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1.
PLoS One ; 15(1): e0227455, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914155

RESUMO

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal expansion of malignant plasma cells. Though durable remissions are possible, MM is considered incurable, with relapse occurring in almost all patients. There has been limited data reported on the lipid metabolism changes in plasma cells during MM progression. Here, we evaluated the feasibility of concurrent lipidomics and proteomics analyses from patient plasma cells, and report these data on a limited number of patient samples, demonstrating the feasibility of the method, and establishing hypotheses to be evaluated in the future. METHODS: Plasma cells were purified from fresh bone marrow aspirates using CD138 microbeads. Proteins and lipids were extracted using a bi-phasic solvent system with methanol, methyl tert-butyl ether, and water. Untargeted proteomics, untargeted and targeted lipidomics were performed on 7 patient samples using liquid chromatography-mass spectrometry. Two comparisons were conducted: high versus low risk; relapse versus newly diagnosed. Proteins and pathways enriched in the relapsed group was compared to a public transcriptomic dataset from Multiple Myeloma Research Consortium reference collection (n = 222) at gene and pathways level. RESULTS: From one million purified plasma cells, we were able to extract material and complete untargeted (~6000 and ~3600 features in positive and negative mode respectively) and targeted lipidomics (313 lipids), as well as untargeted proteomics analysis (~4100 reviewed proteins). Comparative analyses revealed limited differences between high and low risk groups (according to the standard clinical criteria), hence we focused on drawing comparisons between the relapsed and newly diagnosed patients. Untargeted and targeted lipidomics indicated significant down-regulation of phosphatidylcholines (PCs) in relapsed MM. Although there was limited overlap of the differential proteins/transcripts, 76 significantly enriched pathways in relapsed MM were common between proteomics and transcriptomics data. Further evaluation of transcriptomics data for lipid metabolism network revealed enriched correlation of PC, ceramide, cardiolipin, arachidonic acid and cholesterol metabolism pathways to be exclusively correlated among relapsed but not in newly-diagnosed patients. CONCLUSIONS: This study establishes the feasibility and workflow to conduct integrated lipidomics and proteomics analyses on patient-derived plasma cells. Potential lipid metabolism changes associated with MM relapse warrant further investigation.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31609532

RESUMO

OBJECTIVES: There is a paucity of data regarding healthcare costs associated with damage accrual in systemic lupus erythematosus (SLE). We describe costs associated with damage states across the disease course using multi-state modeling. METHODS: Patients from 33 centres in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology (ACR) Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multi-state model. RESULTS: 1687 patients participated, 88.7% female, 49.0% of Caucasian race/ethnicity, mean age at diagnosis 34.6 years (SD 13.3), and mean follow up 8.9 years (range 0.6-18.5). Annual costs were higher in those with higher SDIs (SDI ≥ 5: $22 006 2019 CDN, 95% CI $16 662, $27 350 versus SDI=0: $1833, 95% CI $1134, $2532). Similarly, 10-year cumulative costs were higher in those with higher SDIs at the beginning of the 10-year interval (SDI ≥ 5: $189 073, 95% CI $142 318, $235 827 versus SDI=0: $21 713, 95% CI $13 639, $29 788). CONCLUSION: Patients with the highest SDIs incur 10-year cumulative costs that are almost 9-fold higher than those with the lowest SDIs. By estimating the damage trajectory and incorporating annual costs, damage can be used to estimate future costs, critical knowledge for evaluating the cost-effectiveness of novel therapies.

3.
J Autoimmun ; : 102340, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31629628

RESUMO

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. METHODS: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). RESULTS: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). CONCLUSION: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.

4.
PLoS One ; 14(8): e0221024, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31425520

RESUMO

Cholangiocarcinoma (CCA) is a primary malignant tumor of the epithelial lining of biliary track associated with endemic Opisthorchis viverrini (Ov) infection in northeastern Thailand. Ov-associated periductal fibrosis (PDF) is the precancerous lesion for CCA, and can be detected by ultrasonography (US) to facilitate early detection. However, US cannot be used to distinguish PDF from cancer. Therefore, the objective of this study was to discover and qualify potential urine biomarkers for CCA detection in at-risk population. Biomarker discovery was conducted on pooled urine samples, 42 patients per group, with PDF or normal bile duct confirmed by ultrasound. After depletion of high abundance proteins, 338 urinary proteins were identified from the 3 samples (normal-US, PDF-US, CCA). Based on fold change and literature review, 70 candidate proteins were selected for qualification by multiple reaction monitoring mass spectrometry (MRM-MS) in 90 individual urine samples, 30 per group. An orthogonal signal correction projection to latent structures discriminant analysis (O-PLS-DA) multivariate model constructed from the 70 candidate biomarkers significantly discriminated CCA from normal and PDF groups (P = 0.003). As an independent validation, the expression of 3 candidate proteins was confirmed by immunohistochemistry in CCA tissues: Lysosome associated membrane glycoprotein 1 (LAMP1), lysosome associated membrane glycoprotein 2 (LAMP2) and cadherin-related family member 2 (CDHR2). Further evaluation of these candidate biomarkers in a larger cohort is needed to support their applicability in a clinical setting for screening and monitoring early CCA and for CCA surveillance.

5.
J Proteome Res ; 18(9): 3305-3316, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31310545

RESUMO

Cholangiocarcinoma (CCA) is a major health problem in northeastern Thailand. The majority of CCA cases are clinically silent and difficult to detect at an early stage. Although abdominal ultrasonography (US) can detect premalignant periductal fibrosis (PDF), this method is not suitable for screening populations in remote areas. With the goal of developing a blood test for detecting CCA in the at-risk population, we carried out serum protein biomarker discovery and qualification. Label-free shotgun proteomics was performed on depleted serum samples from 30 participants (n = 10 for US-normal, US-PDF, and CCA groups). Of 40 protein candidates selected using multiple reaction monitoring on 90 additional serum samples (n = 30 per group), 11 discriminatory proteins were obtained using supervised multivariate statistical analysis. We further evaluated 3 candidates using ELISA and immunohistochemistry (IHC). S100A9, thioredoxin (TRX), and cadherin-related family member 2 (CDHR2) were significantly different between CCA and normal, and CCA and PDF groups when measured in an additional 247 serum samples (P < 0.0001). By IHC, TRX and CDHR2 were detected in the cytoplasm and nucleus of CCA and inflammatory cells. S100A9 was detected in the infiltrating tumor stroma immune cells. Proteomics discovery and qualification in depleted sera revealed promising biomarker candidates for CCA diagnosis.

6.
Mol Cell Proteomics ; 18(5): 818-836, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30705123

RESUMO

Kallikrein-related peptidase 7 (KLK7) is a serine peptidase that is over expressed in ovarian cancer. In vitro functional analyses have suggested KLK7 to play a cancer progressive role, although monitoring of KLK7 expression has suggested a contradictory protective role for KLK7 in ovarian cancer patients. In order to help delineate its mechanism of action and thereby the functional roles, information on its substrate repertoire is crucial. Therefore, in this study a quantitative proteomics approach-PROtein TOpography and Migration Analysis Platform (PROTOMAP)-coupled with SILAC was used for in-depth analysis of putative KLK7 substrates from a representative ovarian cancer cell line, SKOV-3, secreted proteins. The Terminal Amine Isotopic Labeling of Substrates (TAILS) approach was used to determine the exact cleavage sites and to validate qPROTOMAP-identified putative substrates. By employing these two technically divergent approaches, exact cleavage sites on 16 novel putative substrates and two established substrates, matrix metalloprotease (MMP) 2 and insulin growth factor binding protein 3 (IGFBP3), were identified in the SKOV-3 secretome. Eight of these substrates were also identified on TAILS analysis of another ovarian cancer cell (OVMZ-6) secretome, with a further seven OVMZ-6 substrates common to the SKOV-3 qPROTOMAP profile. Identified substrates were significantly associated with the common processes of cell adhesion, extracellular matrix remodeling and cell migration according to the gene ontology (GO) biological process analysis. Biochemical validation supports a role for KLK7 in directly activating pro-MMP10, hydrolysis of IGFBP6 and cleavage of thrombospondin 1 with generation of a potentially bioactive N-terminal fragment. Overall, this study constitutes the most comprehensive analysis of the putative KLK7 degradome in any cancer to date, thereby opening new avenues for KLK7 research.

7.
J Rheumatol ; 46(5): 492-500, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30647177

RESUMO

OBJECTIVE: In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes. METHODS: We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively. RESULTS: Compared to controls, baseline OPN was raised 4-fold in SLE cases (p < 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p < 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p < 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p < 0.0001) and impaired estimated glomerular filtration rate (p = 0.01). CONCLUSION: The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time.

8.
Arthritis Care Res (Hoboken) ; 71(7): 893-902, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30044551

RESUMO

OBJECTIVE: The spectrum of antinuclear antibodies (ANAs) is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change is occurring in terminology to anticellular antibodies. This study examined the prevalence of indirect immunofluorescence (IIF) anticellular antibody staining using the Systemic Lupus International Collaborating Clinics inception cohort. METHODS: Anticellular antibodies were detected by IIF on HEp-2000 substrate using the baseline serum. Three serologic subsets were examined: ANA positive (presence of either nuclear or mixed nuclear/CMP staining), anticellular antibody negative (absence of any intracellular staining), and isolated CMP staining. The odds of being anticellular antibody negative versus ANA or isolated CMP positive was assessed by multivariable analysis. RESULTS: A total of 1,137 patients were included; 1,049 (92.3%) were ANA positive, 71 (6.2%) were anticellular antibody negative, and 17 (1.5%) had an isolated CMP. The isolated CMP-positive group did not differ from the ANA-positive or anticellular antibody-negative groups in clinical, demographic, or serologic features. Patients who were older (odds ratio [OR] 1.02 [95% confidence interval (95% CI) 1.00, 1.04]), of white race/ethnicity (OR 3.53 [95% CI 1.77, 7.03]), or receiving high-dose glucocorticoids at or prior to enrollment (OR 2.39 [95% CI 1.39, 4.12]) were more likely to be anticellular antibody negative. Patients on immunosuppressants (OR 0.35 [95% CI 0.19, 0.64]) or with anti-SSA/Ro 60 (OR 0.41 [95% CI 0.23, 0.74]) or anti-U1 RNP (OR 0.43 [95% CI 0.20, 0.93]) were less likely to be anticellular antibody negative. CONCLUSION: In newly diagnosed systemic lupus erythematosus, 6.2% of patients were anticellular antibody negative, and 1.5% had an isolated CMP. The prevalence of anticellular antibody-negative systemic lupus erythematosus will likely decrease as emerging nomenclature guidelines recommend that non-nuclear patterns should also be reported as a positive ANA.

9.
BMC Res Notes ; 11(1): 846, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30497514

RESUMO

OBJECTIVES: The fungus Pyrenophora tritici-repentis is a major pathogen of wheat worldwide, causing the leaf spotting disease tan spot. To best inform approaches for plant genetic resistance, an understanding of the biology and pathogenicity mechanisms of this fungal pathogen is essential. Here, intracellular and extracellular proteins of P. tritici-repentis were extracted, and peptides analysed via high-resolution mass spectrometry. Our objective was to generate a useful proteomics resource for P. tritici-repentis. A survey of proteins secreted by the pathogen into culture filtrate is especially useful, as these are likely to come in direct contact with the wheat host and may play important roles in infection/pathogenicity. The peptide data presented herein, has also been used to successfully verify and refine in silico predicted P. tritici-repentis gene annotations, through the validation of alternative splicing and reading frame shifts. DATA DESCRIPTION: The data sets presented consist of peptide spectra of the extracellular and intracellular proteomes of three P. tritici-repentis isolates. Peptide matches to translated transcripts of the North American reference isolate Pt-1C-BFP are also provided.


Assuntos
Ascomicetos , Proteínas Fúngicas , Doenças das Plantas/microbiologia , Folhas de Planta/microbiologia , Proteoma , Triticum/microbiologia , Ascomicetos/isolamento & purificação , Ascomicetos/metabolismo , Conjuntos de Dados como Assunto , Proteínas Fúngicas/metabolismo , Proteoma/metabolismo
10.
Sci Rep ; 8(1): 3468, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29472571

RESUMO

Childhood maltreatment (CM) can increase the risk of adverse health consequences in adulthood. A deeper insight in underlying biological pathways would be of high clinical relevance for early detection and intervention. The untargeted investigation of all detectable metabolites and lipids in biological samples represents a promising new avenue to identify so far unknown biological pathways associated with CM. Using an untargeted approach, liquid chromatography-mass spectrometry (LC-MS) was performed on peripheral blood serum samples collected three months postpartum from 105 women with varying degrees of CM exposure. Comprehensive univariate and multivariate statistical analyses consistently identified eight biomarker candidates putatively belonging to antioxidant-, lipid-, and endocannabinoid-associated pathways, which differentiated between women with and without CM. Classification algorithms allowed for clear prediction of the CM status with high accuracy scores (~80-90%). Similar results were obtained when excluding all women with a lifetime psychiatric diagnosis. In order to confirm the identities of these promising biomarker candidates, LC-MS/MS analysis was applied, confirming one of the metabolites as bilirubin IXa, a potent antioxidant with immunomodulatory properties. In sum, our results suggest novel pathways that could explain long-term effects of CM on health and disease by influencing biological patterns associated with energy metabolism, inflammation, and oxidative stress.


Assuntos
Impressões Digitais de DNA , Lipídeos/sangue , Metaboloma/genética , Período Pós-Parto/sangue , Adulto , Bilirrubina/sangue , Biomarcadores/sangue , Cromatografia Líquida , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Metabolômica/métodos , Estresse Oxidativo , Estudos Retrospectivos , Espectrometria de Massas em Tandem
11.
Front Plant Sci ; 9: 1882, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619431

RESUMO

Plant pathogens secrete effector molecules that suppress the plant immune response to facilitate disease development. AvrPto is a well-studied effector from the phytopathogenic bacterium Pseudomonas syringae. Here we utilize an in planta proximity dependent biotin ligase labeling technique (BioID) in combination with AvrPto to identify proximal proteins that are potential immune system components. The labeling technique biotinylated proteins proximal to AvrPto at the plasma-membrane allowing their isolation and identification by mass spectrometry. Five AvrPto proximal plant proteins (APPs) were identified and their effect on plant immune function and growth was examined in Nicotiana benthamiana leaves. One protein identified, RIN4, is a central immune component previously shown to interact with AvrPto. Two other proteins were identified which form a complex and when silenced significantly reduced P. syringae tabaci growth. The first was a receptor like protein kinase (APK1) which was required for Pto/Prf signaling and the second was Target of Myb1 (TOM1), a membrane associated protein with a phosphatidylinositol 5-phosphate (PtdIns5P) binding motif. We have developed a technology to rapidly determine protein interactions within living plant tissue. It is particularly useful for identifying plant immune system components by defining pathogenic effector protein interactions within their plant hosts.

12.
Diabetes Care ; 40(11): 1548-1555, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28851702

RESUMO

OBJECTIVE: To assess the ability of plasma apolipoprotein (apo) A-IV (apoA4), apo C-III, CD5 antigen-like (CD5L), complement C1q subcomponent subunit B (C1QB), complement factor H-related protein 2, and insulin-like growth factor binding protein 3 (IBP3) to predict rapid decline in estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Mass spectrometry was used to measure baseline biomarkers in 345 community-based patients (mean age 67.0 years, 51.9% males) from the Fremantle Diabetes Study Phase II (FDS2). Multiple logistic regression was used to determine clinical predictors of rapid eGFR decline trajectory defined by semiparametric group-based modeling over a 4-year follow-up period. The incremental benefit of each biomarker was then assessed. Similar analyses were performed for a ≥30% eGFR fall, incident chronic kidney disease (eGFR <60 mL/min/1.73 m2), and eGFR decline of ≥5 mL/min/1.73 m2/year. RESULTS: Based on eGFR trajectory analysis, 35 participants (10.1%) were defined as "rapid decliners" (mean decrease 2.9 mL/min/1.73 m2/year). After adjustment for clinical predictors, apoA4, CD5L, and C1QB independently predicted rapid decline (odds ratio 2.40 [95% CI 1.24-4.61], 0.52 [0.29-0.93], and 2.41 [1.14-5.11], respectively) and improved model performance and fit (P < 0.001), discrimination (area under the curve 0.75-0.82, P = 0.039), and reclassification (net reclassification index 0.76 [0.63-0.89]; integrated discrimination improvement 6.3% [2.1-10.4%]). These biomarkers and IBP3 contributed to improved model performance in predicting other indices of rapid eGFR decline. CONCLUSIONS: The current study has identified novel plasma biomarkers (apoA4, CD5L, C1QB, and IBP3) that may improve the prediction of rapid decline in renal function independently of recognized clinical risk factors in type 2 diabetes.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Insuficiência Renal Crônica/sangue , Idoso , Apolipoproteína C-III/sangue , Apolipoproteínas A/sangue , Proteínas Sanguíneas/metabolismo , Proteínas de Transporte/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/sangue , Insuficiência Renal Crônica/complicações , Fatores de Risco , Receptores Depuradores Classe B/sangue
13.
Sci Rep ; 7(1): 6789, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754951

RESUMO

The cleavage preferences of Kallikrein-related peptidase 7 (KLK7) have previously been delineated using synthetic peptide libraries of fixed length, or single protein chains and have suggested that KLK7 exerts a chymotryptic-like cleavage preference. Due to the short length of the peptides utilised, only a limited number of subsites have however been assessed. To determine the subsite preferences of KLK7 in a global setting, we used a mass spectrometry (MS)-based in-depth proteomics approach that utilises human proteome-derived peptide libraries of varying length, termed Proteomic Identification of protease Cleavage Sites (PICS). Consistent with previous findings, KLK7 was found to exert chymotryptic-like cleavage preferences. KLK7 subsite preferences were also characterised in the P2-P2' region, demonstrating a preference for hydrophobic residues in the non-prime and hydrophilic residues in the prime subsites. Interestingly, single catalytic triad mutant KLK7 (mKLK7; S195A) also showed residual catalytic activity (kcat/KM = 7.93 × 102 s-1M-1). Catalytic inactivity of KLK7 was however achieved by additional mutation in this region (D102N). In addition to characterising the cleavage preferences of KLK7, our data thereby also suggests that the use of double catalytic triad mutants should be employed as more appropriate negative controls in future investigations of KLK7, especially when highly sensitive MS-based approaches are employed.


Assuntos
Substituição de Aminoácidos , Calicreínas/metabolismo , Proteoma/química , Domínio Catalítico , Células HEK293 , Humanos , Calicreínas/química , Calicreínas/genética , Espectrometria de Massas/métodos , Pichia , Proteólise , Proteoma/metabolismo , Especificidade por Substrato
14.
Proc Natl Acad Sci U S A ; 114(27): 7077-7082, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28630300

RESUMO

G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome. This inefficiency leads to an increase in H3K9me2 at its target promoters. Blocking the methyltransferase activity of G9a inhibited cellular proliferation and migration in vitro and tumor growth in vivo. Furthermore, an increased level of G9a is a crucial factor in mediating the hypoxic response by down-regulating the expression of specific genes, including ARNTL, CEACAM7, GATA2, HHEX, KLRG1, and OGN This down-regulation can be rescued by a small molecule inhibitor of G9a. Based on the hypothesis that the changes in gene expression would influence patient outcomes, we have developed a prognostic G9a-suppressed gene signature that can stratify breast cancer patients. Together, our findings provide an insight into the role G9a plays as an epigenetic mediator of hypoxic response, which can be used as a diagnostic marker, and proposes G9a as a therapeutic target for solid cancers.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Hipóxia/genética , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Prolina/química , Processamento de Proteína Pós-Traducional , RNA Interferente Pequeno/metabolismo , Recidiva , Microambiente Tumoral
16.
BMC Immunol ; 18(1): 17, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28351341

RESUMO

BACKGROUND: To assess the impact of disease activity on health-related quality of life (HRQoL) in systemic lupus erythematosus (SLE). METHODS: Cross-sectional study of patients included in the Swiss SLE Cohort Study between April 2007 and June 2014. HRQoL outcomes were based on the Medical Outcome Study Short Form 36 (SF-36). Disease activity was assessed by the SLE Disease Activity Index score with the Safety of Estrogens in SLE National Assessment modification (SELENA-SLEDAI) and by the physican's global assessment (PGA). RESULTS: Of the 252 patients included, 207 (82%) were women. Median [interquartile range (IQR)] age was 43 [32-57] years. SLE was active in 125 patients (49.6%). Median [IQR] mental component summary (MCS) in active vs inactive SLE was 40.0 [30.2-51.0] compared to 47.3 [39.2-52.8] (p < 0.01) and median [IQR] physical component summary (PCS) 43.7 [37.0-52.8] compared to 49.1 [38.4-55.6], respectively (p < 0.05). Increase in SELENA-SLEDAI or increase in PGA were negatively correlated with PCS and/or MCS. After adjusting for gender, age and disease duration, disease activity impacted on both PCS and MCS and all subscales except general health. Active lupus nephritis and musculoskeletal involvement were associated with physical limitations and emotional problems, increased bodily pain and poor social functioning. Low complement and/or presence of anti-dsDNA antibodies were associated with increased fatigue and reduced mental health. CONCLUSIONS: In patients with SLE, HRQoL is reduced in those with active disease. Impact of disease activity on HRQoL dimensions depends on SELENA-SLEDAI system components.


Assuntos
Lúpus Eritematoso Sistêmico/epidemiologia , Nefrite Lúpica/epidemiologia , Qualidade de Vida , Adulto , Ensaios Clínicos como Assunto , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Inquéritos e Questionários , Suíça/epidemiologia
17.
EuPA Open Proteom ; 14: 1-10, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29900119

RESUMO

A protein biomarker discovery workflow was applied to plasma samples from patients at different stages of diabetic kidney disease. The proteomics platform produced a panel of significant plasma biomarkers that were statistically scrutinised against the current gold standard tests on an analysis of 572 patients. Five proteins were significantly associated with diabetic kidney disease defined by albuminuria, renal impairment (eGFR) and chronic kidney disease staging (CKD Stage ≥1, ROC curve of 0.77). The results prove the suitability and efficacy of the process used, and introduce a biomarker panel with the potential to improve diagnosis of diabetic kidney disease.

18.
Data Brief ; 8: 267-71, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27331100

RESUMO

Rhizoctonia solani is an important root infecting pathogen of a range of food staples worldwide including wheat, rice, maize, soybean, potato, legumes and others. Conventional resistance breeding strategies are hindered by the absence of tractable genetic resistance in any crop host. Understanding the biology and pathogenicity mechanisms of this fungus is important for addressing these disease issues, however, little is known about how R. solani causes disease. The data described in this article is derived from applying mass spectrometry based proteomics to identify soluble, membrane-bound and culture filtrate proteins produced under wheat infection and vegetative growth conditions. Comparisons of the data for sample types in this set will be useful to identify metabolic pathway changes as the fungus switches from saprophytic to a pathogenic lifestyle or pathogenicity related proteins contributing to the ability to cause disease on wheat. The data set is deposited in the PRIDE archive under identifier PRIDE: PXD002806.

19.
PLoS One ; 11(2): e0147221, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26840125

RESUMO

Parastagonospora nodorum, the causal agent of Septoria nodorum blotch (SNB), is an economically important pathogen of wheat (Triticum spp.), and a model for the study of necrotrophic pathology and genome evolution. The reference P. nodorum strain SN15 was the first Dothideomycete with a published genome sequence, and has been used as the basis for comparison within and between species. Here we present an updated reference genome assembly with corrections of SNP and indel errors in the underlying genome assembly from deep resequencing data as well as extensive manual annotation of gene models using transcriptomic and proteomic sources of evidence (https://github.com/robsyme/Parastagonospora_nodorum_SN15). The updated assembly and annotation includes 8,366 genes with modified protein sequence and 866 new genes. This study shows the benefits of using a wide variety of experimental methods allied to expert curation to generate a reliable set of gene models.


Assuntos
Ascomicetos/genética , Ascomicetos/metabolismo , Perfilação da Expressão Gênica , Genoma Fúngico , Genômica , Proteômica , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Anotação de Sequência Molecular , Proteoma , Proteômica/métodos , Transcriptoma
20.
Mol Cell Proteomics ; 15(4): 1188-203, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26811357

RESUMO

Rhizoctonia solaniis an important root infecting pathogen of a range of food staples worldwide including wheat, rice, maize, soybean, potato and others. Conventional resistance breeding strategies are hindered by the absence of tractable genetic resistance in any crop host. Understanding the biology and pathogenicity mechanisms of this fungus is important for addressing these disease issues, however, little is known about howR. solanicauses disease. This study capitalizes on recent genomic studies by applying mass spectrometry based proteomics to identify soluble, membrane-bound and culture filtrate proteins produced under wheat infection and vegetative growth conditions. Many of the proteins found in the culture filtrate had predicted functions relating to modification of the plant cell wall, a major activity required for pathogenesis on the plant host, including a number found only under infection conditions. Other infection related proteins included a high proportion of proteins with redox associated functions and many novel proteins without functional classification. The majority of infection only proteins tested were confirmed to show transcript up-regulation during infection including a thaumatin which increased susceptibility toR. solaniwhen expressed inNicotiana benthamiana In addition, analysis of expression during infection of different plant hosts highlighted how the infection strategy of this broad host range pathogen can be adapted to the particular host being encountered. Data are available via ProteomeXchange with identifier PXD002806.


Assuntos
Proteômica/métodos , Rhizoctonia/patogenicidade , Triticum/microbiologia , Fatores de Virulência/metabolismo , Adaptação Fisiológica , Proteínas Fúngicas/metabolismo , Interações Hospedeiro-Patógeno , Espectrometria de Massas/métodos , Oxirredução , Doenças das Plantas/microbiologia , Rhizoctonia/metabolismo
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