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J Pain Res ; 12: 2875-2889, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686904


Objective: Neuropathic pain and fibromyalgia are two common and poorly understood chronic pain conditions that lack satisfactory treatments, cause substantial suffering and societal costs. Today, there are no biological markers on which to base chronic pain diagnoses, treatment choices or to understand the pathophysiology of pain for the individual patient. This study aimed to investigate cerebrospinal fluid (CSF) protein profiles potentially associated with fibromyalgia and neuropathic pain. Methods: CSF samples were collected from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery, and n=11 for verification), 40 patients with fibromyalgia and 134 controls without neurological disease from two different populations. CSF protein profiling of 55 proteins was performed using antibody suspension bead array technology. Results: We found increased levels of apolipoprotein C1 (APOC1) in CSF of neuropathic pain patients compared to controls and there was a trend for increased levels also in fibromyalgia patients. In addition, levels of ectonucleotide pyrophosphatase family member 2 (ENPP2, also referred to as autotaxin) were increased in the CSF of fibromyalgia patients compared to all other groups including patients with neuropathic pain. Conclusion: The increased levels of APOC1 and ENPP2 found in neuropathic pain and fibromyalgia patients may shed light on the underlying mechanisms of these conditions. Further investigation is required to elucidate their role in maintaining pain and other main symptoms of these disorders.

Clin Transl Allergy ; 9: 6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728947


Background: Atopic dermatitis (AD) is a complex heterogeneous chronic inflammatory skin disease. Specific IgE antibodies against autoantigens have been observed in a subgroup of AD patients, however, little is known about IgG-auto-reactivity in AD. To investigate the presence of autoreactive IgG antibodies, we performed autoantibody profiling of IgG in patients with AD of different severities and in healthy controls (HC). Methods: First, we performed an untargeted screening in plasma samples from 40 severe AD (sAD) patients and 40 HC towards 1152 protein fragments on planar antigen microarrays. Next, based on the findings and addition of more fragments, a targeted antigen suspension bead array was designed to profile a cohort of 50 sAD patients, 123 patients with moderate AD (mAD), and 84 HC against 148 protein fragments representing 96 unique proteins. Results: Forty-nine percent of the AD patients showed increased IgG-reactivity to any of the four antigens representing keratin associated protein 17-1 (KRTAP17-1), heat shock protein family A (Hsp70) member 4 (HSPA4), S100 calcium binding proteins A12 (S100A12), and Z (S100Z). The reactivity was more frequent in the sAD patients (66%) than in those with mAD (41%), whereas only present in 25% of the HC. IgG-reactivity to S100A12, a protein including an antimicrobial peptide, was only observed in AD patients (13/173). Conclusions: Autoantibody profiling of IgG-reactivity using microarray technology revealed an autoantibody-based subgroup in patients with AD. The four identified autoantigens and especially S100A12 could, if characterized further, increase the understanding of different pathogenic mechanisms behind AD and thereby enable better treatment.

Liver Int ; 37(1): 132-140, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27224670


BACKGROUND & AIMS: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. METHODS: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. RESULTS: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. CONCLUSIONS: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

Antígenos CD/sangue , Caderinas/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Acetaminofen/administração & dosagem , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , Feminino , Infecções por HIV , Heparina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica , Fatores de Risco , Tuberculose , Adulto Jovem
J Alzheimers Dis ; 54(4): 1671-1686, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27636840


BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-ß and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. OBJECTIVE: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. METHODS: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. RESULTS: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. CONCLUSIONS: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Micropartículas Derivadas de Células/metabolismo , Endocitose/fisiologia , Exocitose/fisiologia , Líquido Extracelular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Micropartículas Derivadas de Células/genética , Micropartículas Derivadas de Células/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mapas de Interação de Proteínas/fisiologia , Vesículas Transportadoras/genética , Vesículas Transportadoras/metabolismo
PLoS One ; 11(3): e0150672, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26950848


Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.

Doença de Alzheimer/líquido cefalorraquidiano , Proteômica , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Estudos de Casos e Controles , Humanos , Masculino , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/metabolismo , Reprodutibilidade dos Testes , Software
Ann Clin Transl Neurol ; 1(8): 544-53, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25356426


OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease leading to muscular paralysis and death within 3-5 years from onset. Currently, there are no reliable and sensitive markers able to substantially shorten the diagnosis delay. The objective of the study was to analyze a large number of proteins in plasma from patients with various clinical phenotypes of ALS in search for novel proteins or protein profiles that could serve as potential indicators of disease. METHODS: Affinity proteomics in the form of antibody suspension bead arrays were applied to profile plasma samples from 367 ALS patients and 101 controls. The plasma protein content was directly labeled and protein profiles obtained using 352 antibodies from the Human Protein Atlas targeting 278 proteins. A focused bead array was then built to further profile eight selected protein targets in all available samples. RESULTS: Disease-associated significant differences were observed and replicated for profiles from antibodies targeting the proteins: neurofilament medium polypeptide (NEFM), solute carrier family 25 (SLC25A20), and regulator of G-protein signaling 18 (RGS18). INTERPRETATION: Upon further validation in several independent cohorts with inclusion of a broad range of other neurological disorders as controls, the alterations of these three protein profiles in plasma could potentially provide new molecular markers of disease that contribute to the quest of understanding ALS pathology.