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• W2107580083 abstract "In an effort to bring novel diagnostic and prognostic biomarkers or even potential targets for vaccine design for systemic candidiasis (SC) into the open, a systematic proteomic approach coupled with bioinformatic analysis was used to decode the serological response to Candida wall immunome in SC patients. Serum levels of IgG antibodies against Candida wall-associated proteins (proteins secreted from protoplasts in active wall regeneration, separated by two-dimensional gel electrophoresis, and identified by mass spectrometry) were measured in 45 SC patients, 57 non-SC patients, and 61 healthy subjects by Western blotting. Two-way hierarchical clustering and principal component analysis of their serum anti-Candida wall antibody expression patterns discriminated SC patients from controls and highlighted the heterogeneity of their expression profiles. Multivariate logistic regression models demonstrated that high levels of antibodies against glucan 1,3-β-glucosidase (Bgl2p) and the anti-wall phosphoglycerate kinase antibody seropositivity were the only independent predictors of SC. Receiver operating characteristic curve analysis revealed no difference between their combined evaluation and measurement of anti-Bgl2p antibodies alone. In a logistic regression model adjusted for known prognostic factors for mortality, SC patients with high anti-Bgl2p antibody levels or a positive anti-wall enolase antibody status, which correlated with each other, had a reduced 2-month risk of death. After controlling for each other, only the seropositivity for anti-wall enolase antibodies was an independent predictor of a lower risk of fatality, supporting that these mediated the protective effect. No association between serum anti-cytoplasmic enolase antibody levels and outcomes was established, suggesting a specific mechanism of enolase processing during wall biogenesis. We conclude that serum anti-Bgl2p antibodies are a novel accurate diagnostic biomarker for SC and that, at high levels, they may provide protection by modulating the anti-wall enolase antibody response. Furthermore serum anti-wall enolase antibodies are a new prognostic indicator for SC and confer protection against it. Bgl2p and wall-associated enolase could be valuable candidates for future vaccine development. In an effort to bring novel diagnostic and prognostic biomarkers or even potential targets for vaccine design for systemic candidiasis (SC) into the open, a systematic proteomic approach coupled with bioinformatic analysis was used to decode the serological response to Candida wall immunome in SC patients. Serum levels of IgG antibodies against Candida wall-associated proteins (proteins secreted from protoplasts in active wall regeneration, separated by two-dimensional gel electrophoresis, and identified by mass spectrometry) were measured in 45 SC patients, 57 non-SC patients, and 61 healthy subjects by Western blotting. Two-way hierarchical clustering and principal component analysis of their serum anti-Candida wall antibody expression patterns discriminated SC patients from controls and highlighted the heterogeneity of their expression profiles. Multivariate logistic regression models demonstrated that high levels of antibodies against glucan 1,3-β-glucosidase (Bgl2p) and the anti-wall phosphoglycerate kinase antibody seropositivity were the only independent predictors of SC. Receiver operating characteristic curve analysis revealed no difference between their combined evaluation and measurement of anti-Bgl2p antibodies alone. In a logistic regression model adjusted for known prognostic factors for mortality, SC patients with high anti-Bgl2p antibody levels or a positive anti-wall enolase antibody status, which correlated with each other, had a reduced 2-month risk of death. After controlling for each other, only the seropositivity for anti-wall enolase antibodies was an independent predictor of a lower risk of fatality, supporting that these mediated the protective effect. No association between serum anti-cytoplasmic enolase antibody levels and outcomes was established, suggesting a specific mechanism of enolase processing during wall biogenesis. We conclude that serum anti-Bgl2p antibodies are a novel accurate diagnostic biomarker for SC and that, at high levels, they may provide protection by modulating the anti-wall enolase antibody response. Furthermore serum anti-wall enolase antibodies are a new prognostic indicator for SC and confer protection against it. Bgl2p and wall-associated enolase could be valuable candidates for future vaccine development. Not only does systemic candidiasis (SC) 1The abbreviations used are: SC, systemic candidiasis; 2-D, two-dimensional; 2-DE, two-dimensional gel electrophoresis; Bgl2p, glucan 1,3-β-glucosidase or β-1,3-glucosyltransferase; CI, confidence interval; ConA, concanavalin A; Eno1p, enolase; Fba1p, fructose-bisphosphate aldolase; Gap1p, glyceraldehyde-3-phosphate dehydrogenase; Met6p, methionine synthase; OR, odds ratio; Pgk1p, phosphoglycerate kinase; ROC, receiver operating characteristic; Tpi1p, triose-phosphate isomerase. 1The abbreviations used are: SC, systemic candidiasis; 2-D, two-dimensional; 2-DE, two-dimensional gel electrophoresis; Bgl2p, glucan 1,3-β-glucosidase or β-1,3-glucosyltransferase; CI, confidence interval; ConA, concanavalin A; Eno1p, enolase; Fba1p, fructose-bisphosphate aldolase; Gap1p, glyceraldehyde-3-phosphate dehydrogenase; Met6p, methionine synthase; OR, odds ratio; Pgk1p, phosphoglycerate kinase; ROC, receiver operating characteristic; Tpi1p, triose-phosphate isomerase. continue to be significant in incidence (1Pfaller M.A. Diekema D.J. Jones R.N. Sader H.S. Fluit A.C. Hollis R.J. Messer S.A. International surveillance of bloodstream infections due to Candida species: frequency of occurrence and in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole of isolates collected from 1997 through 1999 in the SENTRY antimicrobial surveillance program.J. Clin. Microbiol. 2001; 39: 3254-3259Google Scholar, 2Almirante B. Rodriguez D. Park B.J. Cuenca-Estrella M. Planes A.M. Almela M. Mensa J. Sanchez F. Ayats J. Gimenez M. Saballs P. Fridkin S.K. Morgan J. Rodriguez-Tudela J.L. Warnock D.W. Pahissa A. Barcelona Candidemia Project Study GroupEpidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, Barcelona, Spain, from 2002 to 2003.J. Clin. Microbiol. 2005; 43: 1829-1835Google Scholar, 3Eggimann P. Garbino J. Pittet D. Epidemiology of Candida species infections in critically ill non-immunosuppressed patients.Lancet Infect. Dis. 2003; 3: 685-702Google Scholar), but it also remains a leading infectious cause of morbidity and mortality in intensive care, post-surgical, and cancer patients (3Eggimann P. Garbino J. Pittet D. Epidemiology of Candida species infections in critically ill non-immunosuppressed patients.Lancet Infect. Dis. 2003; 3: 685-702Google Scholar, 4Leleu G. Aegerter P. Guidet B. Systemic candidiasis in intensive care units: a multicenter, matched-cohort study.J. Crit. Care. 2002; 17: 168-175Google Scholar, 5Gudlaugsson O. Gillespie S. Lee K. Vande B.J. Hu J. Messer S. Herwaldt L. Pfaller M. Diekema D. Attributable mortality of nosocomial candidemia, revisited.Clin. Infect. Dis. 2003; 37: 1172-1177Google Scholar) and accounts for substantial healthcare costs (6Miller L.G. Hajjeh R.A. Edwards Jr., J.E. Estimating the cost of nosocomial candidemia in the United States.Clin. Infect. Dis. 2001; 321110 Google Scholar, 7Wilson L.S. Reyes C.M. Stolpman M. Speckman J. Allen K. Beney J. The direct cost and incidence of systemic fungal infections.Value Health. 2002; 5: 26-34Google Scholar). Clinical outcomes might be improved by early initiation of antifungal therapy. SC diagnosis, however, is extremely difficult because signs and symptoms of invasive disease are nonspecific. In addition, its two gold standards, blood cultures and tissue biopsies, may lack sensitivity in the first stages of infection (8Horvath L.L. Hospenthal D.R. Murray C.K. Dooley D.P. Detection of simulated candidemia by the BACTEC 9240 system with plus aerobic/F and anaerobic/F blood culture bottles.J. Clin. Microbiol. 2003; 41: 4714-4717Google Scholar) and become excessively invasive in critically ill patients, respectively. As a result, SC diagnosis is often attained after a long delay or, unfortunately, following autopsy (9Kami M. Machida U. Okuzumi K. Matsumura T. Mori S.S. Hori A. Kashima T. Kanda Y. Takaue Y. Sakamaki H. Hirai H. Yoneyama A. Mutou Y. Effect of fluconazole prophylaxis on fungal blood cultures: an autopsy-based study involving 720 patients with haematological malignancy.Br. J. Haematol. 2002; 117: 40-46Google Scholar, 10Schwesinger G. Junghans D. Schroder G. Bernhardt H. Knoke M. Candidosis and aspergillosis as autopsy findings from 1994 to 2003.Mycoses. 2005; 48: 176-180Google Scholar). This clinical setting has prompted the search for novel prompt and accurate disease markers or, instead, for immunoprophylactic strategies. Research efforts currently focus on screening both for Candida cell wall polysaccharides (mannans or β-1,3-glucans), extracellular proteins (secreted aspartyl proteinase), cytoplasmic proteins (enolase or heat shock protein 90), metabolites (d-arabinitol), or nucleic acids (DNA or RNA) and for anti-Candida antibodies in body fluids of SC patients (11Reiss E. Morrison C.J. Nonculture methods for diagnosis of disseminated candidiasis.Clin. Microbiol. Rev. 1993; 6: 311-323Google Scholar, 12Ellepola A.N. Morrison C.J. Laboratory diagnosis of invasive candidiasis.J. Microbiol. 2005; 43: 65-84Google Scholar, 13Matthews R.C. Rigg G. Hodgetts S. Carter T. Chapman C. Gregory C. Illidge C. Burnie J. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90.Antimicrob. Agents Chemother. 2003; 47: 2208-2216Google Scholar, 14Han Y. Ulrich M.A. Cutler J.E. Candida albicans mannan extract-protein conjugates induce a protective immune response against experimental candidiasis.J. Infect. Dis. 1999; 179: 1477-1484Google Scholar, 15Vilanova M. Teixeira L. Caramalho I. Torrado E. Marques A. Madureira P. Ribeiro A. Ferreira P. Gama M. Demengeot J. Protection against systemic candidiasis in mice immunized with secreted aspartic proteinase 2.Immunology. 2004; 111: 334-342Google Scholar). The relevance of well defined Candida cell wall proteins or their related antibodies in SC diagnosis, prognosis, and therapy, however, has been barely examined (16Martinez J.P. Gil M.L. Lopez-Ribot J.L. Chaffin W.L. Serologic response to cell wall mannoproteins and proteins of Candida albicans..Clin. Microbiol. Rev. 1998; 11: 121-141Google Scholar, 17Chaffin W.L. Lopez-Ribot J.L. Casanova M. Gozalbo D. Martinez J.P. Cell wall and secreted proteins of Candida albicans: identification, function, and expression.Microbiol. Mol. Biol. Rev. 1998; 62: 130-180Google Scholar, 18Lopez-Ribot J.L. Casanova M. Murgui A. Martinez J.P. Antibody response to Candida albicans cell wall antigens.FEMS Immunol. Med. Microbiol. 2004; 41: 187-196Google Scholar). Given their privileged location within the cell (host-fungus interface), it is unsurprising that some of them may be major elicitors of a specific immune response, which could, intriguingly, be brought into play to establish prognosis and develop new diagnostic, prophylactic, and/or therapeutic procedures for SC (16Martinez J.P. Gil M.L. Lopez-Ribot J.L. Chaffin W.L. Serologic response to cell wall mannoproteins and proteins of Candida albicans..Clin. Microbiol. Rev. 1998; 11: 121-141Google Scholar, 18Lopez-Ribot J.L. Casanova M. Murgui A. Martinez J.P. Antibody response to Candida albicans cell wall antigens.FEMS Immunol. Med. Microbiol. 2004; 41: 187-196Google Scholar). For many years, knowledge of the Candida cell wall proteome has, to a certain extent, been limited by a paucity of effective strategies for tackling its study especially because of its low abundance, low solubility, high heterogeneity, hydrophobicity, and interconnections with wall structural polysaccharides (mannan, glucan, and/or chitin) (19Pitarch A. Nombela C. Gil C. Humphery-Smith I. Hecker M. Microbial Proteomes. Greene Publishing Associates and Wiley Interscience, New York2006Google Scholar, 20Pitarch A. Sanchez M. Nombela C. Gil C. Analysis of the Candida albicans proteome. I. Strategies and applications.J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2003; 787: 101-128Google Scholar, 21Niimi M. Cannon R.D. Monk B.C. Candida albicans pathogenicity: a proteomic perspective.Electrophoresis. 1999; 20: 2299-2308Google Scholar). Beyond encouraging chemical and/or enzymatic approaches for its extraction from intact cells or isolated walls (22Pitarch A. Sanchez M. Nombela C. Gil C. Sequential fractionation and two-dimensional gel analysis unravels the complexity of the dimorphic fungus Candida albicans cell wall proteome.Mol. Cell. Proteomics. 2002; 1: 967-982Google Scholar, 23Urban C. Sohn K. Lottspeich F. Brunner H. Rupp S. Identification of cell surface determinants in Candida albicans reveals Tsa1p, a protein differentially localized in the cell.FEBS Lett. 2003; 544: 228-235Google Scholar, 24de Groot P.W. de Boer A.D. Cunningham J. Dekker H.L. de Jong L. Hellingwerf K.J. de Koster C. Klis F.M. Proteomic analysis of Candida albicans cell walls reveals covalently bound carbohydrate-active enzymes and adhesins.Eukaryot. Cell. 2004; 3: 955-965Google Scholar, 25Casanova M. Lopez-Ribot J.L. Martinez J.P. Sentandreu R. Characterization of cell wall proteins from yeast and mycelial cells of Candida albicans by labelling with biotin: comparison with other techniques.Infect. Immun. 1992; 60: 4898-4906Google Scholar) and by-passing their inherent troubles (glucan and/or chitin side-chain residues and protein modifications (19Pitarch A. Nombela C. Gil C. Humphery-Smith I. Hecker M. Microbial Proteomes. Greene Publishing Associates and Wiley Interscience, New York2006Google Scholar, 26Pardo M. Monteoliva L. Pla J. Sanchez M. Gil C. Nombela C. Two-dimensional analysis of proteins secreted by Saccharomyces cerevisiae regenerating protoplasts: a novel approach to study the cell wall.Yeast. 1999; 15: 459-472Google Scholar)), an innovative stratagem, based on the analysis of proteins secreted from protoplasts in active cell wall regeneration, has also recently enabled this Achilles’ heel to be successfully profiled (26Pardo M. Monteoliva L. Pla J. Sanchez M. Gil C. Nombela C. Two-dimensional analysis of proteins secreted by Saccharomyces cerevisiae regenerating protoplasts: a novel approach to study the cell wall.Yeast. 1999; 15: 459-472Google Scholar, 27Pitarch A. Pardo M. Jimenez A. Pla J. Gil C. Sanchez M. Nombela C. Two-dimensional gel electrophoresis as analytical tool for identifying Candida albicans immunogenic proteins.Electrophoresis. 1999; 20: 1001-1010Google Scholar, 28Pardo M. Ward M. Bains S. Molina M. Blackstock W. Gil C. Nombela C. A proteomic approach for the study of Saccharomyces cerevisiae cell wall biogenesis.Electrophoresis. 2000; 21: 3396-3410Google Scholar). This modus operandi draws on the observation that these wall biogenesis-related proteins are not retained into the nascent cell wall during the early stages of the regeneration process and are thus shed into the extracellular medium (26Pardo M. Monteoliva L. Pla J. Sanchez M. Gil C. Nombela C. Two-dimensional analysis of proteins secreted by Saccharomyces cerevisiae regenerating protoplasts: a novel approach to study the cell wall.Yeast. 1999; 15: 459-472Google Scholar, 29Elorza M.V. Marcilla A. Sanjuan R. Mormeneo S. Sentandreu R. Incorporation of specific wall proteins during yeast and mycelial protoplast regeneration in Candida albicans..Arch. Microbiol. 1994; 161: 145-151Google Scholar). On the other hand, there is no doubt either that biomarkers discovered in serum are highly sought after in critically ill and/or severely immunocompromised patients in view of the fact that they may serve as a keystone for the design of noninvasive and easy diagnostic tests and/or of therapeutic strategies. Among the currently available techniques, the combination of proteomics with serology (immunoproteomics (30Krah A. Jungblut P.R. Immunoproteomics.Methods Mol. Med. 2004; 94: 19-32Google Scholar, 31Pitarch A. Nombela C. Gil C. Humphery-Smith I. Hecker M. Microbial Proteomes. Greene Publishing Associates and Wiley Interscience, New York2006Google Scholar, 32Haas G. Karaali G. Ebermayer K. Metzger W.G. Lamer S. Zimny-Arndt U. Diescher S. Goebel U.B. Vogt K. Roznowski A.B. Wiedenmann B.J. Meyer T.F. Aebischer T. Jungblut P.R. Immunoproteomics of Helicobacter pylori infection and relation to gastric disease.Proteomics. 2002; 2: 313-324Google Scholar, 33Hess J.L. Blazer L. Romer T. Faber L. Buller R.M. Boyle M.D. Immunoproteomics.J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2005; 815: 65-75Google Scholar, 34Pedersen S.K. Sloane A.J. Prasad S.S. Sebastian L.T. Lindner R.A. Hsu M. Robinson M. Bye P.T. Weinberger R.P. Harry J.L. An immunoproteomic approach for identification of clinical biomarkers for monitoring disease. Application to cystic fibrosis.Mol. Cell. Proteomics. 2005; 4: 1052-1060Google Scholar)) is largely being used to screen for panels of biomarkers and therapeutic targets in patients with infectious diseases (including SC (27Pitarch A. Pardo M. Jimenez A. Pla J. Gil C. Sanchez M. Nombela C. Two-dimensional gel electrophoresis as analytical tool for identifying Candida albicans immunogenic proteins.Electrophoresis. 1999; 20: 1001-1010Google Scholar, 31Pitarch A. Nombela C. Gil C. Humphery-Smith I. Hecker M. Microbial Proteomes. Greene Publishing Associates and Wiley Interscience, New York2006Google Scholar, 35Pardo M. Ward M. Pitarch A. Sanchez M. Nombela C. Blackstock W. Gil C. Cross-species identification of novel Candida albicans immunogenic proteins by combination of two-dimensional polyacrylamide gel electrophoresis and mass spectrometry.Electrophoresis. 2000; 21: 2651-2659Google Scholar, 36Pitarch A. Abian J. Carrascal M. Sanchez M. Nombela C. Gil C. Proteomics-based identification of novel Candida albicans antigens for diagnosis of systemic candidiasis in patients with underlying hematological malignancies.Proteomics. 2004; 4: 3084-3106Google Scholar)), cancer, or autoimmune disorders (32Haas G. Karaali G. Ebermayer K. Metzger W.G. Lamer S. Zimny-Arndt U. Diescher S. Goebel U.B. Vogt K. Roznowski A.B. Wiedenmann B.J. Meyer T.F. Aebischer T. Jungblut P.R. Immunoproteomics of Helicobacter pylori infection and relation to gastric disease.Proteomics. 2002; 2: 313-324Google Scholar,37Seliger B. Kellner R. Design of proteome-based studies in combination with serology for the identification of biomarkers and novel targets.Proteomics. 2002; 2: 1641-1651Google Scholar, 38Le Naour F. Brichory F. Misek D.E. Brechot C. Hanash S. Beretta L. A distinct repertoire of autoantibodies in hepatocellular carcinoma identified by proteomic analysis.Mol. Cell. Proteomics. 2002; 1: 197-203Google Scholar, 39Fathman C.G. Soares L. Chan S.M. Utz P.J. An array of possibilities for the study of autoimmunity.Nature. 2005; 435: 605-611Google Scholar, 40Huguet S. Labas V. Duclos-Vallee J.C. Bruneel A. Vinh J. Samuel D. Johanet C. Ballot E. Heterogeneous nuclear ribonucleoprotein A2/B1 identified as an autoantigen in autoimmune hepatitis by proteome analysis.Proteomics. 2004; 4: 1341-1345Google Scholar, 41Imafuku Y. Omenn G.S. Hanash S. Proteomics approaches to identify tumor antigen directed autoantibodies as cancer biomarkers.Dis. Markers. 2004; 20: 149-153Google Scholar). This discipline permits characterization of the immunome of a (micro)organism, defined as the subset of the proteome of a (micro)organism that acts as a target for the immune system (42Wilson R.A. Curwen R.S. Braschi S. Hall S.L. Coulson P.S. Ashton P.D. From genomes to vaccines via the proteome.Mem. Inst. Oswaldo Cruz. 2004; 99: 45-50Google Scholar). Remarkably its application in SC research has made it possible to cut back further the false-negative rate associated with low antibody sensitivity in immunocompromised patients undergoing SC (36Pitarch A. Abian J. Carrascal M. Sanchez M. Nombela C. Gil C. Proteomics-based identification of novel Candida albicans antigens for diagnosis of systemic candidiasis in patients with underlying hematological malignancies.Proteomics. 2004; 4: 3084-3106Google Scholar). Because of the huge amounts of data compiled in proteomic investigations, there is now increasing awareness that bioinformatics is certainly an essential tool for their handling and interpretation (43Pollard K.S. van der Laan M.J. Statistical inference for simultaneous clustering of gene expression data.Math. Biosci. 2002; 176: 99-121Google Scholar, 44Grigoriev A. Understanding the yeast proteome: a bioinformatics perspective.Expert Rev. Proteomics. 2004; 1: 193-205Google Scholar, 45Radulovic D. Jelveh S. Ryu S. Hamilton T.G. Foss E. Mao Y. Emili A. Informatics platform for global proteomic profiling and biomarker discovery using liquid chromatography-tandem mass spectrometry.Mol. Cell. Proteomics. 2004; 3: 984-997Google Scholar). In the present study, we used both aforementioned proteomic approaches coupled with bioinformatic analyses (Fig. 1) to systematically explore the serological response to Candida cell wall-associated proteins in SC patients. We investigated their usefulness to diagnose SC, predict outcomes in these patients, and even to outline potential therapeutic targets for prevention and/or treatment of SC. Between December 1997 and March 2003, serum specimens from 48 patients with laboratory-confirmed SC belonging to different risk groups were obtained on the day of culture sampling at the Salamanca University Hospital (Spain) after informed consent was given. SC was defined as isolation of the same Candida species in one or more blood cultures and/or in culture from at least three noncontiguous sites from patients who manifested clinical signs of infection or sepsis. Three patients who had received antifungal drug prophylaxis before diagnosing SC were excluded from the study. To provide data on assay specificity, serum samples from 118 individuals without clinical or microbiological evidence of SC and with a similar age and sex distribution to cases were evaluated as controls. This control group consisted of 57 hospitalized patients with the same primary diagnosis as cases and of 61 healthy subjects. All sera were stored at −80 °C and analyzed in a blinded fashion. The outcome of hospital stay (death or discharge) was also recorded for each patient. Base-line characteristics of the study patients and controls are shown in Table I. By design, no substantial differences were found either in the demographic characteristics among the study groups or in the clinical characteristics between SC and non-SC patients. Not surprisingly, SC patients, however, had a 3 times greater mortality rate than non-SC patients (27 versus 9%; p = 0.02).Table IBase-line characteristics of the 163 subjects included in the screening studyCharacteristicNumber (%) or mean ± S.D.SC patients (n = 45)Control group (n = 118)Non-SC patients (n = 57)Healthy subjects (n = 61)Demographic factors SexMale28 (62.2)35 (61.4)39 (63.9)Female17 (37.8)22 (38.6)22 (36.1) Age (years)61.1 ± 14.260.1 ± 16.959.1 ± 12.4≤65 years24 (53.3)30 (52.6)34 (55.7)>65 years21 (46.7)27 (47.4)27 (44.3)Primary condition Hematological malignancy16 (35.6)19 (33.3)0ap < 0.05 for the comparison with the other groups.Leukemia7 (15.6)9 (15.8)Lymphoma4 (8.9)4 (7.0)Myelodysplasia3 (6.7)3 (5.3)Multiple myeloma2 (4.4)3 (5.3) Solid tumor11 (24.4)15 (26.3)0ap < 0.05 for the comparison with the other groups.Bronchopulmonary neoplasm6 (13.3)8 (14.0)Pancreas/colon adenocarcinoma3 (6.7)5 (8.8)Bladder neoplasm2 (4.4)2 (3.5) Nonmalignant diseases18 (40.0)23 (40.4)0ap < 0.05 for the comparison with the other groups.Respiratory dysfunctionbIncludes the following diseases: pneumonia, chronic obstructive pulmonary disease, and acute respiratory distress syndrome.8 (17.8)10 (17.5)Gastrointestinal pathologycIncludes the following diseases: cholecystitis, angiocholitis, pancreatitis, peritonitis, and hepatitis.6 (13.3)8 (14.0)OthersdIncludes the following diseases: multiple trauma, acute renal insufficiency, and diabetes mellitus.4 (8.9)5 (8.8)Risk factors for SC Iatrogenic predisposing factorsBroad spectrum antibiotics29 (64.4)27 (47.4)0ap < 0.05 for the comparison with the other groups.Immunosuppressive therapy16 (35.6)21 (36.8)0ap < 0.05 for the comparison with the other groups.Central venous catheters15 (33.3)18 (31.6)0ap < 0.05 for the comparison with the other groups.Parenteral nutrition14 (31.1)14 (24.6)0ap < 0.05 for the comparison with the other groups.Abdominal or thoracic surgeryeIncludes colectomy, duodenotomy, cholecystectomy, pancreatectomy, pulmonary lobotomy, and thoracotomy.13 (28.9)9 (15.8)0ap < 0.05 for the comparison with the other groups.Hematopoietic transplantation5 (11.1)4 (7.0)0ap < 0.05 for the comparison with the other groups. No apparent iatrogenic factors10 (22.2)18 (31.6)0ap < 0.05 for the comparison with the other groups.Three or more of them19 (42.2)16 (28.1)0ap < 0.05 for the comparison with the other groups.Four or more of them10 (22.2)9 (15.8)0ap < 0.05 for the comparison with the other groups. Other risk factorsUnderlying malignancy27 (60.0)34 (59.6)0ap < 0.05 for the comparison with the other groups. Intensive care unit stay13 (28.9)17 (29.8)0ap < 0.05 for the comparison with the other groups.NeutropeniafNeutropenia was defined as an absolute neutrophil count below 500 cells/mm3.10 (22.7)9 (16.4)0ap < 0.05 for the comparison with the other groups.Acute renal failure4 (8.9)3 (5.3)0ap < 0.05 for the comparison with the other groups.Outcome of hospital stay Death12 (26.7)gSC patients died within 2 months of Candida isolation.5 (8.8)hp = 0.02 for the comparison with the SC group. The attributable mortality of SC was 18% (95% CI, 3–33%). The risk of death among SC patients, compared with that among non-SC patients, was 3.8 (95% CI, 1.22–11.71).n. a.iNot applicable. Discharge33 (73.3)52 (91.2)n. a.iNot applicable.a p < 0.05 for the comparison with the other groups.b Includes the following diseases: pneumonia, chronic obstructive pulmonary disease, and acute respiratory distress syndrome.c Includes the following diseases: cholecystitis, angiocholitis, pancreatitis, peritonitis, and hepatitis.d Includes the following diseases: multiple trauma, acute renal insufficiency, and diabetes mellitus.e Includes colectomy, duodenotomy, cholecystectomy, pancreatectomy, pulmonary lobotomy, and thoracotomy.f Neutropenia was defined as an absolute neutrophil count below 500 cells/mm3.g SC patients died within 2 months of Candida isolation.h p = 0.02 for the comparison with the SC group. The attributable mortality of SC was 18% (95% CI, 3–33%). The risk of death among SC patients, compared with that among non-SC patients, was 3.8 (95% CI, 1.22–11.71).i Not applicable. Open table in a new tab Proteins secreted into the culture medium during the early stages of the regeneration process of protoplast walls from a clinical Candida albicans isolate (strain SC5314 (46Gillum A.M. Tsay E.Y. Kirsch D.R. Isolation of the Candida albicans gene for orotidine-5′-phosphate decarboxylase by complementation of Saccharomyces cerevisiae ura3 and E. coli pyrF mutations.Mol. Gen. Genet. 1984; 198: 179-182Google Scholar)) were exploited as a source of Candida wall-associated antigens and prepared basically as reported previously (27Pitarch A. Pardo M. Jimenez A. Pla J. Gil C. Sanchez M. Nombela C. Two-dimensional gel electrophoresis as analytical tool for identifying Candida albicans immunogenic proteins.Electrophoresis. 1999; 20: 1001-1010Google Scholar). Briefly yeast cells were grown in YED medium (1% Difco yeast extract and 2% d-glucose) (47Treco D.A. Reynolds A. Lundblad V. Coligan J.E. Dunn B.M. Speicher D.W. Wingfield P.T. Current Protocols in Protein Science. Greene Publishing Associates and Wiley Interscience, New York1998: A.4.L1-A.4.L6Google Scholar) and incubated at 28 °C first in a pretreatment solution (10 mm Tris-HCl, pH 9.0, 5 mm EDTA, 1% 2-mercaptoethanol) for 30 min and then in a solution containing 30 μg/ml Glusulase (DuPont) and 1 m sorbitol (up to 5 × 108 cells/ml) until over 90% protoplasts were obtained. After three washes with 1 m sorbitol, protoplasts were induced to regenerate their cell walls in Lee medium (48Lee K.L. Buckley H.R. Campbell C.C. An amino acid liquid synthetic medium for the development of mycelial and yeast forms of Candida albicans..Sabouraudia. 1975; 13: 148-153Google Scholar) containing 1 m sorbitol at 28 °C for 2 h. Following centrifugation, protease inhibitors were added to the supernatant. This was filtered and ultrafiltered using a pore size of 0.22 μm and 10,000 Da, respectively, and then diluted with water, concentrated a further three times, and eventually lyophilized. All steps were performed with very gentle shaking. Cell lysis was controlled by quantitative determination of alkaline phosphatase (49Cabib E. Duran A. Simple and sensitive procedure for screening yeast mutants that lyse at nonpermissive temperatures.J. Bacteriol. 1975; 124: 1604-1606Google Scholar). Protein concentration was measured with the Bradford assay (Bio-Rad). Candida wall-associated proteins were separated by 2-DE as described elsewhere (22Pitarch A. Sanchez M. Nombela C. Gil C. Sequential fractionation and two-dimensional gel analysis unravels the complexity of the dimorphic fungus Candida albicans cell wall proteome.Mol. Cell. Proteomics. 2002; 1: 967-982Google Scholar) using immobilized, nonl" @default.
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• W2107580083 date "2006-01-01" @default.
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• W2107580083 title "Decoding Serological Response to Candida Cell Wall Immunome into Novel Diagnostic, Prognostic, and Therapeutic Candidates for Systemic Candidiasis by Proteomic and Bioinformatic Analyses" @default.
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• W2107580083 doi "https://doi.org/10.1074/mcp.m500243-mcp200" @default.
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