are altogether absent. 3. Thionol and thionin are probably formed in methylene blue which has been long boiled with dilute alkalies and silver oxide. 4. Good stains of eosin and methylene blue derivatives can be obtained by a variety of manipulations. 5. Methylated spirits is more economical as a solvent for this stain and better adapted for the simple technique above described than is methyl alcohol. There is some evidence that the staining act is of a chemical nature.
Analysis of mononuclear cell subsets in dermis and blood of patients with systemic sclerosis by multicolour flow cytometry
Authors: T. Hugle, V. Bigley, T. Holden, Jacob. M. van Laar
Journal: Annals of the Rheumatic Diseases (2010)

Background Infl ammation is a predominant feature in the early phase of systemic sclerosis (SSc) and putatively an important driver of fi brogenesis.Little is known about the homeostasis of monocytes, dendritic cells (DC), macrophages and lymphocytes in SSc skin and blood.Methods Multicolour fl ow cytometry of dermis and peripheral blood in seven patients with SSc and dermis of one healthy control.After digestion of the skin in dispase and collagenase, cells were stained for CD45, human leukocyte antigen DR (HLA-DR), CD14, CD16 and CD1a.Lymphocytes were identifi ed as CD45+HLA-DR-SC/FClow/SClow, macrophages were identifi ed by auto-fl uorescence (AF).Dermal DC were divided in CD45+DR+AF-CD1a+ (Langerhans) or CD45+DR+AF-CD14+ subsets.Whole blood was stained on July 29,
Tumour biomarkers: diagnostic, prognostic, and predictive:
Authors: Abigail Shaw, Marcus D Bradley, Sean Elyan, Kathreena M Kurian
Journal: BMJ (2015)

<h3>Summary</h3> In single-stage hernia repair in the setting of contaminated fields there is a high rate of infection following mesh repair. New strategies to decrease infection in this challenging patient population are needed. Stimulan calcium sulfate antibiotic beads (CSAB) are a biodegradable material that deliver high concentrations of antibiotics locally to a site of insertion. Their use in the prevention of infection has not been described in hernia graft implantation. Here we describe our use of CSAB in a series of 11 patients with modified Ventral Hernia Working Group class III and Centers for Disease Control and Prevention class II–IV wounds undergoing single-stage incisional ventral hernia repair. We found that implantation of CSAB in single-stage hernia repair in the setting of contaminated fields was feasible with low systemic antibiotic levels. Further research should be undertaken to investigate the efficacy of this novel tool in hernia repair.
Proceedings of the Fifth International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer: Conference Summary Statement
Authors: Steven E. Come, Aman U. Buzdar, James N. Ingle, Carlos L. Arteaga, Myles Brown, Mitch Dowsett, Susan G. Hilsenbeck, Rakesh Kumar, Stephen R.D. Johnston, Adrian V. Lee, Soonmyung Paik, Kathleen I. Pritchard, Eric P. Winer, Carol Hart
Journal: Clinical Cancer Research (2006)

The Fifth International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, co-chaired by Steven Come, M.D., and Aman Buzdar, M.D., was held in Cambridge, Massachusetts, June 13-14, 2005.

The conference was organized with the objective of analyzing recent
Influence of Dietary Calcium and Vitamin D on Diet-Induced Epithelial Cell Hyperproliferation in Mice
Authors: L. Xue, M. Lipkin, H. Newmark, J. Wang
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Previous epidemiologic and laboratory studies, including some from our own laboratory, have suggested that a high-fat diet increases risk of cancer development in the pancreas, prostate, colon, and breast and that carcinogenesis in some of these organs may be influenced by alterations in dietary calcium and vitamin D. In this study, we sought to investigate the effect of added dietary calcium or vitamin D on the development of epithelial cell hyperproliferation induced by a Western-style diet in the exocrine pancreas, prostate, and mammary gland of mice. METHODS: Four-week-old C57BL/6J mice were given either a control diet (American Institute of Nutrition [ AIN]-76A), a Western-style diet (containing reduced calcium and vitamin D and the fat level of the average human Western diet), or a putative chemopreventive diet (a Western-style diet with the addition of dietary calcium and vitamin D). Nine weeks after dietary intervention, osmotic pumps were implanted in the mice to provide 3 days of bromodeoxyuridine (BrdU) infusion. All P values are two-sided. RESULTS: Mice on the Western-style diet had statistically significant increases in BrdU-labeling indices of epithelial cells in the interlobular ( P = .015) and intralobular ( P = .012) ducts and centroacinar cells ( P = .001) of the pancreatic duct system, the dorsal lobe of the prostate ( P = .045), and the terminal ducts of the mammary gland ( P = .032), compared with mice in the respective control diet groups. Adding dietary calcium and vitamin D markedly suppressed the Western-style diet-induced hyperproliferation of epithelial cells in those tissues ( P = .001-.033). CONCLUSIONS: This study confirms previous findings that a Western-style diet produces hyperproliferation of epithelial cells in several organs and that the changes can be prevented by increasing dietary calcium and vitamin D alone.
Distribution of COPD patients in the GOLD assessment framework by exacerbations
Authors: G. Nadeau, L. Adamek, M. Small
Journal: European Respiratory Journal (2012)

GOLD 2011 proposes a new COPD assessment framework focussed on symptoms measured by the COPD Assessment Test (CAT™) or the mMRC and on risk based on poor lung function (FEV 1   The 2011 Adelphi Disease Specific Programme dataset was used to understand the distribution of patients in the GOLD framework. Exacerbation events defined as those not brought under control by rescue medication were recorded by physicians. We included 1041 EU COPD patients with documented CAT, mMRC, FEV 1  and exacerbation history in the last year: 401 (38.5%) were from primary care and 640 (61.5%) from specialty clinics. Almost all (97.7%) were on maintenance treatment.  104 subjects (10%) reported good health status (CAT  In observational databases, 1 exacerbation increases the risk of future exacerbations 1  and negatively impacts health status and outcomes 2 . Therapeutic interventions reduce the number and severity of exacerbations in patients with 1 or more exacerbations. Nearly 1/5 of patients in the Adelphi dataset had 1 exacerbation in the previous year and would fail to be included in GOLD high risk category. These observations may have important clinical implications.  1. Hurst JR, NEJM 2010  2. Cote C, CHEST 2007.
<i>FZD4</i> as a Mediator of <i>ERG</i> Oncogene–Induced WNT Signaling and Epithelial-to-Mesenchymal Transition in Human Prostate Cancer Cells
Authors: Santosh Gupta, Kristiina Iljin, Henri Sara, John Patrick Mpindi, Tuomas Mirtti, Paula Vainio, Juha Rantala, Kalle Alanen, Matthias Nees, Olli Kallioniemi
Journal: Cancer Research (2010)

Abstract TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active β1-integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active β1-integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion. Cancer Res; 70(17); 6735–45. ©2010 AACR.
Production of auto-anti-idiotypic antibody during the normal immune response to TNP-ficoll. III. Absence in nu/nu mice: evidence for T-cell dependence of the anti-idiotypic-antibody response.
Authors: A F Schrater, E A Goidl, G J Thorbecke, G W Siskind
Journal: The Journal of Experimental Medicine (1979)

Although athymic mice make an excellent immune response to the thymus-independent antigen trinitrophenyl-lys-Ficoll (TNP-F), nude mice of AKR/J and BALB/c strains lack the anti-idiotypic response that occurs in euthymic mice of both of these strains within the first 1--2 wk after injection of more TNP-F. Anti-idiotypic antibody-blocked (hapten-augmentable) anti-TNP splenic plaque-forming cells (PFC) do not occur at any time and serum anti-idiotypic antibody is absent in both congenitally athymic mice, and thymectomized, irradiated, bone marrow-reconstituted mice. Nevertheless, nu/nu mice do have PFC which can be inhibited by exposure to anti-idiotypic antibody produced in +/+ mice. As a consequence of the failure to produce anti-idiotypic antibodies, the anti-TNP PFC response is athymic as compared to euthymic mice is of greater magnitude, declines less precipitously, and shows an increase rather than a decrease in affinity between days 4 and 7 after antigen injection. It is concluded that the anti-idiotypic antibody response is thymus dependent and that athymic mice lack a helper cell required for the induction of anti-idiotypic antibodies.