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Fissolo, Nicolás, Clara Matute-Blanch, Mohamoud Osman, Carme Costa, Rucsanda Pinteac, Berta Miró, Alex Sanchez, et al. "CSF SERPINA3 Levels Are Elevated in Patients With Progressive MS." Neurology - Neuroimmunology Neuroinflammation 8, no. 2 (January 12, 2021): e941. http://dx.doi.org/10.1212/nxi.0000000000000941.
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ObjectiveTo identify biomarkers associated with progressive phases of MS and with neuroprotective potential.MethodsCombined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs).ResultsIntegrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01).ConclusionThese results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS.
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Nadif, Rachel, Mickael Febrissy, Miora Valérie Andrianjafimasy, Nicole Le Moual, Frederic Gormand, Jocelyne Just, Isabelle Pin, et al. "Endotypes identified by cluster analysis in asthmatics and non-asthmatics and their clinical characteristics at follow-up: the case-control EGEA study." BMJ Open Respiratory Research 7, no. 1 (December 2020): e000632. http://dx.doi.org/10.1136/bmjresp-2020-000632.
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BackgroundIdentifying relevant asthma endotypes may be the first step towards improving asthma management. We aimed identifying respiratory endotypes in adults using a cluster analysis and to compare their clinical characteristics at follow-up.MethodsThe analysis was performed separately among current asthmatics (CA, n=402) and never asthmatics (NA, n=666) from the first follow-up of the French EGEA study (EGEA2). Cluster analysis jointly considered 4 demographic, 22 clinical/functional (respiratory symptoms, asthma treatments, lung function) and four blood biological (allergy-related, inflammation-related and oxidative stress-related biomarkers) characteristics at EGEA2. The clinical characteristics at follow-up (EGEA3) were compared according to the endotype identified at EGEA2.ResultsWe identified five respiratory endotypes, three among CA and two among NA: CA1 (n=53) with active treated adult-onset asthma, poor lung function, chronic cough and phlegm and dyspnoea, high body mass index, and high blood neutrophil count and fluorescent oxidation products level; CA2 (n=219) with mild asthma and rhinitis; CA3 (n=130) with inactive/mild untreated allergic childhood-onset asthma, high frequency of current smokers and low frequency of attacks of breathlessness at rest, and high IgE level; NA1 (n=489) asymptomatic, and NA2 (n=177) with respiratory symptoms, high blood neutrophil and eosinophil counts. CA1 had poor asthma control and high leptin level, CA2 had hyper-responsiveness and high interleukin (IL)-1Ra, IL-5, IL-7, IL-8, IL-10, IL-13 and TNF-α levels, and NA2 had high leptin and C reactive protein levels. Ten years later, asthmatics in CA1 had worse clinical characteristics whereas those in CA3 had better respiratory outcomes than CA2; NA in NA2 had more respiratory symptoms and higher rate of incident asthma than those in NA1.ConclusionThese results highlight the interest to jointly consider clinical and biological characteristics in cluster analyses to identify endotypes among adults with or without asthma.
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Koutsonikoli, A., A. Taparkou, P. Pratsidou-Gertsi, V. Sgouropoulou, and M. Trachana. "POS0497 A STUDY ON THE IMMUNOREGULATORY ROLE OF THE PD1 PATHWAY IN JUVENILE IDIOPATHIC ARTHRITIS - PRELIMINARY RESULTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 503.2–503. http://dx.doi.org/10.1136/annrheumdis-2022-eular.5099.
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BackgroundThe Programmed cell Death protein-1 (PD1) pathway promotes self-tolerance, by inhibiting immune responses. The PD1 soluble form (sPD1), by antagonizing the binding of the membrane-bound PD1 with its ligands, may lead to the blocking of the pathway’s functions. Data regarding the role of the PD1 pathway in Juvenile Idiopathic Arthritis (JIA) are still limited.ObjectivesTo investigate the immunoregulatory role of the PD1 pathway in JIA patients.MethodsJIA patients and healthy controls participated in this study with peripheral blood (PB) and/or synovial fluid (SF) samples. sPD1 levels in serum and SF were determined by ELISA. The PD1 expression on T-helper (CD4+) and T-cytotoxic (CD8+) cells in PB and SF was analyzed by flow cytometry. A search for any association between the above biomarkers, as well as their relation with JIA activity was then performed. Inactive disease was defined according to Wallace criteria.Results77 Caucasian patients (52 female) participated so far in this study, with a median (range) age of 13 (2-19) years; their JIA subtypes were: oligoarthritis (33%), polyarthritis (26%), psoriatic (12%), enthesitis-related (16%), systemic (10%) and undifferentiated (3%). Ten healthy children served as controls. As compared to controls, a subpopulation of these JIA patients (n=46) had a significantly higher median percentage of PD1+CD4+ (1.15 vs. 0.32%, p=0.029) and PD1+CD8 T cells (1.34 vs. 0.4%, p=0.006) in PB. In regard to the JIA status, patients with activity (n=33) had a significantly higher median percentage of both PD1+CD4+ and PD1+CD8 T cells in PB, as compared to those with inactive disease (n=13) (1.36 vs. 0.87%, p=0.034 and 2.03 vs. 0.45%, p<0.001, respectively). Additionally, in a sample of the patients with disease activity (n=22), the median serum sPD1 level was statistically significantly higher, as compared to a sample of those with inactive JIA (n=10) (218.3 vs. 186.7pg/ml, p=0.035). In patients with concurrent serum and SF samples (n=7), the median sPD1 level was statistically significantly higher in the SF than in the serum [1104.4 vs. 773.4pg/ml, p=0.028). No correlation was though found between the sPD1 levels and the PD1 cellular surface expression (n=16 PB/serum, n=11 SF).ConclusionThese preliminary results indicated an sPD1 compartmentalization in active JIA, as sPD1 levels were more prominently raised in the inflamed joint than in the PB. Α higher number of circulating T-helper and T-cytotoxic cells expressing PD1 were also detected in active JIA. Further investigation in a larger sample of JIA patients may verify these observations and contribute to unraveling the precise role of the PD1 pathway in the pathogenesis and persistence of the joint inflammation.References[1]Leong et al. Recent advances in our understanding of the pathogenesis of juvenile idiopathic arthritis and their potential clinical implications. Expert Rev Clin Immunol. 2018 Nov;14(11):933-944.[2]Zhang et al. The PD-1/PD-L pathway in rheumatic diseases. J Formos Med Assoc. 2021 Jan;120(1 Pt 1):48-59.Disclosure of InterestsNone declared.
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Cognat, Emmanuel, François Mouton Liger, Anne-Cécile Troussière, David Wallon, Julien Dumurgier, Eloi Magnin, Emmanuelle Duron, et al. "What is the clinical impact of cerebrospinal fluid biomarkers on final diagnosis and management in patients with mild cognitive impairment in clinical practice? Results from a nation-wide prospective survey in France." BMJ Open 9, no. 5 (May 2019): e026380. http://dx.doi.org/10.1136/bmjopen-2018-026380.
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ObjectivesNew diagnostic criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics.DesignWe performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey.Setting29 secondary and tertiary memory clinics in France.ParticipantsClinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP.Primary and secondary outcome measuresAssessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine.Results977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4).ConclusionThis nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.
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Soldan, Anja, Corinne Pettigrew, Anne M. Fagan, Suzanne E. Schindler, Abhay Moghekar, Christopher Fowler, Qiao-Xin Li, et al. "ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes." Neurology 92, no. 14 (March 6, 2019): e1567-e1579. http://dx.doi.org/10.1212/wnl.0000000000007248.
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ObjectiveTo examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles.MethodsPooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1–42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years).ResultsUsing different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A−T−N−). Replicating prior findings using the 2011 National Institute on Aging–Alzheimer's Association/suspected non–Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0).ConclusionThe results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.
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Targonska-Stepniak, B., A. Drelich-Zbroja, and K. Grzechnik. "AB0782 Serum pentraxin 3 as a biomarker in patients with spondyloarthritis." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1517.2–1518. http://dx.doi.org/10.1136/annrheumdis-2022-eular.606.
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BackgroundA proper evaluation and management of patients with spondyloarthritis (SpA) requires the use of biomarkers, facilitating early diagnosis, reflecting disease activity and clinical response to therapies. The chronic, systemic inflammatory process is responsible for increased CV risk in SpA patients. Pentraxin 3 (PTX3) is an inflammatory marker, a member of long pentraxin superfamily, argued to be involved in pathogenesis of both inflammation and atherosclerosis. PTX3 is produced locally in the inflamed tissue, by different cell types including macrophages, endothelial cells, synoviocytes, but not hepatocytes. PTX3 is produced in walls of blood vessels, in atherosclerotic plaques, as a response to pro-inflammatory cytokines.ObjectivesThe aim of the study was to assess the role of PTX3 as a biomarker in patients with SpA and to evaluate the relationship between PTX3 and CV risk markers (carotid intima-media thickness (cIMT), lipid profile).MethodsThe study group consisted of 40 consecutive patients with SpA: 29 patients with psoriatic arthritis (PsA) and 11 patients with ankylosing spondylitis (AS). The group consisted of 16 (40%) women and 24 (60%) men, with the mean (SD) age 43.9 (12.0) (range 25–68) and disease duration 7,8 (7,6) years (range 1–32). An assessment of the disease activity included: laboratory inflammatory parameters (erythrocyte sedimentation rate (ESR), C-reactive protein, CRP) and clinical assessment (in patients with peripheral SpA (pSpA) joints counts and disease activity score in 28 joints (DAS28); in patients with axial SpA (axSpA) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and pain of the spine according to the patient in visual analogue scale (VAS). A measurement of carotid intima-media thickness (cIMT) was performed using high-resolution B-mode ultrasonography to estimate features of atherosclerosis (cIMT> 0.9 mm and/or presence of atherosclerotic plaques).ResultsThe median (IQR) PTX3 concentration in SpA patients was 3.39 (2.22-3.88) ng/ml. The mean (SD) value of ESR was 27.7 (28.3) mm/h and CRP concentration 13.6 (19.9) mg/l.The mean values of clinical indices were as follows: DAS28 3.8 (1.1), BASDAI 4.02 (2.1), BASFI 4.22 (2.2), VAS spine pain 41.4 (24.0).The mean (SD) cIMT value was 0.77 (0.23) mm (range 0.48-1.33). The features of atherosclerosis were detected in 7 (17.5%) patients.No significant correlations were found between PTX3 and other inflammatory markers (ESR, CRP). There were no correlations between PTX3 concentration the clinical indices of the disease activity (DAS28, BASDAI, BASFI, VAS spine pain). No differences of PTX3 concentrations were detected between pSpA and axSpA patients.The PTX3 concentrations were significantly higher in patients with definite atherosclerosis (cIMT > 0.9 mm) than in patients with subclinical or no atherosclerosis (cIMT=< 0.9) (5.79 (3.84-8.59) vs 3.06 (2.0-3.52) ng/ml, p=0.01), as well as in patients with atherosclerotic plaques in comparison with no plaques (6.79 (4.86-8.59) vs 3.26 (2.0-3.71) ng/ml, p=0.02) (Figure 1).ConclusionThe results of our study suggest that in patients with SpA, PTX3 could be regarded as a biomarker indicating intensity of atherosclerosis. However PTX3 was not associated with parameters of disease activity in patients with SpA.References[1]Maksymowych WP. Biomarkers in axial spondyloarthritis. Curr Opin Rheumatol. 2015 Jul;27(4):343-8. doi: 10.1097/BOR.0000000000000180.[2]Nisihara R, Skare TL, Zeni JO, Rasera H, Lidani K, Messias-Reason I. Plasma levels of pentraxin 3 in patients with spondyloarthritis. Biomarkers. 2018 Feb;23(1):14-17. doi: 10.1080/1354750X.2016.1278265.Disclosure of InterestsNone declared
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Myachikova, V., E. Kuvardin, K. Zotkina, O. Tkachenko, S. Lapin, and A. Maslyanskiy. "POS1344 USEFULNESS OF TRADITIONAL AND NOVEL BIOMARKERS FOR EVALUATION OF ADULT-ONSET STILL’s DISEASE ACTIVITY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1010.1–1010. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2645.
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BackgroundAdult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder with unknown etiology. The main problem for rheumatologists is a lack of generally accepted methods for assessing AOSD activity.ObjectivesTo compare the usefulness of traditional and novel biomarkers for assessing the AOSD activityMethodsThe cross-sectional study included 27 patients over the age of 18 with a relapse of AOSD who were examined at the Almazov National Medical Research Centre from 2018 to 2021.All patients fulfilled the AOSD classification criteria by Yamaguchi. Clinical manifestations were scored in a Pouchot AOSD activity score. The serum concentrations of IL-1, IL-6, IL-18, ferritin, calgranulin, procalcitonin and the level of glycosylated ferritin (GF) were examined. Standard commercial reagents were used for detection clinical analysis of blood, C-reactive protein (CRP) and aminotransferases. Statistical analysis was performed using the licensed statistical applications Statistica 10.0 for Windows (StatSoft Inc., USA), and Prisma GraphPad 8.0 (GraphPad Software, USA). Results were expressed as median (25th–75th percentile) and analysed for statistical significance using nonparametric tests. For quantitative features comparison, the Mann–Whitney U test was used. The correlation coefficient was obtained by nonparametric Spearman’s rank correlation test. P values < 0.05 were considered statistically significant. Data from commercial test systems are taken as the basis for normal biomarker indicators.ResultsClinical data were available from 27 patients with AOSD (6 male and 21 female). The median age was 41.3 [26;50]. The median Pouchot activity score was 6 [4.5;7]. The course of AOSD was monocyclic in 1 patient, polycyclic in 23, and chronic in 3. Elevated leukocyte count > 10,000/μl was detected in 17 patients (63%), 9 patients (33%) had an elevated leukocyte count > 15,000/μl.An increase in biomarkers was detected in most patients: calgranulin was increased in 24 out of 26 patients (92.3%), ferritin was increased and GF was decreased in 21 out of 25 patients (84%). Among those 25 patients, the decrease in GF was less than 20% in 13 patients (52%). IL-18 increased in 17 patients (63%), IL-6 increased in 22 patients (81.5%), and procalcitonin increased in 16 out of 26 patients (61.6%). The median of procalcitonin concentration was 0.08 [0.01; 30.1]. No increase in IL-1 beta was detected.A correlation analysis revealed a direct relationship between the concentration of IL-18, ferritin and the Pouchot system score. An inverse relationship existed between these indicators and the level of GF (rs=0.803, p=0.001) and between calgranulin and IL-6 (rs=0.46, p=0.02). It was noted that the younger the age of the patients, the higher the concentration of IL-18 (rs=-0.449, p=0.019).ConclusionThe most promising additional laboratory biomarkers for assessing AOSD activity are calprotectin, IL-18, and ferritin. Despite a slight increase in procalcitonin as one of the indicators of the acute phase of inflammation, it remains an effective biomarker of sepsis; however, it is recommended to focus on threshold concentrations above 0.5.References[1]Ruscitti P, Cipriani P, Masedu F, Iacono D, Ciccia F, Liakouli V, Guggino G, Carubbi F, Berardicurti O, Di Benedetto P, Valenti M, Triolo G, Valentini G, Giacomelli R. Adult-onset Still’s disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers. BMC Med. 2016 Dec 1;14(1):194. doi: 10.1186/s12916-016-0738-8.[2]Feist E, Mitrovic S, Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still’s disease. Nat Rev Rheumatol. 2018 Oct;14(10):603-618. doi: 10.1038/s41584-018-0081-x.[3]Lapin S, Maslyansky A., Lazareva N., Vasilyeva E., Totolyan A. The significance of the quantitative determination of procalcitonin for the diagnosis of septic complications in patients with autoimmune rheumatic diseases. Clinical laboratory diagnostics. 2013. No. 1.Disclosure of InterestsValentina Myachikova Speakers bureau: Novartis, Sobi, Evgenii Kuvardin: None declared, Kira Zotkina Speakers bureau: Novartis Amgen, Olga Tkachenko: None declared, Sergey Lapin: None declared, Alexey Maslyanskiy Speakers bureau: Boehringer Ingelheim Pharmaceuticals, Novartis, R-PHARM. Eli Lilly
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Gordh, Torsten, Anne-Li Lind, Constantin Bodolea, Ellen Hewitt, and Anders Larsson. "Cathepsin S is increased in cerebrospinal fluid from patients with neuropathic pain—A support of the microglia hypothesis in humans." Scandinavian Journal of Pain 5, no. 3 (July 1, 2014): 208–9. http://dx.doi.org/10.1016/j.sjpain.2014.05.015.
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AbstractAimsCathepsin S has been reported to be a biomarker of spinal microglial activation, a process suggested to be involved in the pathophysiology of chronic neuropathic pain. So far this has been shown only in animal experiments. The aim of this study was to investigate the concentrations of cathepsin S in human cerebrospinal fluid (CSF) samples from a well-defined patient cohort suffering from neuropathic pain as compared to controls.MethodsCSF samples from patients suffering from chronic neuropathic pain (n = 14) were analyzed for cathepsin S levels using commercial sandwich ELISAs (DY1183, R&D Systems, Minneapolis, MN, USA). Control CSF was sampled from patients undergoing minor urological surgical procedures under spinal anaesthesia (n = 70), having no obvious pain suffering.ResultsThe neuropathic pain group had significantly higher levels of CSF cathepsin S (median 15189 pg/mL, range 3213–40,040), than the control group (median 5911 pg/mL, range 1909–17,188) (p < 0.005, Mann–Whitney U-test).ConclusionThe results support the existence of microglial activation in chronic neuropathic pain patients. CSF Cathepsin S may serve as a potential biomarker for this specific mechanism linked to neuropathic pain. In the future, Cathepsin S inhibiting drugs might become a new treatment alternative for neurophatic pain.
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Abdulrahman, Ziena, Natasja Hendriks, Arnold J Kruse, Antonios Somarakis, Anna J M van de Sande, Heleen J van Beekhuizen, Jurgen M J Piek, et al. "Immune-based biomarker accurately predicts response to imiquimod immunotherapy in cervical high-grade squamous intraepithelial lesions." Journal for ImmunoTherapy of Cancer 10, no. 11 (November 2022): e005288. http://dx.doi.org/10.1136/jitc-2022-005288.
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BackgroundThe complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On the other hand, conventional surgical large loop excision therapy is associated with increased risk of premature births in subsequent pregnancies. An in-depth analysis of the cHSIL immune microenvironment was performed in order to identify and develop a predictive biomarker for response to imiquimod, to maximize therapy efficacy and to avoid adverse effects in patients unlikely to respond.MethodsBiopsies of 35 cHSIL patients, before and 10 weeks on imiquimod treatment, were analyzed by two multispectral seven-color immunofluorescence panels for T cell and myeloid cell composition in relation to treatment response. Based on these results a simplified immunohistochemical detection protocol was developed. Samples were scanned with the Vectra multispectral imaging system and cells were automatically identified using machine learning.ResultsThe immune microenvironment of complete responders (CR) is characterized by a strong and coordinated infiltration by T helper cells (activated PD1+/type 1 Tbet+), M1-like macrophages (CD68+CD163-) and dendritic cells (CD11c+) prior to imiquimod. The lesions of non-responders (NRs) displayed a high infiltration by CD3+FOXP3+regulatory T cells. At 10 weeks on imiquimod, a strong influx of intraepithelial and stromal CD4+T cells was observed in CR but not NR patients. A steep decrease in macrophages occurred both in CR and NR patients, leveling the pre-existing differences in myeloid cell composition between the two groups. Based on the pre-existing immune composition differences, the sum of intraepithelial CD4 T cell, macrophage and dendritic cell counts was used to develop a quantitative simplified one color immunohistochemical biomarker, the CHSIL immune biomarker for imiquimod (CIBI), which can be automatically and unbiasedly quantified and has an excellent predictive capacity (receiver operating characteristic area under the curve 0.95, p<0.0001).ConclusionThe capacity of cHSIL patients to respond to imiquimod is associated with a pre-existing coordinated local immune process, fostering an imiquimod-mediated increase in local T cell infiltration. The CIBI immunohistochemical biomarker has strong potential to select cHSIL patients with a high likelihood to experience a complete response to imiquimod immunotherapy.
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Yan, Benedict, Shoa Nian Choo, Patricia Mulyadi, Supriya Srivastava, Chee Wee Ong, Kol Jia Yong, Thomas Putti, Manuel Salto-Tellez, and Gkeok Stzuan Diana Lim. "Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation enables accurate assessment of HER2 genomic status in ovarian tumours." Journal of Clinical Pathology 64, no. 12 (September 6, 2011): 1097–101. http://dx.doi.org/10.1136/jclinpath-2011-200082.
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BackgroundOvarian cancer is a leading cause of gynaecological cancer-related morbidity and mortality. There has been increasing interest in the potential utility of anti-human epidermal growth factor receptor 2 (anti-HER2) agents in the treatment of this disease, with the attendant need to identify suitable predictive biomarkers of response to treatment.Aims/methodsThe authors studied the prevalence of HER2 genomic amplification and overexpression in 85 ovarian tumours in the local patient cohort of this study, as well as the concordance rate between immunohistochemistry, fluorescent in situ hybridisation (FISH) and a dual-colour HER2/chromosome 17 centromere chromogenic in situ hybridisation (CISH) assay.ResultsThe authors identified HER2 genomic amplification and protein overexpression in 35.3% (6/17) and 29.4% (5/17), respectively, of primary ovarian mucinous carcinomas. No other cancer subtypes displayed HER2 amplification or protein overexpression. The authors also found a perfect concordance between FISH and dual-colour CISH analysis (κ coefficient 1.0, p<0.001).ConclusionThe results of this study support existing reports that HER2 genomic amplification and protein overexpression are predominantly found in primary ovarian mucinous carcinomas. Given the perfect concordance between the FISH and dual-colour CISH assays and the advantages of CISH over FISH analysis, future clinical trials investigating the use of anti-HER2 therapeutics in ovarian carcinomas should incorporate dual-colour CISH as part of the HER2 status assessment algorithm.
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Scorilas, Andreas, Carla A. Borgoño, Nadia Harbeck, Julia Dorn, Barbara Schmalfeldt, Manfred Schmitt, and Eleftherios P. Diamandis. "Human Kallikrein 13 Protein in Ovarian Cancer Cytosols: A New Favorable Prognostic Marker." Journal of Clinical Oncology 22, no. 4 (February 15, 2004): 678–85. http://dx.doi.org/10.1200/jco.2004.05.144.
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PurposeHuman kallikrein 13 (hK13; encoded by the KLK13 gene) is a secreted serine protease expressed in endocrine tissues, including the prostate, testis, breast, and ovary. We have previously reported steroid hormone regulation of the KLK13 gene and its clinical value as a marker of favorable prognosis in breast cancer at the mRNA level. We hypothesized that hK13 may represent a potential biomarker for ovarian carcinomas.Patients and MethodsUsing a newly developed enzyme-linked immunosorbent assay (ELISA), hK13 levels were quantified in 131 ovarian tumor extracts and correlated with various clinicopathological variables and outcome (progression-free survival [PFS], overall survival [OS]), over a median follow-up period of 42 months.ResultshK13 concentration in ovarian tumor cytosols ranged from 0 to 18.4 ng/mg of total protein. An optimal cutoff value of 0.13 ng/mg (67thpercentile) was selected, based on the ability of hK13 values to predict the PFS of the study population, to categorize tumors as hK13-positive or negative. Women with hK13-positive tumors most often had early stage (stage I/II) disease, no residual tumor after surgery and optimal debulking success (P < .05). Univariate and multivariate Cox regression analyses revealed that patients with hK13-positive tumors had a significantly longer PFS and OS than hK13-negative patients (P < .05). Kaplan-Meier survival curves further confirmed a reduced risk of relapse and death in women with hK13-positive tumors (P = .007 and P = .002, respectively).ConclusionThese results indicate that hK13 is an independent marker of favorable prognosis in ovarian cancer.
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Fogang, Balotin, Jean C. Djontu, Rosette Megnekou, and Lawrence Ayong. "PO 8289 ASSOCIATION BETWEEN PLASMA LEVELS OF IL-27, IL-6 CYTOKINES AND P. FALCIPARUM INFECTION IN PREGNANT WOMEN LIVING IN MBALMAYO, CAMEROON." BMJ Global Health 4, Suppl 3 (April 2019): A27.1—A27. http://dx.doi.org/10.1136/bmjgh-2019-edc.68.
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BackgroundThe appropriate balance between anti-inflammatory and pro-inflammatory cytokines is necessary for protection against pregnancy-associated malaria and poor pregnancy outcomes. This study therefore aims to investigate the relationship between plasma levels of some regulatory cytokines and P. falciparum infection in Cameroonian women during pregnancy.MethodsPeripheral blood was collected from 131 women during pregnancy and 27 non-pregnant women living in the Mbalmayo area between May and December 2014. Parasitaemia was determined by microscopy and haemoglobin level using a haematological counter. Plasma levels of IL-27 and IL-6 cytokines were measured using the Magnetic Luminex Screening Assay technique.ResultsParasitaemia associated negatively with haemoglobin level (rs=–0.43; p<0.001). The plasma level of IL-6 was higher in pregnant women than in non-pregnant women (p=0.05). Regarding parasitaemia, plasma level of IL-27 was significantly higher in non-infected than in infected women (p=0.028) while that of IL-6 was significantly higher in infected women (p<0.0001). Moreover, parasitaemia correlated negatively with the plasma level of IL-27 (p=0.034) and positively with that of IL-6 (p<0.0001). In addition, level of IL-6 was significantly higher in anaemia-positive than in anaemia-negative women (p=0.028). On the other hand, level of IL-27 negatively associated with the parity (p=0.022) and gestation age (p=0.014).ConclusionThese results show that in pregnant women, P. falciparum malaria infection is associated with high plasma level of IL-6 and low level of IL-27, suggesting that IL-27 could have a protective effect against pregnancy-associated malaria while IL-6 seem to be a potential biomarker of the disease.
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Speziali, M., F. Ceccarelli, F. Natalucci, A. I. Celia, T. Colasanti, C. Barbati, G. Olivieri, et al. "POS0553 NEW BIOMARKERS IN RHEUMATOID ARTHRITIS: ROLE OF HOMOCYSTEINYLATED ANTI-ALPHA1 ANTITRYPSIN ANTIBODIES." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 541.2–541. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3289.
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BackgroundRheumatoid Arthritis (RA) is a multifactorial, chronic, systemic, inflammatory disease that can lead to progressive joint destruction (Alamanos et al, Autoimmun Rev 2005). Positivity for Rheumatoid Factor (RF) and antibodies against citrullinated proteins (ACPA) is useful for diagnostic and prognostic purposes. Nevertheless, in about 20% of patients, it is not possible to detect the presence of these autoantibodies. This has led to the identification of new antibody specificities, such as antibodies directed against carbamylated proteins (Mastrangelo A et al, J Immunol Res 2015) and, more recently, against homocysteinylated alpha 1 antitrypsin (anti-HATA) (Colasanti T et al, J Autoimmun 2020).ObjectivesTo evaluate the prevalence of anti-HATA in a large cohort of patients with RA and their correlation with serological, clinical and erosive bone damage assessed by musculo-skeletal ultrasound (US).MethodsConsecutive outpatients with RA, diagnosed according to the 2010 ACR/EULAR criteria, were enrolled. Demographic and clinical-laboratory data were recorded, including FR and ACPA determination. Disease activity was assessed by DAS28. The presence of anti-HATA antibodies was investigated by homemade ELISA using native alpha 1 antitrypsin modified in vitro to obtain homocysteinylated alpha 1 antitrypsin. US assessment was performed at the level of bilateral metacarpophalangeal and proximal interphalangeal joints; the presence of erosions and inflammatory features was identified according to OMERACT definitions (Wakefield RJ et al, J Rheumatol 2005).ResultsThe present analysis included 91 RA patients (M/F 22/69; mean age 62 years; mean disease duration 12.5 years). Overall, the prevalence of anti-HATA was 69.2%. Anti-HATA antibodies were found in 63/91 (69.2%) of the entire patient cohort, whereas 68/91 (74.3%) patients were positive for ACPA and 63/91 (69.4%) for FR. 41.4% of patients had concomitant positivity for the three autoantibodies (FR, ACPA, anti-HATA). The analysis of patients with triple positivity for related arthritis antibodies (FR, ACPA, anti-HATA) was particularly interesting: indeed, in this subgroup, 80% of patients presented erosive damage, compared to 42.1% of patients who did not present simultaneously the three autoantibodies (p=0.0001). Patients with simultaneous positivity for RF, ACPA and anti-HATA showed a more aggressive disease phenotype (p=0.0001). Finally, a positive correlation was also found between disease activity (expressed by DAS28) and total inflammatory and erosive ultrasonographic score (p=0.005 and p=0.001, respectively).ConclusionThe results of the present study confirm a high prevalence of anti-HATA in RA patients; furthermore, patients with concomitant presence of anti-HATA, ACPA and RF showed a more aggressive disease phenotype, in terms of erosive damage. Our analysis underlines as the characterization of new antibody specificities in RA could help in the early diagnosis of this disease and in the characterization of the different severity degrees.References[1]Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev. 2005 Mar;4(3):130-6.[2]Mastrangelo A, Colasanti T, Barbati C, Pecani A, Sabatinelli D, Pendolino M, Truglia S, Massaro L, Mancini R, Miranda F, Spinelli FR, Conti F, Alessandri C. The Role of Posttranslational Protein Modifications in Rheumatological Diseases: Focus on Rheumatoid Arthritis. J Immunol Res. 2015;2015:712490;[3]Colasanti T, Sabatinelli D, Mancone C, Giorgi A, Pecani A, Spinelli FR, Di Giamberardino A, Navarini L, Speziali M, Vomero M, Barbati C, Perricone C, Ceccarelli F, Finucci A, Celia AI, Currado D, Afeltra A, Schininà ME, Barnaba V, Conti F, Valesini G, Alessandri C. Homocysteinylated alpha 1 antitrypsin as an antigenic target of autoantibodies in seronegative rheumatoid arthritis patients. J Autoimmun. 2020 Sep;113:102470.[4]Wakefield RJ, Balint PV, Szkudlarek M, et al. Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol 2005; 32: 2485-2487.Disclosure of InterestsNone declared.
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Okdahl, Tina, Anne-Marie Wegeberg, Flemming Pociot, Birgitte Brock, Joachim Størling, and Christina Brock. "Low-grade inflammation in type 2 diabetes: a cross-sectional study from a Danish diabetes outpatient clinic." BMJ Open 12, no. 12 (December 2022): e062188. http://dx.doi.org/10.1136/bmjopen-2022-062188.
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ObjectivesTo investigate low-grade inflammation in type 2 diabetes and explore associations to clinical aspects as well as microvascular and macrovascular complications.DesignCross-sectional analysis.SettingThe outpatient diabetes clinic at the Department of Endocrinology at Aalborg University Hospital, Denmark.Participants100 participants with type 2 diabetes confirmed by a haemoglobin A1c (HbA1c)≥6.5% for a minimum of 1 year and 21 healthy controls.Outcome measuresSerum levels of 27 inflammation-related biomarkers measured by immunoassay. Associations with microvascular and macrovascular complications, body weight, glycaemic control, medication and sex were investigated in the diabetes cohort.ResultsSerum levels of tumour necrosis factor (TNF)-α and eotaxin were elevated in type 2 diabetes (p<0.05), while interleukin (IL)-7 was decreased (p<0.001). IL-12/IL-23p40, IL-15, macrophage-derived chemokine (MDC) and C reactive protein (CRP) levels were increased with body weight (p<0.05), while eotaxin and TNF-α were increased with elevated HbA1c levels (p<0.04). Dipeptidyl peptidase-4 inhibitor therapy was associated with lower levels of induced protein-10, MDC and thymus and activation regulated chemokine (p<0.02), while females had higher levels of MDC (p=0.027). Individuals with ≥3 diabetic complications had elevated levels of IL-6, IL-10, IL-12/IL-23p40, IL-15 and CRP compared with those with ≤3 (p<0.05).ConclusionThe level of low-grade inflammation in type 2 diabetes is associated with obesity, glycaemic regulation, therapeutical management, sex and complications. Our results underline the importance of addressing inflammatory issues in type 2 diabetes, as these may predispose for crippling comorbidities.
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Brown, Jacqueline T., Yuan Liu, Julie M. Shabto, Dylan Martini, Deepak Ravindranathan, Emilie Elise Hitron, Greta Anne Russler, et al. "Modified Glasgow Prognostic Score associated with survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors." Journal for ImmunoTherapy of Cancer 9, no. 7 (July 2021): e002851. http://dx.doi.org/10.1136/jitc-2021-002851.
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BackgroundThe modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI.MethodsWe retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP>10 mg/L and/or albumin<3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis.Results156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, p<0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p<0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno’s c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533).ConclusionThe mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.
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Avdeeva, A., Z. Verizhnikova, V. Rybakova, V. Kozlova, T. Popkova, A. Lila, and E. Nasonov. "AB0088 DOUBLE-STRANDED DNA BREAKS ARE A MARKER OF THE INFLAMMATORY ACTIVITY OF RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1175.2–1176. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4462.
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BackgroundDouble-strand DNA breaks (DNA-DSB) are one of the most biologically significant DNA damage lesions that leads to chromosome breakage and/or rearrangement, mutagenesis and loss or gain of genetic information. The phosphorylation of H2AX histone proteins which are located in the vicinity of the DSBs is known as one of the earliest responses to DNA DSBs in cells. Induction of DNA DSBs in live mammalian cells triggers the phosphorylation near the C-terminal of H2AX protein, which results in the phosphorylated form of H2AX, termed yH2AX. [1,2].ObjectivesTo examine DNA-DSB among patients with systemic autoimmune rheumatic diseases (SARDs) by evaluating phosphorylation yH2AX and 53BP1 at the site of injury.MethodsThe analysis included 25 patients with SARDs (19 with RA (16 women, Me;IQR the disease duration 60 (20-103) months, DAS28-ESR 5.05(4.06-5.9)); 4 - with systemic lupus erythematosus (4 women, the disease duration 324 (204-372) months, SLEDAI-2K 9.5 (4.5-16.5) and 2 women with Sjogren’s disease. The control group consisted of 14 healthy donors, comparable in gender and age with the examined patients. DNA-DSB breaks were determined as a discrete focus during immunofluorescence staining with anti-yH2AX and anti-53BP1 antibodies of the lymphocyte culture, followed by analysis on the automated platform AKLIDES (Medipan, Berlin/Dahlewitz, Germany).ResultsThere were no significant differences in the number of DNA breaks among patients with SARDs and healthy donors (p>0.05). There was a positive correlation between % pos. cells by yH2AX and CDAI (r=0.45 p=0.035), Nuclei with foci by 53BP1 and ESR (r=0.53 p=0.02) and IgM RF (r=0.63 p=0.005). Among patients with high CDAI activity (n=10), there was a greater number of Nuclei with foci by yH2AX - (22.5 (6.0-43.0); a higher average number of foci mean (0.39 (0.19-0.62) and a higher % pos. cells (32.6 (18.7-39.1) comparing with patients with low/moderate inflammatory activity (9,0 (2-12); 0,12 (0,02-0,28); 11,5 (1,8-23,5) accordingly, p<0.05, n=9).ConclusionThe evaluation of double-stranded DNA breaks can be beneficial as an additional marker for assessing the disease activity among patients with RA.References[1]Reddig A, Voss L, Guttek K, Roggenbuck D et al. Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage. Clinical Medicine. 2021;1;10(7):1431 DOI: 10.3390/jcm10071431[2]Leifert WR, Siddiqui SM. γH2AX is a biomarker of modulated cytostatic drug resistance. Cytometry A. 2015;87(8):692-5. DOI: 10.1002/cyto.a.22672Disclosure of InterestsNone declared
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Robert, M., L. Lessard, T. Fenouil, A. Hot, T. Laumonier, A. Bouche, B. Chazaud, N. Streichenberger, and L. Gallay. "POS0490 USEFULNESS OF MHC-II IMMUNO-STAINING ON MUSCLE BIOPSIES IN IDIOPATHIC INFLAMMATORY MYOPATHIES." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 499.2–500. http://dx.doi.org/10.1136/annrheumdis-2022-eular.5186.
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BackgroundIdiopathic inflammatory myopathies (IIMs) constitute a group of acquired muscular diseases that occur during childhood and adulthood, exhibit a variety of phenotypes and are potentially life-threatening. IIM diagnosis considers clinical, serological, and histological data. Muscle pathological analysis of IIM patients gives relevant elements for the diagnosis (immune cell infiltrate, vascular and connective tissues, as well as myofiber morphology). Immunochemistry (IHC) labeling for major histocompatibility complex class I (MHC-I), and C5b9, that are negative in normal muscle, appeared of interest in IIM diagnosis and the understanding of IIM pathogenesis. In normal muscle, myofibers are negative for MHC-II IHC. Its interest in the neuropathological exam of IIM muscle remains to be better characterized.ObjectivesThis study aims to analyze the pattern of MHC-II expression in various IIMs.MethodsA historical cohort was designed using the MYOLYON register (IIM patients diagnosed between 2016 and 2020 at the University Hospital of Lyon, France). Inclusion criteria were IIM diagnosis that was established histologically and available frozen muscle samples for additional analyses. Exclusion criterium was any treatment before muscle biopsy. Demographical data and final diagnosis were collected retrospectively from medical records. A centralized, standardized, and blind analysis of muscle MHC-II immuno-staining was conducted to define the various patterns of MHC-II by myofibers and by capillaries. The study complied with ethical requirements.ResultsSeventy-three patients were included: 23 dermatomyositis (DM), 13 anti-synthetase syndrome (ASS), 13 immune-mediated necrotizing myopathies (IMNM), 13 inclusion body myositis (IBM), and 11 overlap myositis (OM). MHC-II immuno-staining of myofibers or capillaries was abnormal for 91.8% of the analyzed biopsies (Figure 1). The analysis of MHC-II myofiber immuno-staining revealed distinguishable patterns according to IIM subtype: the labeling was diffuse in IBM (69.2%, n=9/13), perifascicular in ASS (61.5%, n=8/13), and variable in OM (patchy for 27.3% n=3/11 or clustered for 36.4%, n=4/11). MHC-II immuno-staining was negative in IMNM (84.6%, n=11/13) and in DM (47.8%, n=11/23). DM exhibiting positive MHC-II myofibers (n=12) were associated with the presence of anti-TIF1γ, anti-NXP2 and anti-SAE auto antibodies (n=5, n=3 and n=2, respectively). Among the 12 patients, there were juvenile cases (n=5, 41.7%) or DM associated with ongoing neoplasia (n=4, 33.3%). Three main architectures were described for capillaries: giant, leaky and capillary dropout. Patterns of MHC-II positive capillaries were the following: DM was characterized by capillary dropout (68.2%), IMNM showed leaky capillaries (75.0%), IBM giant capillaries (66.7%), ASS exhibited both giant (61.5%) and/or leaky (58.3%) capillaries, while OM showed giant (63.6%) or/and leaky (80.0%) capillaries and capillaries dropout (60.0%).ConclusionThe present work establishes the usefulness of MHC-II immuno-staining for IIM diagnosis, and gives additional elements on the impairment of myofibers and capillaries in the various IIM subgroups. MHC-II expression is known to be induced by inflammatory cytokine such as interferon type II. This could be linked to myofiber and/or capillary impairment in some IIMs, such as IBM, ASS and OM. These results also support the implication of vasculopathy in IIM pathogenesis, with various structural and cellular consequences regarding the different subgroups. Finally, MHC-II immuno-staining in IIM muscle biopsies enables a foremost analysis of myofibers and capillaries, and represents an additional biomarker to distinguish IIM subgroups.References[1]De Bleecker, J.L. et al. 205th ENMC International Workshop: Pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands. Neuromuscul Disord 2015, 25, 268-272.Disclosure of InterestsNone declared.
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Gao, Yujun, Xin Tong, Jianxiu Hu, Hanjun Huang, Tian Guo, Gang Wang, Yi Li, and Gaohua Wang. "Decreased resting-state neural signal in the left angular gyrus as a potential neuroimaging biomarker of schizophrenia: An amplitude of low-frequency fluctuation and support vector machine analysis." Frontiers in Psychiatry 13 (August 25, 2022). http://dx.doi.org/10.3389/fpsyt.2022.949512.
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ObjectiveSchizophrenia (SCH) is primarily diagnosed based on specific clinical symptoms, with the lack of any objective SCH-related biomarkers often resulting in patient misdiagnosis and the underdiagnosis of this condition. This study was developed to assess the utility of amplitude of low-frequency fluctuation (ALFF) values analyzed via support vector machine (SVM) methods as a means of diagnosing SCH.MethodsIn total, 131 SCH patients and 128 age- and gender-matched healthy control (HC) individuals underwent resting-state functional magnetic resonance imaging (rs-fMRI), with the resultant data then being analyzed using ALFF values and SVM methods.ResultsRelative to HC individuals, patients with SCH exhibited ALFF reductions in the left angular gyrus (AG), fusiform gyrus, anterior cingulate cortex (ACC), right cerebellum, bilateral middle temporal gyrus (MTG), and precuneus (PCu) regions. No SCH patient brain regions exhibited significant increases in ALFF relative to HC individuals. SVM results indicated that reductions in ALFF values in the bilateral PCu can be used to effectively differentiate between SCH patients and HCs with respective accuracy, sensitivity, and specificity values of 73.36, 91.60, and 54.69%.ConclusionThese data indicate that SCH patients may exhibit characteristic reductions in regional brain activity, with decreased ALFF values of the bilateral PCu potentially offering value as a candidate biomarker capable of distinguishing between SCH patients and HCs.
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Li, Yuchen, Keyu Yang, Fang Zhang, Jing Wang, Huijun Shen, Miaomiao Liu, Junhong Guo, and Jie Wang. "Identification of cerebrospinal fluid biomarker candidates for anti-N-methyl-D-aspartate receptor encephalitis: High-throughput proteomic investigation." Frontiers in Immunology 13 (October 26, 2022). http://dx.doi.org/10.3389/fimmu.2022.971659.
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BackgroundAlthough the diagnosis is mainly dependent on the detection of anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in cerebrospinal fluid (CSF) and/or serum, there was no direct correlations between anti-NMDAR antibody titers in CSF and disease severity and prognosis in anti-NMDAR encephalitis patients. Here, we aimed to extensively identify CSF biomarkers related to the occurrence, development, and prognosis of anti-NMDAR encephalitis using a high-throughput proteomic approach.MethodsA CSF cytokine antibody array containing 80 cytokines and inflammatory mediators related to immune and inflammatory responses was applied to identify biomarker candidates in individual CSF samples from a well-characterized cohort comprising patients with anti-NMDAR encephalitis (n = 6) and controls (n = 6). Validation and specific detection were performed in an extended cohort consisting of anti-NMDAR encephalitis patients (n = 13), controls (n = 13), and viral encephalitis (n = 13) by enzyme-linked immunosorbent assay (ELISA). Additionally, the levels of some inflammatory proteins in three groups in cohort 2 reported in previous literatures that may be involved in the development of anti-NMDAR encephalitis were also tested by ELISA. Correlations between candidate biomarkers and clinical characteristics of anti-NMDAR encephalitis patients were analyzed.ResultsThree differentially expressed cytokines and inflammatory mediators were screened from the 80-cytokine array in cohort 1. Functional enrichment analysis results suggested that these differentially expressed proteins were related to autophagy, immune/inflammatory responses, cell death, and other processes. In cohort 2, the elevations of cellular inhibitor of apoptosis protein-1 (cIAP-1), macrophage colony-stimulating factor (MCSF), CXC chemokine ligand 13 (CXCL13), and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) in anti-NMDAR encephalitis were validated by ELISA. Linear regression revealed that the levels of CSF CXCL13 and cIAP-1 were positively correlated with the highest modified Rankin scale (mRS) score in the acute phase (p < 0.05). The level of cIAP-1 was positively correlated with the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score (p < 0.05).ConclusionThese biomarkers show promising functions to evaluate severity or prognosis of anti-NMDAR encephalitis. The biological processes of immune/inflammatory responses, altered levels of autophagy, and the tumor necrosis factor (TNF) signal pathway may be involved in the pathophysiology of anti-NMDAR encephalitis to some extent.
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Morales, Eva, Azahara M. García-Serna, Elvira Larqué, María Sánchez-Campillo, Ana Serrano-Munera, Carmen Martinez-Graciá, Marina Santaella-Pascual, et al. "Dietary Patterns in Pregnancy and Biomarkers of Oxidative Stress in Mothers and Offspring: The NELA Birth Cohort." Frontiers in Nutrition 9 (April 12, 2022). http://dx.doi.org/10.3389/fnut.2022.869357.
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BackgroundAlthough adherence to the Mediterranean and antioxidant-rich diets during pregnancy is suggested to improve maternal-fetal health by reducing oxidative stress, yet there is no study available.ObjectiveWe examined whether maternal dietary patterns in pregnancy impact the biomarkers of oxidative stress in mothers and their offspring.MethodsStudy population included 642 mothers and 335 newborns of the “Nutrition in Early Life and Asthma” (NELA) birth cohort. Maternal diet during pregnancy was assessed by a validated food frequency questionnaire and a priori-defined dietary indices (relative Mediterranean Diet [rMED], alternative Mediterranean Diet [aMED], Dietary Approach to Stop Hypertension [DASH], Alternate Healthy Index [AHEI], and AHEI-2010) were calculated. Biomarkers measured were: hydroperoxides, carbonyl groups, and 8-hydroxydeoxyguanosine (8OHdG) determined in maternal blood and newborn cord blood, and urinary maternal and offspring 15-F2t-isoprostane. Multivariate linear regression models were performed.ResultsMaternal rMED score was inversely associated with the maternal levels of 8OHdG at mid-pregnancy (beta per 1-point increase = −1.61; 95% CI −2.82, −0.39) and the newborn levels of hydroperoxides (beta per 1-point increase = −4.54; 95% CI −9.32, 0.25). High vs. low maternal rMED score was marginally associated with the decreased levels of 8OHdG in newborns (beta = −9.17; 95% CI −19.9, 1.63; p for trend 0.079). Maternal DASH score tended to be inversely associated with maternal urinary 15-F2t-isoprostane (beta per 1-point increase = −0.69; 95% CI, −1.44, 0.06). High vs. low maternal AHEI score was associated with reduced offspring urinary levels of 15-F2t-isoprostane (beta = −20.2; 95% CI −38.0, −2.46; p for trend 0.026).ConclusionThese results suggest that maternal adherence to healthy dietary patterns during pregnancy may reduce DNA damage and lipid oxidation in mothers and offspring.
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Dörner, Thomas, Yoshiya Tanaka, Ernst R. Dow, Alisa E. Koch, Maria Silk, Jorge A. Ross Terres, Jonathan T. Sims, Zhe Sun, Inmaculada de la Torre, and Michelle Petri. "Mechanism of action of baricitinib and identification of biomarkers and key immune pathways in patients with active systemic lupus erythematosus." Annals of the Rheumatic Diseases, May 24, 2022, annrheumdis—2022–222335. http://dx.doi.org/10.1136/annrheumdis-2022-222335.
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ObjectivesTo elucidate the mechanism of action of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, and describe immunological pathways related to disease activity in adults with systemic lupus erythematosus (SLE) receiving standard background therapy in a phase II trial.MethodsPatients with SLE were treated with baricitinib 2 mg or 4 mg in a phase II randomised, placebo-controlled study. Sera from 239 patients (baricitinib 2 mg: n=88; baricitinib 4 mg: n=82; placebo: n=69) and 49 healthy controls (HCs) were collected at baseline and week 12 and analysed using a proximity extension assay (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using an mRNA panel. Analytes were compared in patients with SLE versus HCs and in changes from baseline at week 12 between baricitinib 2 mg, 4 mg and placebo groups using a restricted maximum likelihood-based mixed models for repeated measures. Spearman correlations were computed for analytes and clinical measurements.ResultsAt baseline, SLE sera had strong cytokine dysregulation relative to HC sera. C-C motif chemokine ligand (CCL) 19, C-X-C motif chemokine ligand (CXCL) 10, tumour necrosis factor alpha (TNF-α), TNF receptor superfamily member (TNFRSF)9/CD137, PD-L1, IL-6 and IL-12β were significantly reduced in patients treated with baricitinib 4 mg versus placebo at week 12. Inflammatory biomarkers indicated correlations/associations with type I IFN (CCL19, CXCL10, TNF-α and PD-L1), anti-double stranded DNA (dsDNA) (TNF-α, CXCL10) and Systemic Lupus Erythematosus Disease Activity Index-2000, tender and swollen joint count and worst joint pain (CCL19, IL-6 and TNFRSF9/CD137).ConclusionThese results suggest that baricitinib 4 mg downregulated key cytokines that are upregulated in patients with SLE and may play a role in a multitargeted mechanism beyond the IFN signature although clinical relevance remains to be further delineated.Trial registration numberNCT02708095.
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Huybrechts, Inge, Fernanda Rauber, Geneviève Nicolas, Corinne Casagrande, Nathalie Kliemann, Roland Wedekind, Carine Biessy, et al. "Characterization of the degree of food processing in the European Prospective Investigation into Cancer and Nutrition: Application of the Nova classification and validation using selected biomarkers of food processing." Frontiers in Nutrition 9 (December 16, 2022). http://dx.doi.org/10.3389/fnut.2022.1035580.
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BackgroundEpidemiological studies have demonstrated an association between the degree of food processing in our diet and the risk of various chronic diseases. Much of this evidence is based on the international Nova classification system, which classifies food into four groups based on the type of processing: (1) Unprocessed and minimally processed foods, (2) Processed culinary ingredients, (3) Processed foods, and (4) “Ultra-processed” foods (UPF). The ability of the Nova classification to accurately characterise the degree of food processing across consumption patterns in various European populations has not been investigated so far. Therefore, we applied the Nova coding to data from the European Prospective Investigation into Cancer and Nutrition (EPIC) in order to characterize the degree of food processing in our diet across European populations with diverse cultural and socio-economic backgrounds and to validate this Nova classification through comparison with objective biomarker measurements.MethodsAfter grouping foods in the EPIC dataset according to the Nova classification, a total of 476,768 participants in the EPIC cohort (71.5% women; mean age 51 [standard deviation (SD) 9.93]; median age 52 [percentile (p)25–p75: 58–66] years) were included in the cross-sectional analysis that characterised consumption patterns based on the Nova classification. The consumption of food products classified as different Nova categories were compared to relevant circulating biomarkers denoting food processing, measured in various subsamples (N between 417 and 9,460) within the EPIC cohort via (partial) correlation analyses (unadjusted and adjusted by sex, age, BMI and country). These biomarkers included an industrial transfatty acid (ITFA) isomer (elaidic acid; exogenous fatty acid generated during oil hydrogenation and heating) and urinary 4-methyl syringol sulfate (an indicator for the consumption of smoked food and a component of liquid smoke used in UPF).ResultsContributions of UPF intake to the overall diet in % grams/day varied across countries from 7% (France) to 23% (Norway) and their contributions to overall % energy intake from 16% (Spain and Italy) to >45% (in the UK and Norway). Differences were also found between sociodemographic groups; participants in the highest fourth of UPF consumption tended to be younger, taller, less educated, current smokers, more physically active, have a higher reported intake of energy and lower reported intake of alcohol. The UPF pattern as defined based on the Nova classification (group 4;% kcal/day) was positively associated with blood levels of industrial elaidic acid (r = 0.54) and 4-methyl syringol sulfate (r = 0.43). Associations for the other 3 Nova groups with these food processing biomarkers were either inverse or non-significant (e.g., for unprocessed and minimally processed foods these correlations were –0.07 and –0.37 for elaidic acid and 4-methyl syringol sulfate, respectively).ConclusionThese results, based on a large pan-European cohort, demonstrate sociodemographic and geographical differences in the consumption of UPF. Furthermore, these results suggest that the Nova classification can accurately capture consumption of UPF, reflected by stronger correlations with circulating levels of industrial elaidic acid and a syringol metabolite compared to diets high in minimally processed foods.
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Cai, Min, Ge Dang, Xiaolin Su, Lin Zhu, Xue Shi, Sixuan Che, Xiaoyong Lan, Xiaoguang Luo, and Yi Guo. "Identifying Mild Cognitive Impairment in Parkinson’s Disease With Electroencephalogram Functional Connectivity." Frontiers in Aging Neuroscience 13 (July 1, 2021). http://dx.doi.org/10.3389/fnagi.2021.701499.
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ObjectiveCognitive impairment occurs frequently in Parkinson’s disease (PD) and negatively impacts the patient’s quality of life. However, its pathophysiological mechanism remains unclear, hindering the development of new therapies. Changes in brain connectivity are related to cognitive impairment in patients with PD, with the dorsolateral prefrontal cortex (DLPFC) being considered the essential region related to PD cognitive impairment. Nevertheless, few studies have focused on the global connectivity responsible for communication with the DLPFC node, the posterior division of the middle frontal gyrus (PMFG) in patients with PD; this was the focus of this study.MethodsWe applied resting-state electroencephalography (EEG) and calculated a reliable functional connectivity measurement, the debiased weighted phase lag index (dWPLI), to examine inter-regional functional connectivity in 68 patients with PD who were classified into two groups according to their cognitive condition.ResultsWe observed that altered left and right PMFG-based functional connectivity associated with cognitive impairment in patients with PD in the theta frequency bands under the eyes closed condition (r = −0.426, p < 0.001 and r = −0.437, p < 0.001, respectively). Exploratory results based on the MoCA subdomains indicated that poorer visuospatial function was associated with higher right PMFG-based functional connectivity (r = −0.335, p = 0.005), and poorer attention function was associated with higher left and right PMFG-based functional connectivity (r = −0.380, p = 0.001 and r = −0.256, p = 0.035, respectively). Further analysis using logistic regression and receiver operating characteristic (ROC) curves found that this abnormal functional connectivity was an independent risk factor for cognitive impairment [odds ratio (OR): 2.949, 95% confidence interval (CI): 1.294–6.725, p = 0.01 for left PMFG; OR: 11.278, 95% CI: 2.578–49.335, p = 0.001 for right PMFG, per 0.1 U], and provided moderate classification power to discriminate between cognitive abilities in patients with PD [area under the ROC curve (AUC) = 0.770 for left PMFG; AUC = 0.809 for right PMFG].ConclusionThese preliminary findings indicate that abnormal PMFG-based functional connectivity patterns associated with cognitive impairment in the theta frequency bands under the eyes closed condition and altered functional connectivity patterns have the potential to act as reliable biomarkers for identifying cognitive impairment in patients with PD.
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Yin, Mengting, He Zhang, Qianhui Liu, Fei Ding, Yiping Deng, Lisha Hou, Hui Wang, Jirong Yue, and Yong He. "Diagnostic Performance of Clinical Laboratory Indicators With Sarcopenia: Results From the West China Health and Aging Trend Study." Frontiers in Endocrinology 12 (December 10, 2021). http://dx.doi.org/10.3389/fendo.2021.785045.
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BackgroundSarcopenia is an age-related and skeletal muscle disorder involving the loss of muscle mass or strength, and physiological function. Although the diagnostic indicators used in the different guidelines are for muscle mass, strength and physical performance, there are currently no uniform diagnostic criteria. Therefore, we aimed to explore the relationship between a series of biomarkers with sarcopenia in southwest China.MethodsWe included 4302 patients from West China Health and Aging Trend (WCHAT) study. Sarcopenia was defined according to the Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. Thyroxine、albumin、total protein、prealbumin、albumin to globulin ratio (A/G)、25(OH)VD、fasting insulin、adrenal cortisol、triglyceride、high-density lipoprotein、hemoglobin and aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT) were measured. The receiver operating characteristic curves (ROC) were established to describe the predictive value for sarcopenia and we also used multivariate logistic regression analysis to identify risk factors of the disease.ResultsIn terms of protein state, patients with sarcopenia had lower value in total protein, albumin, prealbumin, A/G than the control (P<0.001). Patients had lower value in triglyceride but higher value in high-density lipoprotein compared with the healthy in the indicators of lipid metabolism (P<0.001). In the aspect of hormone state, patients had lower free triiodothyronine, fasting insulin but higher free tetraiodothyronine and adrenal cortisol than the healthy (P<0.001). The fasting insulin level (AUC=0.686) and the AST/ALT ratio (AUC=0.682) were the best predictors of sarcopenia among biomarkers. The diagnostic performance of fasting insulin combined with the AST/ALT ratio (AUC=0.720) is equal to multiple indicators (AUC=0.742).ConclusionThe fasting insulin combined with the AST/ALT ratio exhibits good diagnostic performance for sarcopenia.
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Gao, Yujun, Xinfu Zhao, JiChao Huang, Sanwang Wang, Xuan Chen, Mingzhe Li, Fengjiao Sun, Gaohua Wang, and Yi Zhong. "Abnormal regional homogeneity in right caudate as a potential neuroimaging biomarker for mild cognitive impairment: A resting-state fMRI study and support vector machine analysis." Frontiers in Aging Neuroscience 14 (September 1, 2022). http://dx.doi.org/10.3389/fnagi.2022.979183.
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ObjectiveMild cognitive impairment (MCI) is a heterogeneous syndrome characterized by cognitive impairment on neurocognitive tests but accompanied by relatively intact daily activities. Due to high variation and no objective methods for diagnosing and treating MCI, guidance on neuroimaging is needed. The study has explored the neuroimaging biomarkers using the support vector machine (SVM) method to predict MCI.MethodsIn total, 53 patients with MCI and 68 healthy controls were involved in scanning resting-state functional magnetic resonance imaging (rs-fMRI). Neurocognitive testing and Structured Clinical Interview, such as Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) test, Activity of Daily Living (ADL) Scale, Hachinski Ischemic Score (HIS), Clinical Dementia Rating (CDR), Montreal Cognitive Assessment (MoCA), and Hamilton Rating Scale for Depression (HRSD), were utilized to assess participants' cognitive state. Neuroimaging data were analyzed with the regional homogeneity (ReHo) and SVM methods.ResultsCompared with healthy comparisons (HCs), ReHo of patients with MCI was decreased in the right caudate. In addition, the SVM classification achieved an overall accuracy of 68.6%, sensitivity of 62.26%, and specificity of 58.82%.ConclusionThe results suggest that abnormal neural activity in the right cerebrum may play a vital role in the pathophysiological process of MCI. Moreover, the ReHo in the right caudate may serve as a neuroimaging biomarker for MCI, which can provide objective guidance on diagnosing and managing MCI in the future.
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Hu, Xiaoxin, Jianwen Li, Yinan Sun, Yiqun Sun, and Tong Tong. "Percentage of Tumor Invasion at Pretreatment High-Resolution Magnetic Resonance Imaging: Associating With Aggressive and Tumor Response in Chinese T3 Rectal Cancer-Preliminary Results." Frontiers in Oncology 12 (April 7, 2022). http://dx.doi.org/10.3389/fonc.2022.616310.
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PurposeThe purpose of the study was to assess the ability of percentage of tumor invasion (PTI) of T3 rectal cancer on pretreatment MRI as an imaging biomarker to reflect aggressiveness and to predict tumor response after neoadjuvant chemoradiation (NCRT) in Chinese population.MethodsA total of 107 Chinese rectal cancer patients who underwent pretreatment MRI staging as T3 were included. The extramural depth of tumor invasion (EMD), the distance between outer border of muscularis propria (MP) and mesorectal fascia (MRF) we called “thickness of the mesorectum (TM)”) at the same slice and direction were measured at pretreatment MRI, and PTI was equal to EMD/TM, was calculated. The EMD and PTI of subgroups based on pretreatment CEA, CA19-9 levels; N category and pathological complete response (pCR) were compared. The parameters, which described tumor invasion, were compared between pCR and non-pCR group. Student t-tests and logistic analysis were applied.ResultsThe pretreatment PTI was higher in CEA ≥5.2 ng/ml patients (58.52% ± 27.68%) than in CEA <5.2 ng/ml patients (47.27% ± 24.15%) (p = 0.034). The pretreatment EMD in non-pCR group (7.21 ± 2.85 mm) was higher than in pCR group (6.14 ± 3.56 mm) (p = 0.049). The pretreatment PTI in non-pCR group (57.4% ± 26.4%) was higher than in pCR group (47.3% ± 29.1%) (p = 0.041). Compared with patients with PTI ≥50%, MRF (+), more patients with PTI <50%, MRF (−) showed pCR (OR = 8.44, p = 0.005; OR = 6.32, p = 0.024).ConclusionThe PTI obtained at pretreatment MRI may serve as an imaging biomarker to reflect tumor aggressiveness and predict which T3 rectal cancer patients may benefit from NCRT in Chinese population.
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Huang, Chunyan, Yang Zhou, Yi Zhong, Xi Wang, and Yunhua Zhang. "The Bilateral Precuneus as a Potential Neuroimaging Biomarker for Right Temporal Lobe Epilepsy: A Support Vector Machine Analysis." Frontiers in Psychiatry 13 (June 15, 2022). http://dx.doi.org/10.3389/fpsyt.2022.923583.
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Background and ObjectiveWhile evidence has demonstrated that the default-mode network (DMN) plays a key role in the broad-scale cognitive problems that occur in right temporal lobe epilepsy (rTLE), little is known about alterations in the network homogeneity (NH) of the DMN in TLE. In this study, we used the NH method to investigate the NH of the DMN in TLE at rest, and an support vector machine (SVM) method for the diagnosis of rTLE.MethodsA total of 43 rTLE cases and 42 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were analyzed with the NH and SVM methods.ResultsrTLE patients have a decreased NH in the right inferior temporal gyrus (ITG) and left middle temporal gyrus (MTG), but increased NH in the bilateral precuneus (PCu) and right inferior parietal lobe (IPL), compared with HCs. We found that rTLE had a longer performance reaction time (RT). No significant correlation was found between abnormal NH values and clinical variables of the patients. The SVM results showed that increased NH in the bilateral PCu as a diagnostic biomarker distinguished rTLE from HCs with an accuracy of 74.12% (63/85), a sensitivity 72.01% (31/43), and a specificity 72.81% (31/42).ConclusionThese findings suggest that abnormal NH of the DMN exists in rTLE, and highlights the significance of the DMN in the pathophysiology of cognitive problems occurring in rTLE, and the bilateral PCu as a neuroimaging diagnostic biomarker for rTLE.
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Li, Shushan, Haitao Wang, Yi Zhang, Renqiu Qiao, Peige Xia, Zhiheng Kong, Hongbo Zhao, and Li Yin. "COL3A1 and MMP9 Serve as Potential Diagnostic Biomarkers of Osteoarthritis and Are Associated With Immune Cell Infiltration." Frontiers in Genetics 12 (August 27, 2021). http://dx.doi.org/10.3389/fgene.2021.721258.
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BackgroundOsteoarthritis (OA) is one of the most common age-related degenerative diseases. In recent years, some studies have shown that pathological changes in the synovial membrane occur earlier than those in the cartilage in OA. However, the molecular mechanism of synovitis in the pathological process of OA has not been elucidated. This study aimed to identify novel biomarkers associated with OA and to emphasize the role of immune cells in the pathogenesis of OA.MethodsMicroarray datasets were obtained from the Gene Expression Omnibus (GEO) and ArrayExpress databases and were then analyzed using R software. To determine differential immune cell subtype infiltration, the CIBERSORT deconvolution algorithm was used. Quantitative reverse transcription PCR (qRT-PCR) was used to determine the relative expressions of selected genes. Besides, Western blotting was used to assess the protein expression levels in osteoarthritic chondrocytes.ResultsAfter analyzing the database profiles, two potential biomarkers, collagen type 3 alpha 1 chain (COL3A1), and matrix metalloproteinase 9 (MMP9), associated with OA were discovered, which were confirmed by qRT-PCR and Western blotting. Specifically, the results revealed that, as the concentration of IL-1β increased, so did the gene and protein expression levels of COL3A1 and MMP9.ConclusionThe findings provide valuable information and direction for future research into novel targets for OA immunotherapy and diagnosis and aids in the discovery of the underlying biological mechanisms of OA pathogenesis.
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Bi, Zhao, Peng-Fei Qiu, Yue Zhang, Xing-Guo Song, Peng Chen, Li Xie, Yong-Sheng Wang, and Xian-Rang Song. "A Three lncRNA Set: AC009975.1, POTEH-AS1 and AL390243.1 as Nodal Efficacy Biomarker of Neoadjuvant Therapy for HER-2 Positive Breast Cancer." Frontiers in Oncology 11 (December 6, 2021). http://dx.doi.org/10.3389/fonc.2021.779140.
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PurposeThe study aimed to explore whether the expression of lncRNAs in primary tumors could predict nodal efficacy after neoadjuvant therapy (NAT) for HER2+ breast cancer.MethodsTotal RNA was extracted from HER2+ breast cancer tissues before NAT (n=103) and from 48 pairs of cancers and para-cancers tissues that did not receive NAT. Different lncRNAs were selected by microarray, validated by qPCR, and analyzed to illuminate their potential as nodal efficacy biomarkers after NAT.ResultsOur results demonstrated that three lncRNA sets, lncRNA-AL390243.1, POTEH-AS1, and lncRNA-AC009975.1, were up-regulated in non-apCR tissues. The AUC value was 0.789 (95%CI: 0.703-0.876). The multivariate logistic regression analysis identified the expression of lncRNA-AL390243.1 (OR 5.143; 95% CI: 1.570-16.847), tumor type (OR 0.144; 95% CI: 0.024-0.855), and nodal stage (OR 0.507; 95% CI: 0.289-0.888) as independent predictors for apCR after NAT in HER2+ patients (all p<0.05). Then the three predictors were used to create a predictive nomogram. The AUC value was 0.859 (95%CI: 0.790-0.929). The calibration curve showed a satisfactory fit between predictive and actual observation based on internal validation with a bootstrap resampling frequency of 1000. Patients with higher expression of lncRNA-AL390243.1 had worse survival. LncRNA-AL390243.1 was up-regulated more in the nodal positive subgroup than in the nodal negative subgroup (p=0.0271).ConclusionThe lncRNA-AL390243.1, POTEH-AS1, and lncRNA-AC009975.1 were upregulated in non-apCR breast cancer tissues. These three lncRNAs might have the potential to be used as predictive biomarkers of nodal efficacy of HER2+ breast cancer. Further studies are required to illuminate the underlying molecular mechanisms further.
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Huang, Xiaoming, Fenglin Zhang, Dong He, Xiaoshuai Ji, Jiajia Gao, Wenqing Liu, Yunda Wang, Qian Liu, and Tao Xin. "Immune-Related Gene SERPINE1 Is a Novel Biomarker for Diffuse Lower-Grade Gliomas via Large-Scale Analysis." Frontiers in Oncology 11 (May 20, 2021). http://dx.doi.org/10.3389/fonc.2021.646060.
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BackgroundGlioma is one of the highly fatal primary tumors in the central nervous system. As a major component of tumor microenvironment (TME), immune cell has been proved to play a critical role in the progression and prognosis of the diffuse lower-grade gliomas (LGGs). This study aims to screen the key immune-related factors of LGGs by investigating the TCGA database.MethodsThe RNA-sequencing data of 508 LGG patients were downloaded in the TCGA database. ESTIMATE algorithm was utilized to calculate the stromal, immune, and ESTIMATE scores, based on which, the differentially expressed genes (DEGs) were analyzed by using “limma” package. Cox regression analysis and the cytoHubba plugin of Cytoscape software were subsequently applied to screen the survival-related genes and hub genes, the intersection of which led to the identification of SERPINE1 that played key roles in the LGGs. The expression patterns, clinical features, and regulatory mechanisms of SERPINE1 in the LGGs were further analyzed by data mining of the TCGA database. What’s more, the above analyses of SERPINE1 were further validated in the LGG cohort from the CGGA database.ResultWe found that stromal and immune cell infiltrations were strongly related to the prognosis and malignancy of the LGGs. A total of 54 survival-related genes and 46 hub genes were screened out in the DEGs, within which SERPINE1 was identified to be significantly overexpressed in the LGG samples compared with the normal tissues. Moreover, the upregulation of SERPINE1 was more pronounced in the gliomas of WHO grade III and IDH wild type, and its expression was correlated with poor prognosis in the LGG patients. The independent prognostic value of SERPINE1 in the LGG patients was also confirmed by Cox regression analysis. In terms of the functions of SERPINE1, the results of enrichment analysis indicated that SERPINE1 was mainly enriched in the immune‐related biological processes and signaling pathways. Furthermore, it was closely associated with infiltrations of immune cells in the LGG microenvironment and acted synergistically with PD1, PD-L1, PD-L2.ConclusionThese findings proved that SERPINE1 could serve as a prognostic biomarker and potential immunotherapy target of LGGs.
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Yang, Aimin, Wilson Adrian Wijaya, Lei Yang, Yinhai He, Ying Cen, and Junjie Chen. "The impact of merkel cell polyomavirus positivity on prognosis of merkel cell carcinoma: A systematic review and meta-analysis." Frontiers in Oncology 12 (September 30, 2022). http://dx.doi.org/10.3389/fonc.2022.1020805.
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IntroductionThere are numerous findings over the past decade have indicated that Merkel cell carcinoma (MCC) may have two pathways of pathogenesis: one related to ultraviolet irradiation and the other to the Merkel cell polyomavirus (MCPyV). However, the predictive and clinicopathological value of MCPyV positivity in MCC patients is still debatable. This article aims to examine the most recent data regarding this issue.MethodsThe thorough literature searches were conducted in the Medline Ovid, PubMed, Web of Science, the Cochrane CENTRAL Databases, and Embase Databases until December 31, 2021. The associations between overall survival (OS), Merkel cell carcinoma-specific survival (MSS), recurrence-free survival (RFS), progression-free survival (PFS), clinicopathologic features, and MCPyV positivity were examined in our meta-analysis.ResultsThis meta-analysis included a total of 14 studies involving 1595 patients. Our findings demonstrated a significant correlation between MCPyV positivity and improved OS (HR=0.61, 95%CI:0.39-0.94, P=0.026) and improved PFS (HR=0.61, 95% CI: 0.45-0.83, P=0.002). MCPyV positivity did not, however, appear to be associated with either MSS (HR=0.61, 95%CI: 0.28-1.32, P=0.209) or RFS (HR= 0.93, 95%CI: 0.37-2.34, P=0.873). Pooled results revealed a correlation between MCPyV positivity with gender (male vs. female, OR=0.606, 95%CI: 0.449-0.817, P=0.001), histopathological stage (AJCC I-II vs. III-IV, OR=1.636, 95%CI: 1.126-2.378, P=0.010) and primary site (head and neck vs. other sites, OR=0.409, 95%CI: 0.221-0.757, P=0.004).ConclusionThese results imply that MCPyV positivity may present a promising predictive biomarker for human MCC and call for further study.
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Yuan, Jinghong, Zhao Yuan, Aifang Ye, Tianlong Wu, Jingyu Jia, Jia Guo, Jian Zhang, Tao Li, and Xigao Cheng. "Low GNG12 Expression Predicts Adverse Outcomes: A Potential Therapeutic Target for Osteosarcoma." Frontiers in Immunology 12 (October 6, 2021). http://dx.doi.org/10.3389/fimmu.2021.758845.
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BackgroundG protein subunit gamma 12 (GNG12) is observed in some types of cancer, but its role in osteosarcoma is unknown. This study hypothesized that GNG12 may be a potential biomarker and therapeutic target. We aimed to identify an association between GNG12 and osteosarcoma based on the Gene Expression Omnibus and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases.MethodsOsteosarcoma samples in GSE42352 and TARGET database were selected as the test cohorts. As the external validation cohort, 78 osteosarcoma specimens from The Second Affiliated Hospital of Nanchang University were collected. Patients with osteosarcoma were divided into high and low GNG12 mRNA-expression groups; differentially expressed genes were identified as GNG12-related genes. The biological function of GNG12 was annotated using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis, and immune infiltration analysis. Gene expression correlation analysis and competing endogenous RNA regulatory network construction were used to determine potential biological regulatory relationships of GNG12. Overall survival, Kaplan–Meier analysis, and log-rank tests were calculated to determine GNG12 reliability in predicting survival prognosis.ResultsGNG12 expression decreased in osteosarcoma samples. GNG12 was a highly effective biomarker for osteosarcoma [area under the receiver operating characteristic (ROC) curve (AUC) = 0.920], and the results of our Kaplan–Meier analysis indicated that overall survival and progression-free survival differed significantly between low and high GNG-expression group (p < 0.05). Functional analyses indicated that GNG12 may promote osteosarcoma through regulating the endoplasmic reticulum. Expression correlation analysis and competing endogenous RNA network construction showed that HOTTIP/miR-27a-3p may regulate GNG12 expression. Furthermore, the subunit suppresses adaptive immunity via inhibiting M1 and M2 macrophage infiltration. GNG12 was inhibited in metastatic osteosarcoma compared with non-metastatic osteosarcoma, and its expression predicted survival of patients (1, 3, and 5-year AUCs were 0.961, 0.826, and 0.808, respectively).ConclusionThis study identified GNG12 as a potential biomarker for osteosarcoma prognosis, highlighting its potential as an immunotherapy target.
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Ma, Aiping, Liang Zhang, Xiaokai Ye, Jing Chen, Jie Yu, Liangjin Zhuang, Chaohang Weng, Frank Petersen, Zhanxiang Wang, and Xinhua Yu. "High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19." Frontiers in Immunology 12 (January 29, 2021). http://dx.doi.org/10.3389/fimmu.2021.626235.
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ObjectivesThe coordinated immune response of the host is the key of the successful combat of the body against SARS-CoV-2 infection and is decisive for the development and progression of COVID-19. In this study, we aimed to investigate whether the immunological phenotype of patients are associated with duration of illness in patients with severe COVID-19.MethodIn this single-center study, 69 patients with severe or critical COVID-19 were recruited retrospectively. Immunological parameters including counts of white blood cells, neutrophils, lymphocytes, the neutrophil-to-lymphocyte ratio, and levels of circulating cytokines and cytokine receptors were screened for their association with disease severity, survival and duration of illness of COVID-19.ResultsOur data confirmed previous results that neutrophil-to-lymphocyte ratio and circulating levels of IL-6 represent prominent biomarker for the prediction of disease severity and survival of COVID-19. However, this study shows for the first time that duration of illness in patients with severe COVID-19 is positively associated with serum levels of IL-8 (P=0.004) and soluble IL-2Rα (P=0.025).ConclusionThe significant association of duration of illness with circulating levels of IL-8 and soluble IL-2Rα in patients with severe COVID-19 implicates that neutrophils and T cells are involved in the evolution of COVID-19.
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Shao, Guangyu, Patricia Hawle, Kaveh Akbari, Andreas Horner, Rainer Hintenberger, Bernhard Kaiser, Bernd Lamprecht, and David Lang. "Clinical, imaging, and blood biomarkers to assess 1-year progression risk in fibrotic interstitial lung diseases—Development and validation of the honeycombing, traction bronchiectasis, and monocyte (HTM)-score." Frontiers in Medicine 9 (November 16, 2022). http://dx.doi.org/10.3389/fmed.2022.1043720.
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IntroductionProgression of fibrotic interstitial lung disease (ILD) leads to irreversible loss of lung function and increased mortality. Based on an institutional ILD registry, we aimed to evaluate biomarkers derived from baseline patient characteristics, computed tomography (CT), and peripheral blood for prognosis of disease progression in fibrotic ILD patients.MethodsOf 209 subsequent ILD-board patients enregistered, 142 had complete follow-up information and were classified fibrotic ILD as defined by presence of reticulation or honeycombing using a standardized semi-quantitative CT evaluation, adding up typical ILD findings in 0–6 defined lung fields. Progression at 1 year was defined as relative loss of ≥10% in forced vital capacity, of ≥15% in diffusion capacity for carbon monoxide, death, or lung transplant. Two-thirds of the patients were randomly assigned to a derivation cohort evaluated for the impact of age, sex, baseline lung function, CT finding scores, and blood biomarkers on disease progression. Significant variables were included into a regression model, its results were used to derive a progression-risk score which was then applied to the validation cohort.ResultsIn the derivation cohort, age, monocyte count ≥0.65 G/L, honeycombing and traction bronchiectasis extent had significant impact. Multivariate analyses revealed the variables monocyte count ≥0.65 G/L (1 point) and combined honeycombing or traction bronchiectasis score [0 vs. 1–4 (1 point) vs. 5–6 lung fields (2 points)] as significant, so these were used for score development. In the derivation cohort, resulting scores of 0, 1, 2, and 3 accounted for 1-year progression rates of 20, 25, 46.9, and 88.9%, respectively. Similarly, in the validation cohort, progression at 1 year occurred in 0, 23.8, 53.9, and 62.5%, respectively. A score ≥2 showed 70.6% sensitivity and 67.9% specificity, receiver operating characteristic analysis for the scoring model had an area under the curve of 71.7%.ConclusionThe extent of honeycombing and traction bronchiectasis, as well as elevated blood monocyte count predicted progression within 1 year in fibrotic ILD patients.
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Zhou, Qian, Chuyi Han, Yanmei Wang, Shunlian Fu, Yiding Chen, and Qiu Chen. "The Effect of Chinese Medicinal Formulas on Biomarkers of Oxidative Stress in STZ-Induced Diabetic Kidney Disease Rats: A Meta-Analysis and Systematic Review." Frontiers in Medicine 9 (April 15, 2022). http://dx.doi.org/10.3389/fmed.2022.848432.
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BackgroundDiabetic kidney disease (DKD), defined broadly as persistent proteinuria with low estimated glomerular filtration rate in patients with diabetes, is a main cause of end-stage renal disease. Excessive production of reactive oxygen species is an important mechanism underlying the pathogenesis of DKD and many antioxidants have been investigated as therapeutic agents. Among them, Chinese medicine antioxidative stress therapies have been widely used to combat DKD, which may offer new insights into therapeutic development of DKD. There are several discrepancies among the efficacy of Western medicine (WM) and Chinese medicinal formula (CMF) action.MethodsWe searched PubMed, Cochrane Library, the Web of Science databases, Embase, and Scopus from inception to December 2021 using relevant keywords and a comprehensive search for randomized controlled trials (RCTs) was performed. Calculating the pooled weighted mean difference (MD) and 95% CI by the method of inverse-variance with a random-effect. All the related statistical analyses were performed using Stata version 15.1 software (Stata Corporation) and Rvman version 5.3 (Nordic Cochrane Center).ResultsA total of 8 articles with the 9 groups including 106 in the model group, 105 in the CMF group, and 99 in the WM group. Pooled data from 8 studies (9 groups) showed a statistical improvement in superoxide dismutase compared with the model group [standardized MD (SMD) = 1.57; 95 CI: 1.16–1.98; P < 0.05] and the WM group (SMD = 0.56; 95 CI: 0.19–0.92; P < 0.05). For glutathione peroxidase (GSH-Px), it was significantly improved in the CMF group vs. the model group and the WM group. For malondialdehyde (MDA), it was significantly reduced in the CMF group (CMF vs. model group: SMD = −1.52; 95 CI: −1.88 −1.17; P < 0.05; CMF vs. WM group: SMD = −0.64; 95 CI: −0.95 −0.33; P < 0.05).ConclusionThis systematic review and meta-analysis have demonstrated that the therapy of CMF had a notable curative effect on relieving oxidative stress in STZ-induced DKD rats and CMF was significantly more effective than the WM control group. For the clinical application, the results providing confidence and some theoretical reference for DKD via evaluating the efficacy of CMF to a certain extent.Systematic Review Registration[PROSPERO], identifier [CRD42022313737].
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Lin, Renzhao, Chanping Zhi, Yalin Su, Jiaxin Chen, Debao Gao, Sihan Li, and Dayou Shi. "Effect of Echinacea on gut microbiota of immunosuppressed ducks." Frontiers in Microbiology 13 (January 5, 2023). http://dx.doi.org/10.3389/fmicb.2022.1091116.
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IntroductionImmunosuppression puts animals in a susceptible state and disrupts the balance of intestinal flora, which can increase the risk of disease and cause serious harm to the farm. Echinacea can exert its immunomodulatory effect in various ways, but its influence on intestinal flora is unclear.MethodsTherefore, we investigated the effect of Echinacea extract (EE) on gut microbiota in immunosuppressed ducks by 16s-RNA sequencing in this experiment.ResultsThe results showed that EE significantly improved the weight gain of immunosuppressed ducks (p<0.001). It also increased the immune organ index (p<0.01) and upregulated the levels of TNF-α and IFN-γ (p<0.05) as well as IL-2 in the serum. The lesions of the bursa were evident compared to the spleen and thymus. After treatment in the EE group, the lymphocyte count of the bursa returned to healthy levels and the lesions were significantly improved. The diversity analysis showed that neither of the alpha-diversity indices showed a significant difference (p>0.05). However, the EE group had a trend closer to the healthy group compared to the M group. β-diversity analysis revealed a high degree of sample separation between the healthy and immunosuppressed groups. The sequencing result showed a significantly higher relative abundance of Prevotella and Prevotella_UCG_001 in the dexamethasone-treated group, which could be potential biomarkers of dexamethasone-induced immunosuppression. EE increased the relative abundance of Akkermansia, Bacteroides, and Alistipes and significantly decreased the relative abundance of Megamonas, Streptococcus, and Enterococcus (p<0.05).ConclusionThe results showed that Echinacea extract improves the development of immunosuppressed ducks and modulates intestinal immune function by increasing the abundance of beneficial bacterial genera in the intestine.
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Overbeek, Kasper A., Iris J. M. Levink, Brechtje D. M. Koopmann, Femme Harinck, Ingrid C. A. W. Konings, Margreet G. E. M. Ausems, Anja Wagner, et al. "Long-term yield of pancreatic cancer surveillance in high-risk individuals." Gut, April 5, 2021, gutjnl—2020–323611. http://dx.doi.org/10.1136/gutjnl-2020-323611.
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ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.Results366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1–32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).ConclusionThe diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.
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Chen, Qiuni, Yue Chen, Yijing Zhang, Lijuan Zhang, Kankan Chen, Zhengmei He, Chunling Wang, and Liang Yu. "Prognostic Impact of Platelet-Large Cell Ratio In Myelodysplastic Syndromes." Frontiers in Oncology 12 (April 1, 2022). http://dx.doi.org/10.3389/fonc.2022.846044.
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BackgroundMyelodysplastic syndromes (MDSs) are a very heterogeneous group of myeloid disorders with high prevalence and risk of developing acute myeloid leukemia. The more accurate risk stratification can provide a better guidance of treatment. The platelet–large cell ratio (P-LCR) is a parameter reported in complete blood cell count tests, and was associated with many diseases, but its role in MDS is not clear.PurposeThis study aims to explore the impact of the P-LCR on the prognosis of patients with MDS, which is of great significance for clinical treatment.MethodsIn the retrospective study, 122 newly diagnosed MDS patients were enrolled. We used the bioinformatics tool X-tile to define a P-LCR threshold of 36.7% to predict prognosis. Patients were divided into P-LCRlow and P-LCRhigh groups, and their characteristics were compared between the two groups.ResultsResults show that the P-LCRlow was associated with worse overall survival (OS) than the P-LCRhigh patients (median OS, 18.53 months versus 25.77 months, p=0.0057), but there were no statistical differences in progression-free survival (PFS) between the two groups (p=0.2001). The results of univariate and multivariate Cox proportional hazard analyses adjusted for gender, bone marrow blast level, platelet count, and International Prognostic Scoring System scores showed that the P-LCR was useful in the evaluation of PFS [hazard ratio (HR) 0.212, 95%CI 0.064–0.702, p=0.011] and OS of MDS (HR 0.464, 95%CI 0.284–0.757, p=0.002).ConclusionThis study is the first report showing that the P-LCR would be a simple and immediately available biomarker for predicting the prognosis of MDS.
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Olwenyi, Omalla A., Samuel D. Johnson, Mehdi Bidokhti, Vandana Thakur, Kabita Pandey, Michellie Thurman, Arpan Acharya, et al. "Systems biology analyses reveal enhanced chronic morphine distortion of gut-brain interrelationships in simian human immunodeficiency virus infected rhesus macaques." Frontiers in Neuroscience 16 (October 13, 2022). http://dx.doi.org/10.3389/fnins.2022.1001544.
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BackgroundCommonly used opioids, such as morphine have been implicated in augmented SIV/HIV persistence within the central nervous system (CNS). However, the extent of myeloid cell polarization and viral persistence in different brain regions remains unclear. Additionally, the additive effects of morphine on SIV/HIV dysregulation of gut-brain crosstalk remain underexplored. Therefore, studies focused on understanding how drugs of abuse such as morphine affect immune dynamics, viral persistence and gut-brain interrelationships are warranted.Materials and methodsFor a total of 9 weeks, rhesus macaques were ramped-up, and twice daily injections of either morphine (n = 4) or saline (n = 4) administered. This was later followed with infection with SHIVAD8EO variants. At necropsy, mononuclear cells were isolated from diverse brain [frontal lobe, cerebellum, medulla, putamen, hippocampus (HIP) and subventricular zone (SVZ)] and gut [lamina propria (LP) and muscularis (MUSC) of ascending colon, duodenum, and ileum] regions. Multiparametric flow cytometry was used to were profile for myeloid cell polarity/activation and results corroborated with indirect immunofluorescence assays. Simian human immunodeficiency virus (SHIV) DNA levels were measured with aid of the digital droplet polymerase chain reaction (PCR) assay. Luminex assays were then used to evaluate soluble plasma/CSF biomarker levels. Finally, changes in the fecal microbiome were evaluated using 16S rRNA on the Illumina NovaSeq platform.ResultsFlow Cytometry-based semi-supervised analysis revealed that morphine exposure led to exacerbated M1 (CD14/CD16)/M2 (CD163/CD206) polarization in activated microglia that spanned across diverse brain regions. This was accompanied by elevated SHIV DNA within the sites of neurogenesis–HIP and SVZ. HIP/SVZ CD16+ activated microglia positively correlated with SHIV DNA levels in the brain (r = 0.548, p = 0.042). Simultaneously, morphine dependence depleted butyrate-producing bacteria, including Ruminococcus (p = 0.05), Lachnospira (p = 0.068) genera and Roseburia_sp_831b (p = 0.068). Finally, morphine also altered the regulation of CNS inflammation by reducing the levels of IL1 Receptor antagonist (IL1Ra).ConclusionThese findings are suggestive that morphine promotes CNS inflammation by altering receptor modulation, increasing myeloid brain activation, distorting gut-brain crosstalk, and causing selective enhancement of SHIV persistence in sites of neurogenesis.
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Li, Mingkang, Linqing Li, Yuhan Qin, Erfei Luo, Dong Wang, Yong Qiao, Chengchun Tang, and Gaoliang Yan. "Elevated TyG Index Predicts Incidence of Contrast-Induced Nephropathy: A Retrospective Cohort Study in NSTE-ACS Patients Implanted With DESs." Frontiers in Endocrinology 13 (February 22, 2022). http://dx.doi.org/10.3389/fendo.2022.817176.
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BackgroundTriglyceride-glucose (TyG) index is a reliable and specific biomarker for insulin resistance and is associated with renal dysfunction. The present study sought to explore the relationship between TyG index and the incidence of contrast-induced nephropathy (CIN) in non-ST elevation acute coronary syndrome (NSTE-ACS) patients implanted with drug-eluting stents (DESs).MethodsA total of 1108 participants were recruited to the study and assigned to two groups based on occurrence of CIN. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Baseline characteristics and incidence of CIN were compared between the two groups. Logistic regression analysis was performed to evaluate the relationship between TyG index and CIN.ResultsThe results showed that 167 participants (15.1%) developed CIN. Subjects in the CIN group had a significantly higher TyG index compared with subjects in the non-CIN group (8.9 ± 0.7 vs. 9.3 ± 0.7, P<0.001). TyG index was significantly correlated with increased risk of CIN after adjusting for confounding factors irrespective of diabetes mellitus status and exhibited a J-shaped non-linear association. Subgroup analysis showed a significant gender difference in the relationship between TyG index and CIN. Receiver operating characteristic (ROC) curve analysis indicated that the risk assessment performance of TyG index was superior compared with other single metabolic indexes. Addition of TyG index to the baseline model increased the area under the curve from 0.713 (0.672-0.754) to 0.742 (0.702-0.782) and caused a reclassification improvement of 0.120 (0.092-0.149).ConclusionThe findings from the present study show that a high TyG index is significantly and independently associated with incidence of CIN in NSTE-ACS patients firstly implanted with DESs. Routine preoperative assessment of TyG index can alleviate CIN and TyG index provides a potential target for intervention in prevention of CIN.
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Scherrer, Emilie, Ashley Kang, Lisa M. Bloudek, and Vadim S. Koshkin. "HER2 expression in urothelial carcinoma, a systematic literature review." Frontiers in Oncology 12 (October 21, 2022). http://dx.doi.org/10.3389/fonc.2022.1011885.
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BackgroundUrothelial carcinoma (UC) is a common malignancy with significant associated mortality. Recent clinical trials suggest an emerging role for HER2-targeted therapy. Testing for HER2 expression in UC is not part of current routine clinical practice. In consequence, the prevalence of HER2 expression in UC is not well defined.MethodsA systematic literature review (SLR) was conducted to characterize HER2 expression in both locally advanced unresectable or metastatic (LA/mUC) and earlier stage UC, classified as HER2+, HER2-low, HER2-. HER2+ was defined as an immunohistochemistry (IHC) score of 3+ or IHC 2+ and ISH/FISH+. HER2-low was defined as an IHC score of 2+ and ISH/FISH- or IHC 1+. HER2- was defined as an IHC score of 0. Weighted averages were calculated to generate an estimate of the population prevalence.ResultsA total of 88 studies were identified, with 45, 30, and 13 studies investigating LA/mUC, earlier stage UC, and mixed stage/unspecified, respectively. The most common assays used were Dako HercepTest and Ventana Pathway anti-HER2/neu (4B5) for IHC to assess HER2 protein expression; Abbott PathVysion HER-2 DNA Probe Kit, FoundationOne CDx, and Guardant360 CDx for assessing HER2 gene amplification. The most frequently cited scoring guidelines were ASCO/CAP guidelines for breast cancer and gastric cancer, though most studies defined their own criteria for HER2 expression. Using the pre-specified definition, HER2+ prevalence ranged from 6.7% to 37.5% with a weighted average of 13.0% in LA/mUC. Only 1 study presented data that could be classified as HER2+ based on pre-specified criteria in earlier stage UC patients, and this study represented a likely outlier, at 76.0%.ConclusionThe results from this SLR help to shed light on HER2 expression in UC, a potentially clinically relevant biomarker-driven subpopulation for emerging HER2-directed regimens. Results of this SLR illuminate the variability in how HER2+ status expression levels are being assessed and how HER2+ is defined. Consensus on standardized HER2 testing and scoring criteria is paramount to better understand the clinical relevance in patients with UC.
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Purroy, Francisco, Mikel Vicente-Pascual, Gloria Arque, Robert Begue, Joan Farre, Yhovany Gallego, Maria Pilar Gil-Villar, et al. "Risk of New-Diagnosed Atrial Fibrillation After Transient Ischemic Attack." Frontiers in Neurology 13 (July 14, 2022). http://dx.doi.org/10.3389/fneur.2022.905304.
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BackgroundTransient ischemic attack (TIA) provides a unique opportunity to optimize secondary preventive treatments to avoid subsequent ischemic stroke (SIS). Although atrial fibrillation (AF) is the leading cause of cardioembolism in IS and anticoagulation prevents stroke recurrence (SR), limited data exists about the risk of new-diagnosed AF (NDAF) after TIA and the consequences of the diagnostic delay. The aim of our study was to determine this risk in a cohort of TIA patients with long-term follow-up.MethodsWe carried out a prospective cohort study of 723 consecutive TIA patients from January 2006 to June 2010. Median follow-up was 6.5 (5.0–9.6) years. In a subgroup of 204 (28.2%) consecutive patients, a panel of biomarkers was assessed during the first 24 h of the onset of symptoms. Multivariate analyses were performed to find out the associated factors of NDAF. Kaplan-Meier analysis was also performed to analyzed risk of SIS.ResultsNDAF was indentified in 116 (16.0%) patients: 42 (36.2%) during admission, 18 (15.5%) within first year, 29 (25%) between one and five years and 27 (23.3%) beyond 5 years. NDAF was associated with sex (female) [hazard ratio (HR) 1.61 (95% CI, 1.07- 2.41)], age [[HR 1.05 (95% CI, 1.03–1.07)], previous ischemic heart disease (IHD) [HR 1.84, (95% CI 1.15–2.97)] and cortical DWI pattern [HR 2.81 (95% CI, 1.87–4.21)]. In the Kaplan-Meier analysis, NT-proBNP ≥ 218.2 pg/ml (log-rank test P < 0.001) was associated with significant risk of NDAF during the first 5 years of follow-up. Patients with NDAF after admission and before 5 years of follow-up had the highest risk of SIS (P = 0.002).ConclusionThe risk of NDAF after TIA is clinically relevant. We identified clinical and neuroimaging factors of NDAF. In addition, NT-proBNP was related to NDAF. Our results can be used to evaluate the benefit of long-term cardiac monitoring in selected patients.
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Han, Muzhou, Hao Wang, Shuyue Yang, Siying Zhu, Guiping Zhao, Haiyun Shi, and Peng Li. "Triglyceride glucose index and Atherogenic index of plasma for predicting colorectal neoplasms in patients without cardiovascular diseases." Frontiers in Oncology 12 (November 14, 2022). http://dx.doi.org/10.3389/fonc.2022.1031259.
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Background and aimsColorectal neoplasms (CRN) include colorectal cancer (CRC) and colorectal adenoma (CRA). The relationship between CRN and triglyceride-glucose (TyG) index or between CRN and atherogenic index of plasma (AIP) is unclear. This study aims to investigate the roles of TyG index and AIP in predicting CRN in people without cardiovascular disease (CVD).Methods2409 patients without CVD underwent colonoscopy were enrolled. Clinical information and relevant laboratory test results of these patients were collected and recorded. According to endoscopic and pathological results, all participants were divided into a neoplasms group and a non-neoplasms group. The TyG index was calculated as ln (TGs×FPG/2), while AIP was calculated as log (TGs/HDL-C). We used uni- and multivariate logistic regression and restricted cubic spline (RCS) to analyze the association between the TyG inedx, AIP and CRN, develop predictive models and construct the nomograms. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive value for CRN.ResultsParticipants in the neoplasms group were more likely to be older, have higher TyG index, higher AIP and higher rates of fecal occult blood test positivity, and were more likely to be male, smokers and those with the family history of CRC (P < 0.05). The higher TyG index was related to the higher risk of CRN [OR (95% CI): 1.23 (1.08 - 1.41), P = 0.003]. The higher AIP was related to the higher risk of CRN [OR (95% CI): 1.55 (1.16 - 2.06), P = 0.003]. These two indicators are better for predicting CRN in women than men. The combined use of the TyG index and other independent risk factors (age, sex, smoking status, family history and FOBT) to distinguish CRN was effective, with a sensitivity of 61.0%, a specificity of 65.1% and an AUC of 0.669 (95%CI, 0.639 - 0.698). Likewise, the combined use of the AIP and other independent risk factors to distinguish CRN was also effective, the model had an overall 56.3% sensitivity and 68.7% specificity with an AUC of 0.667 (95%CI, 0.638 - 0.697).ConclusionThis study showed that the TyG index and the AIP might be biomarkers that could be used to predict the risk of CRN in patients without CVD.
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Yang, Jingqi, Xiaochao Ouyang, Ming Yang, Guobo Xie, and Qianqiang Cao. "Identification of key programmed cell death-related genes and immune infiltration in extracorporeal membrane oxygenation treatment for acute myocardial infarction based on bioinformatics analysis." Frontiers in Cardiovascular Medicine 9 (December 2, 2022). http://dx.doi.org/10.3389/fcvm.2022.1018662.
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BackgroundExtracorporeal membrane oxygenation (ECMO) is an important clinical treatment for acute myocardial infarction (AMI) combined with cardiogenic shock, but the role of programmed cell death (PCD)-related genes in prognostication has not yet been investigated. Therefore, we explored the key prognostic biomarkers and immune infiltration in ECMO treatment in AMI combined with cardiogenic shock.MethodsThe GSE93101 dataset was analyzed from the Gene Expression Omnibus (GEO) database, and the expression levels of PCD-related genes in AMI under ECMO were identified. Differentially expressed PCD-related genes between successful and failed treatment samples were analyzed, and Least absolute shrinkage and selection operator (LASSO) logistic regression and random forest were used to screen PCD-related molecular markers for ECMO treatment in AMI combined with cardiogenic shock. Co-expressed regulatory network and enrichment functions of the hub PCD-related genes were performed. In addition, the single-sample gene set enrichment analysis (ssGSEA) algorithm was used to calculate the immune cell infiltration of the ECMO treatment samples.ResultsA total of 115 differentially expressed genes were identified from the GSE93101 dataset, and 76 genes were associated with PCD. Then, two hub PCD-related genes, Cell division cycle associated 7 (CDCA7), ankyrin repeat and SOCS box containing 13 (ASB13) were identified as prognostic markers of ECMO treatment in AMI combined with cardiogenic shock. The most significant Gene Ontology (GO) enriched terms of the co-expressed protein of ASB13 are related to post-translational protein modification, cullin-RING ubiquitin ligase complex, and cullin family protein binding, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that ubiquitin mediated proteolysis is the most enriched pathway. The results of GO and KEGG analysis in CDCA7 were mainly involved in DNA and cell cycle related activities and pathways. Moreover, we found that the successful treatment samples contained a lower proportion of nature killer T cells using immune infiltration analysis. Immune cell infiltration analysis revealed that ASB13 was positively correlated with natural killer cell (r = 0.591, p = 0.026), monocyte (r = 0.586, p = 0.028), and gamma delta T cell (r = 0.562, p = 0.036).ConclusionThe results of this study showed that ASB13 and CDCA7 may contribute to the occurrence and progression of AMI with cardiogenic shock under ECMO.
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Chen, Juncao, Weiben Huang, Hong Zhang, Xiangwen Peng, Jun Yang, Yong Yang, Jinzhen Su, Siyao Wang, and Wei Zhou. "Quantitative proteomics on the cerebrospinal fluid of hydrocephalus in neonatal bacterial meningitis." Frontiers in Pediatrics 10 (August 16, 2022). http://dx.doi.org/10.3389/fped.2022.972032.
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ObjectiveHydrocephalus in bacterial meningitis (BM) is a devastating infectious neurological disease and the proteins and pathways involved in its pathophysiology are not fully understood.Materials and methodsLabel-free quantitative (LFQ) proteomics analyses was used to identify differentially expressed proteins (DEPs) in cerebrospinal fluid (CSF) samples from infants with hydrocephalus and bacterial meningitis (HBM group, N = 8), infants with bacterial meningitis (BM group, N = 9); and healthy infants (N group, N = 11). Bioinformatics analysis was subsequently performed to investigate Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enriched signaling pathways of these DEPs. Six proteins (AZU1, COX4I1, EDF1, KRT31, MMP12, and PRG2) were selected for further validation via enzyme-linked immunosorbent assay (ELISA).ResultsCompared with BM group and N group, HBM group had a higher whole CSF protein level (5.6 ± 2.7 vs. 1.7 ± 1.0 vs. 1.2 ± 0.5 g/l) and lower whole CSF glucose level (0.8 ± 0.6 vs. 1.8 ± 0.7 vs. 3.3 ± 0.8 mmol/l) (both P < 0.05). Over 300 DEPs were differentially expressed in HBM group compared with BM group and BM compared with N group, of which 78% were common to both. Cluster analysis indicated that the levels of 226 proteins were increased in BM group compared with N group and were decreased in HBM group compared with BM group. Bioinformatics analysis indicated the involvement of the cell adhesion, immune response and extracellular exosome signaling were significantly enriched in HBM compared with BM group and BM compared with N group. 267 DEPs were identified between HBM group with N group, KEGG analysis indicated that DEPs mainly involved in filament cytoskeleton and immune response. The ELISA results further verified that the expression levels of AZU1 were significantly different from among three groups (both P < 0.05).ConclusionThis is the first reported characterization of quantitative proteomics from the CSF of infants with HBM. Our study also demonstrated that AZU1 could be a potential biomarker for the diagnosis of hydrocephalus in bacterial meningitis.
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Furtado, Guilherme Eustáquio, Rubens Vinícius Letieri, Adriana Silva-Caldo, Joice C. S. Trombeta, Clara Monteiro, Rafael Nogueira Rodrigues, Ana Vieira-Pedrosa, et al. "Combined Chair-Based Exercises Improve Functional Fitness, Mental Well-Being, Salivary Steroid Balance, and Anti-microbial Activity in Pre-frail Older Women." Frontiers in Psychology 12 (March 25, 2021). http://dx.doi.org/10.3389/fpsyg.2021.564490.
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IntroductionRegular exercise has long been shown to positively impact the immune system responsiveness and improve mental well-being (MWB). However, the putative links between biomarkers of mental health and immune efficiency in exercising subjects have been scarcely investigated. The aim of this study was to verify the effect of a 14-week combined chair-based exercise program (CEP) on salivary steroid hormones and anti-microbial proteins, functional fitness, and MWB indexes in pre-frail older women.MethodsThe participant women (82.8 4.6 years old; n = 32) were randomly divided into the exercising group (CEP, n = 17) and the non-exercising control group (CG, n = 15). The pre/post assessment included: (1) salivary anti-microbial proteins lysozyme; (Lys) and immunoglobulin-A (IgA); (2) salivary steroid hormones of testosterone (TT) and cortisol (COR); (3) functional fitness (gait speed, hand grip strength, and static balance); (4) MWB questionnaires (happiness, depression state, satisfaction with life, and stress).ResultsSignificant differences with large Cohen’s (d) effect sizes were found on increased salivary TT (p < 0.05; d = 0.60) after exercise intervention. The results revealed a decrease in IgA levels after CEP (p < 0.01, d = 0.30). The increase in subjective happiness levels (p < 0.05, d = 0.30) and decrease of stress perception (p < 0.01, d = 2.60) and depressive state (p < 0.05, d = 0.30) were found after intervention in the CEP group. Robust statistical differences in gait speed (p < 0.05; d = 0.60) and balance tests (p < 0.05; d = 0.80) were also found in the CEP group. In control, COR increased moderately (p < 0.05; d = 0.65) while no changes were found for the other indicators. Correlation analyses showed inter-dependence between pre–post variations of MWB, biochemical indexes, and fitness function (e.g., COR inverse correlation with hand grip strength and balance tests).ConclusionThe CEP program was able to improve functional-fitness performance, decrease feelings of stress, and increase happiness. The CEP also induced clinically relevant hormonal and immune responses, which suggests that chair exercises that combine muscular strength, balance, and gait speed training are promising interventions to improve physical and mental health of older pre-frail adults.
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He, Qiheng, Tianfei Li, Ying Xiong, Xiaoyu Xia, Yuanyuan Dang, Xueling Chen, Xiaoli Geng, Jianghong He, Yi Yang, and Jizong Zhao. "Elevated cerebrospinal fluid protein levels associated with poor short-term outcomes after spinal cord stimulation in patients with disorders of consciousness." Frontiers in Aging Neuroscience 14 (November 3, 2022). http://dx.doi.org/10.3389/fnagi.2022.1032740.
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BackgroundSpinal cord stimulation (SCS) is a promising treatment for patients with disorders of consciousness (DoC); however, the laboratory examinations and different electrodes (permanent #39286 vs. temporary percutaneous #3777, Medtronic, USA) that are associated with postoperative outcomes are unclear. The study aims to study the association between the change in postoperative cerebrospinal fluid (CSF) protein level and improvement in consciousness after SCS in DoC patients and to explore whether different electrodes were associated with elevated CSF protein levels.Materials and methodsA total of 66 DoC patients who received SCS treatment from December 2019 to December 2021 were retrospectively analyzed. Patients were grouped according to their elevated CSF protein level. The clinical characteristics of the patients and SCS stimulation parameters were compared. The preoperative sagittal diameter of the spinal canal is the distance from the midpoint of the posterior border of the vertebral body to the midpoint of the posterior wall of the spinal canal at the level of the superior border of C3. The postoperative sagittal diameter of the spinal canal is the distance from the midpoint of the posterior edge of the vertebral body to the anterior edge of the stimulation electrode. Patients with improved postoperative CRS-R scores greater than 3 or who progressed to the MCS + /eMCS were classified as the improved group and otherwise regarded as poor outcome.ResultsWe found that more DoC patients had elevated CSF protein levels among those receiving SCS treatment with permanent electrodes than temporary percutaneous electrodes (P = 0.001), and elevated CSF protein levels were significantly associated with a reduced sagittal diameter (P = 0.044). In DoC patients receiving SCS treatment, we found that elevated CSF protein levels (P = 0.022) and preoperative diagnosis (P = 0.003) were significantly associated with poor outcomes at 3 months. Logistic regression analysis showed that elevated CSF protein levels were significantly associated with poor outcomes (OR 1.008, 95% CI 1.001–1.016, P = 0.032).ConclusionThe results suggest that reducing the effect of electrode pads on anatomical changes may help improve the outcomes of DoC patients receiving SCS treatment. CSF protein levels are associated with poor postoperative outcomes and whether they are potential biomarkers in DoC patients receiving SCS treatment remain further exploration.
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Grijalva, Alicia, Lucia Gallo Vaulet, Roberto Nicolas Agüero, Analia Toledano, Marikena Guadalupe Risso, Juan Quarroz Braghini, David Sosa, Paula Ruybal, Silvia Repetto, and Catalina Dirney Alba Soto. "Interleukin 10 Polymorphisms as Risk Factors for Progression to Chagas Disease Cardiomyopathy: A Case-Control Study and Meta-Analysis." Frontiers in Immunology 13 (July 4, 2022). http://dx.doi.org/10.3389/fimmu.2022.946350.
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BackgroundChagas disease is a lifelong infection caused by the protozoa Trypanosoma cruzi endemic in Latin-America and emergent worldwide. Decades after primary infection, 20-30% of infected people develop chronic Chagas cardiomyopathy (CCC) while the others remain asymptomatic. CCC pathogenesis is complex but associated with sustained pro-inflammatory response leading to tissue damage. Hence, levels of IL-10 could have a determinant role in CCC etiology. Studies with Latin-American populations have addressed the association of genetic variants of IL-10 and the risk of developing CCC with inconsistent results. We carried out a case control study to explore the association between IL-10-1082G>A (rs18008969), -819C>T (rs1800871), -592A>C (rs1800872) polymorphisms and CCC in a population attending a hospital in Buenos Aires Argentina. Next, a systematic review of the literature and a meta-analysis were conducted combining present and previous studies to further study this association.MethodsOur case control study included 122 individuals with chronic T. cruzi infection including 64 patients with any degree of CCC and 58 asymptomatic individuals. Genotyping of IL-10 -1082G>A, -819C>T, -592A>C polymorphisms was performed by capillary sequencing of the region spanning the three polymorphic sites and univariate and multivariate statistical analysis was undertaken. Databases in English, Spanish and Portuguese language were searched for papers related to these polymorphisms and Chagas disease up to December 2021. A metanalysis of the selected literature and our study was performed based on the random effect model.ResultsIn our cohort, we found a significant association between TT genotype of -819 rs1800871 and AA genotype of -592 rs1800872 with CCC under the codominant (OR=5.00; 95%CI=1.12-23.87 P=0,04) and the recessive models (OR=5.37; 95%CI=1.12-25.68; P=0,03). Of the genotypes conformed by the three polymorphic positions, the homozygous genotype ATA was significantly associated with increased risk of CCC. The results of the meta-analysis of 754 cases and 385 controls showed that the TT genotype of -819C>T was associated with increased CCC risk according to the dominant model (OR=1.13; 95% CI=1.02–1.25; P=0,03).ConclusionThe genotype TT at -819 rs1800871 contributes to the genetic susceptibility to CCC making this polymorphism a suitable candidate to be included in a panel of predictive biomarkers of disease progression.
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Salim, A. P. A. A., S. P. Suman, S. Li, Y. Wang, J. Chen, H. Zhu, and C. A. Conte-Junior. "Endpoint Temperature Influences Sarcoplasmic Proteome Profile of Cooked Beef Longissimus Lumborum." Meat and Muscle Biology 3, no. 2 (December 1, 2019). http://dx.doi.org/10.22175/mmb.10722.
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ObjectivesCooking ensures safety and enhances the palatability attributes of meat. Denaturation of myoglobin results in the dull-brown color of cooked meats. The denaturation of sarcoplasmic proteins is influenced by the degree of heat treatment, and their solubility is decreased with an increase in the endpoint cooking temperature. While previous studies examined the relationship between myoglobin denaturation, cooked color, and internal temperature in beef, investigations are yet to be undertaken to characterize the association between endpoint temperature, sarcoplasmic proteome, and color attributes in cooked steaks. Therefore, the objective of the present study was to examine the influence of endpoint cooking temperature (60 and 71°C) on sarcoplasmic proteome and internal color of beef longissimus lumborum (LL) steaks.Materials and MethodsEight (n = 8) beef LL muscles (14 d postmortem; USDA Choice) were obtained from a commercial packing plant. Two 2.5-cm thick steaks were fabricated from the center of the muscles and were cooked to internal endpoint temperature of 60°C (C-60) or 71°C (C-71) in a clam-shell grill. Cooked steaks were immediately cooled in slushed ice, sliced parallel to the grilled surface, and internal redness (a* value) and color stability (R630/580) were evaluated instrumentally. Sarcoplasmic proteome from the interiors of the cooked steaks was analyzed using 2-dimensional electrophoresis, and the gel images were digitally analyzed. The protein spots exhibiting more than 2.5-fold intensity differences (P < 0.05) between C-60 and C-71 were subjected to in-gel tryptic digestion and were identified by tandem mass spectrometry.ResultsThe C-60 steaks demonstrated greater (P < 0.05) a* and R630/580 than their C-71 counterparts. Seven differentially abundant proteins were identified and were over-abundant (P < 0.05) in C-60 compared to C-71. The differentially abundant proteins belong to 6 functional groups, i.e., transport proteins (serum albumin and hemoglobin), energy metabolism (adenylate kinase isoenzyme 1), chaperones (heat shock protein β-1), antioxidant (thioredoxin-dependent peroxide reductase), glycolytic enzymes (fructose-bisphosphate aldolase B), and protease (cytosol aminopeptidase).ConclusionThe findings indicated that the endpoint cooking temperature influences the internal cooked color and the sarcoplasmic proteome profile of beef LL steaks. The overabundant proteins in steaks cooked to 60°C may be utilized as potential biomarkers for undercooked beef, which is a source for foodborne infections.
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Wang, Meng, Xueyu Chen, Zhaoyang Tang, Wenran Zhang, Haifeng Hou, Xiangfu Sun, Yuqing Shi, et al. "Association Between Immunoglobulin G N-glycosylation and Vascular Cognitive Impairment in a Sample With Atherosclerosis: A Case-Control Study." Frontiers in Aging Neuroscience 14 (February 10, 2022). http://dx.doi.org/10.3389/fnagi.2022.823468.
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BackgroundAtherosclerosis is considered a crucial component in the pathogenesis of decreased cognitive function, as occurs in vascular cognitive impairment (VCI). Inflammation and the immune response play a significant role in the development of many chronic diseases. Immunoglobulin G (IgG) N-glycosylation has been implicated in the development of a variety of diseases by affecting the anti-inflammatory and proinflammatory responses of IgG. This study aimed to investigate the association between IgG N-glycosylation and VCI in a sample of patients with atherosclerosis through a case-control study.MethodWe recruited a total of 330 patients with atherosclerosis to participate in this case-control study, including 165 VCI patients and 165 sex- and age-matched participants with normal cognitive function. The plasma IgG N-glycans of participants were separated by ultrahigh-performance liquid chromatography. An enzyme-linked immunosorbent assay (ELISA) kit was used to determine the corresponding serum inflammatory factors. Atherosclerosis was diagnosed by carotid ultrasound, and the diagnosis of VCI was based on the “Guidelines for the Diagnosis and Treatment of Vascular Cognitive Impairment in China (2019)”. A multivariate logistic regression model was used to explore the association between IgG N-glycans and VCI. We also analyzed the relationship between IgG N-glycans and the inflammatory state of VCI through canonical correlation analysis (CCA).ResultsThrough the multivariate logistic regression analysis, 8 glycans and 13 derived traits reflecting decreased sialylation and galactosylation and increased bisecting GlcNAc significantly differed between the case and control groups after adjusting for confounding factors (P < 0.05, q < 0.05). Similarly, the differences in TNF-α, IL-6, and IL-10 were statistically significant between the case and control groups after adjusting for the effects of confounding factors (P < 0.05, q < 0.05). The CCA results showed that VCI-related initial N-glycans were significantly correlated with VCI-related inflammatory factors (r = 0.272, P = 0.004). The combined AUC value (AUCcombined = 0.885) of 7 initial glycans and inflammatory factors was higher than their respective values (AUCinitial glycans = 0.818, AUCinflammatory factors = 0.773).ConclusionThe findings indicate that decreased sialylation and galactosylation and increased bisecting GlcNAc reflected by IgG N-glycans might affect the occurrence of VCI in patients with atherosclerosis though promoting the proinflammatory function of IgG. IgG N-glycans may serve as potential biomarkers to distinguish VCI in individuals with atherosclerosis.