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1.
Clin Biochem ; 101: 1-4, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34929151

ABSTRACT

BACKGROUND: The disialoganglioside GD2 is a circulating tumor biomarker for the childhood cancer, neuroblastoma. This study establishes reference intervals for GD2 concentration in children within the age range where neuroblastoma commonly occurs. METHODS: Leftover plasma samples taken for routine clinical laboratory tests from children without cancer were collected and assayed for the 18-carbon fatty acid chain length lipoform of GD2 using a validated high-pressure liquid chromatography tandem mass spectrometry method with a lower limit of quantification of 3 nM. Samples were stratified into 5 age cohorts (0-6 months, 6-12 months, 12-36 months, 3-10 years and > 10 years). Non-parametric statistical methods were used to define the upper bound of the reference interval for each age cohort. RESULTS: GD2 was measurable in 90% of samples from children < 10 years of age and GD2 concentration was age-dependent, peaking at 9 months followed by a gradual decline. GD2 was below the lower limit of quantification in 55% of samples in the > 10 years cohort. Upper bounds of reference intervals were 15.5 nM in 0-6 month cohort, 35.1 nM in 6-12 month cohort, 24.9 nM in 12-36 month cohort, 18.4 in 3-10 year cohort and 10.4 nM in > 10 year cohort. CONCLUSIONS: Age-dependent reference intervals were defined for circulating GD2 in children. GD2 concentration was highest in the 6-12 month age cohort, which is below the age of most children with high-risk neuroblastoma. The peak GD2 concentration at 9 months may reflect neurodevelopmental events in the brain.


Subject(s)
Biomarkers, Tumor/standards , Gangliosides/standards , Neuroblastoma/blood , Age Factors , Biomarkers, Tumor/blood , Child , Child, Preschool , Female , Gangliosides/blood , Humans , Infant , Infant, Newborn , Male , Reference Values
2.
Int J Mol Sci ; 22(21)2021 Oct 26.
Article in English | MEDLINE | ID: mdl-34768952

ABSTRACT

The fact that Parkinson's disease (PD) pathologies are well advanced in most PD patients by the time of clinical elucidation attests to the importance of early diagnosis. Our attempt to achieve this has capitalized on our previous finding that GM1 ganglioside is expressed at subnormal levels in virtually all tissues of sporadic PD (sPD) patients including blood cells. GM1 is present in most vertebrate cells, is especially abundant in neurons where it was shown essential for their effective functioning and long term viability. We have utilized peripheral blood mononuclear cells (PBMCs) which, despite their low GM1, we found to be significantly lower in sPD patients compared to age-matched healthy controls. To quantify GM1 (and GD1a) we used high performance thin-layer chromatography combined with cholera toxin B linked to horseradish peroxidase, followed by densitometric quantification. GM1 was also deficient in PBMCs from PD patients with mutations in the glucocerebrosidase gene (PD-GBA), apparently even lower than in sPD. Reasons are given why we believe these results obtained with patients manifesting fully developed PD will apply as well to PD patients in preclinical stages-a topic for future study. We also suggest that these findings point to a potential disease altering therapy for PD once the early diagnosis is established.


Subject(s)
G(M1) Ganglioside/blood , G(M1) Ganglioside/deficiency , Parkinson Disease/blood , Parkinson Disease/diagnosis , Aged , Biomarkers/blood , Blood Chemical Analysis , Case-Control Studies , Early Diagnosis , Female , Gangliosides/blood , Glucosylceramidase/genetics , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Mutation , Parkinson Disease/genetics , ROC Curve
3.
Life Sci Alliance ; 5(1)2022 01.
Article in English | MEDLINE | ID: mdl-34764206

ABSTRACT

Understanding pathways that might impact coronavirus disease 2019 (COVID-19) manifestations and disease outcomes is necessary for better disease management and for therapeutic development. Here, we analyzed alterations in sphingolipid (SL) levels upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection induced elevation of SL levels in both cells and sera of infected mice. A significant increase in glycosphingolipid levels was induced early post SARS-CoV-2 infection, which was essential for viral replication. This elevation could be reversed by treatment with glucosylceramide synthase inhibitors. Levels of sphinganine, sphingosine, GA1, and GM3 were significantly increased in both cells and the murine model upon SARS-CoV-2 infection. The potential involvement of SLs in COVID-19 pathology is discussed.


Subject(s)
COVID-19/metabolism , Disease Models, Animal , Sphingolipids/metabolism , Virus Replication/physiology , Animals , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Chromatography, Liquid/methods , Dioxanes/pharmacology , Gangliosides/blood , Gangliosides/metabolism , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Humans , Mass Spectrometry/methods , Mice, Transgenic , Pyrrolidines/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sphingolipids/blood , Sphingosine/analogs & derivatives , Sphingosine/blood , Sphingosine/metabolism , Vero Cells , Virus Replication/drug effects
4.
s.l; s.n; 1991. 5 p. ilus, tab, graf.
Non-conventional in English | SES-SP, SES-SP, HANSEN, HANSENIASE, SESSP-ILSLACERVO, SES-SP | ID: biblio-1236554
5.
Rapid Commun Mass Spectrom ; 35(7): e9041, 2021 Apr 15.
Article in English | MEDLINE | ID: mdl-33415785

ABSTRACT

RATIONALE: Gangliosides (GS) are attractive targets in biomarker discovery because of their physiological significance in numerous human diseases including certain cancers and developmental and metabolic disorders. The robust strategy described here enables the profiling of numerous GS while obtaining quantitative data of exploratory biomarkers present in human plasma and whole blood. METHOD: The GS from human blood, human plasma, and several cell lines were extracted using a mixture of methanol and isopropanol/0.1% formic acid followed by direct analysis of the supernatant. The simultaneous Qualitative and Quantitative (Qual/Quan) approach involves micro flow (20 µL/min) high pressure liquid chromatography (HPLC)/high-resolution mass spectrometry (HRMS) and post-acquisition data processing with Skyline software for profiling numerous GS in biological matrices. The quantitative assay involves reverse-phase liquid chromatography/HRMS and calibration curves using commercially available GS. RESULTS: Protein precipitation resulted in ~60%-80% GS recovery from biological matrices. Direct injection of the extract allowed for quantification of targeted GS in human blood, plasma, and cancer cell lines. The lower limit of detection for the target analytes, GM1, GT1, GD1, spiked into 1% BSA/PBS, ranged from 1 to 10 ng/mL. Human lung cancer cell lines contained variable amounts (1-130 ng/mL) of soluble Fuc-GM1 analogs, potential biomarkers of lung cancer. CONCLUSIONS: A combination of simple extraction and micro-HPLC/HRMS allowed for quantification of GS in human serum and whole blood. Integration of HRMS with Skyline allowed for GS profiling in the same samples using post-acquisition HRMS data without the need for reanalysis. The strategy presented here is expected to play an important role in profiling exploratory GS biomarkers in discovery bioanalytical research.


Subject(s)
Chromatography, High Pressure Liquid/methods , Gangliosides/blood , Lipidomics/methods , Mass Spectrometry/methods , Biomarkers/blood , Cell Line, Tumor , Humans , Software
6.
Asia Pac J Clin Nutr ; 29(3): 584-592, 2020.
Article in English | MEDLINE | ID: mdl-32990619

ABSTRACT

BACKGROUND AND OBJECTIVES: Gangliosides (GAs) are important components of neural tissue and cell membrane. This study aims to investigate the association between toddlers' neurodevelopment, dietary GA intake, and serum GA concentration. METHODS AND STUDY DESIGN: A cross-sectional study was conducted in Beijing and Xuchang, Henan Province in China. 110 eligible healthy toddlers aged 24-48 months were recruited. Food frequency questionnaire (FFQ) and 24-h dietary recall were used to collect dietary information. Blood serum samples obtained from participants were used to perform GA composition analysis with high-performance liquid chromatographymass spectrometry (HPLC-MS). The neurodevelopment level was assessed with the Gesell Developmental Scale (GDS). RESULTS: Dietary ganglioside GD3, total GA, and seafood intake were identified to be associated with the gross motor developmental quotient (DQ). An inverse association was revealed between the fine motor DQ and fruit intake. No correlation was detected between serum GA concentration and DQ. CONCLUSIONS: Dietary GA intake but not serum GA concentration is associated with neurodevelopment. Further prospective studies are needed to probe the relationships between the recommended dietary GA intake and toddlers.


Subject(s)
Child Development/drug effects , Diet , Feeding Behavior , Gangliosides/administration & dosage , Child, Preschool , Cross-Sectional Studies , Female , Gangliosides/blood , Humans , Language Development , Male , Motor Skills , Social Skills
7.
Clin Pharmacol Drug Dev ; 10(1): 86-98, 2021 01.
Article in English | MEDLINE | ID: mdl-32851809

ABSTRACT

Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide-based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single-dose and food-effect studies: NCT01674036; repeated-dose study: NCT01710826). Following a single oral dose of venglustat l-malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax , 3.00-5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18-6.43 L/h), and pooled geometric mean t1/2z of 28.9 hours. Following repeated once-daily oral doses of venglustat l-malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0-24 , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0-24 ) was 26.3% to 33.1%. Plasma GL-1 and GM3 decreased time- and dose-dependently. Venglustat demonstrated a favorable safety and tolerability profile.


Subject(s)
Carbamates , Enzyme Inhibitors/pharmacokinetics , Glucosyltransferases/antagonists & inhibitors , Quinuclidines , Administration, Oral , Adolescent , Adult , Carbamates/administration & dosage , Carbamates/adverse effects , Carbamates/pharmacokinetics , Cross-Over Studies , Double-Blind Method , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacology , Female , Gangliosides/blood , Glucosylceramides/blood , Healthy Volunteers , Humans , Male , Middle Aged , Quinuclidines/administration & dosage , Quinuclidines/adverse effects , Quinuclidines/pharmacokinetics , Young Adult
8.
Anal Chem ; 92(15): 10830-10838, 2020 08 04.
Article in English | MEDLINE | ID: mdl-32648742

ABSTRACT

Ganglioside is an important class of lipid species involved in intercellular signaling and various diseases, especially for neurodegenerative diseases. Systematic ganglioside profiling is challenging because of their naturally low abundance and highly diverse species. Herein, a new data-independent acquisition and parallel reaction monitoring (DIA/PRM) method with superior sensitivity was developed. The untargeted DIA acquisition consecutively records all the precursor ion and fragment ions at the same time, while the targeted PRM analysis with versatile higher collisional dissociation generates full MS/MS spectra for structure elucidation and verification. As compared with traditional data-dependent acquisition (DDA), the DIA/PRM method unbiasedly detected the majority of abundant ganglioside species and as low as 50 pg of ganglioside in an untargeted manner. Gangliosides in four kinds of biological samples including the mouse brain, mouse plasma, HeLa cell, and human colon cancer tissue were systematically identified, and low-abundance ganglioside species were further extended on the basis of linear chromatography retention rules of the most frequently detected ganglioside species. A total of 383 ganglioside features were defined with 329 of them derived from 32 ganglioside species. Taking advantage of the high-resolution MS analysis, rare ganglioside species were further elucidated according to their characteristic fragment ions and neutral losses. In total, 18 gangliosides with a ceramide carbon number from 20 to 25 and modified gangliosides, including 18 acetylated, 8 diacetylated, 1 phosphorylated, 36 N-glycolyneuraminic acid (NeuGc)-containing, and 7 di-NeuGc-containing gangliosides, were newly identified. The developed DIA/PRM method therefore generated a rich ganglioside resource for further functional exploration and is a unique alternative for DDA analysis for global ganglioside profiling in various biological systems.


Subject(s)
Gangliosides/metabolism , Lipidomics/methods , Analytic Sample Preparation Methods , Animals , Brain/metabolism , Colonic Neoplasms/metabolism , Gangliosides/blood , HeLa Cells , Humans , Mice
9.
BMJ Case Rep ; 13(7)2020 Jul 09.
Article in English | MEDLINE | ID: mdl-32646933

ABSTRACT

A 56-year-old man with a remote history of bilateral recurrent facial palsies presented with a week of ophthalmoplegia with intact deep tendon reflexes and lack of ataxia, cerebrospinal fluid with albuminocytologic dissociation and elevated serum anti-ganglioside Q1b (GQ1b) IgG antibody. We diagnosed the patient with acute ophthalmoplegia without ataxia, a condition under the spectrum of anti-GQ1b antibody syndromes which also includes Miller Fisher syndrome. Given the rarity of recurrent facial palsies and anti-GQ1b antibody syndromes as well as reports associating facial palsies and this syndrome, we suggest that our case may be an unusual presentation of an anti-GQ1b antibody syndrome beginning with recurrent facial palsies several years prior to ophthalmoplegia. Prior studies of human nerves provide insight into the pathophysiology, including ganglioside distribution and cross-reactivities underlying the heterogeneity of anti-GQ1b antibody syndromes. This report may expand the differential diagnosis in patients with recurrent facial palsies and broaden the phenotype of anti-GQ1b syndromes.


Subject(s)
Autoantibodies/blood , Gangliosides/blood , Miller Fisher Syndrome/diagnosis , Miller Fisher Syndrome/immunology , Humans , Male , Middle Aged
10.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Article in English | MEDLINE | ID: mdl-32610096

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/pathology , Exosomes/metabolism , G(M3) Ganglioside/blood , Gangliosides/blood , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Adult , Aged , Betacoronavirus , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19 , Diglycerides/blood , Female , Humans , Male , Metabolome/physiology , Metabolomics/methods , Middle Aged , Pandemics , SARS-CoV-2 , Sphingomyelins/blood , Tandem Mass Spectrometry , Young Adult
11.
Nutrients ; 12(3)2020 Mar 07.
Article in English | MEDLINE | ID: mdl-32155999

ABSTRACT

Gangliosides are glycosphingolipids present in mammalian cell membranes, playing important structural and functional roles. Human studies on the health benefits of gangliosides are increasing, but knowledge gaps regarding ganglioside analysis exist. The study aimed to investigate blood sample type (serum/plasma), storage conditions, diurnal, day-to-day variation and acute effects of consuming bovine-derived gangliosides on circulating monosialylated gangliosides. Seventy-one women (18-40 yrs, 20-≤30.0 kg/m2) were enrolled and 61 completed the intervention. They visited the clinic three times following overnight fasting. Serum/plasma gangliosides were analyzed over 2 h (visit-1), 8 h (visit-2) and 8 h following either zero or high ganglioside meals (visit-3). Samples stored at -20 °C and -70 °C were analyzed at 3-, 6-, 12- and 18-months. Plasma and serum GM3-gangliosides did not differ, plasma GM3 did not change diurnally, from day-to-day, in response to a high vs. low ganglioside meal or after 7-days low ganglioside vs. habitual diet (P > 0.05). GM3 concentrations were lower in samples stored at -70 °C vs. -20 °C from 6-months onwards and decreased over time with lowest levels at 12- and 18-months stored at -70 °C. In conclusion, either serum/plasma stored at -20- or -70 °C for up to 6 months, are acceptable for GM3-ganglioside analysis. Blood samples can be collected at any time of the day and participants do not have to be in the fasted state.


Subject(s)
Blood Preservation/methods , Cold Temperature , Eating/physiology , Freezing , Gangliosides/administration & dosage , Gangliosides/blood , Milk/chemistry , Specimen Handling/methods , Adolescent , Adult , Animals , Cattle , Circadian Rhythm/physiology , Fasting , Female , Humans , Nutritional Physiological Phenomena , Time Factors , Young Adult
12.
J Neurol Sci ; 408: 116576, 2020 Jan 15.
Article in English | MEDLINE | ID: mdl-31726381

ABSTRACT

Gangliosides are sialylated glycosphingolipids, highly abundant in our nervous system. Antibodies targeting gangliosides are usually developed as a consequence of molecular mimicry following infections. Antiganglioside antibodies are implicated in many neurological disorders such as acute and chronic polyradiculoneuropathies which includes different variants of Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy. Presence of such antibodies in paraneoplastic peripheral neuropathy, neurodegenerative disorders, multiple sclerosis, myasthenia gravis and amyotrophic lateral sclerosis have also been reported. Recent evidence supports a role of antiganglioside antibodies in the pathogenesis of acute vestibular syndrome. Binding of antibodies to gangliosides on axonal membranes, nodes of Ranvier, myelin sheath components, Schwann cells, neuromuscular junctions or other neural cell surfaces may elicit inflammatory damage through complement-dependent and independent mechanisms, resulting in nerve conduction blocks and subsequent axonal degeneration. Gangliosides are essential for proper cell signaling, transduction and influences neuroplasticity, all of which are affected by autoimmune mediated damage. Better insight into the pathophysiological role of antiganglioside antibodies in different neurological diseases may improve their utility as diagnostic and prognostic biomarkers.


Subject(s)
Autoantibodies/blood , Gangliosides/blood , Nervous System Diseases/blood , Nervous System Diseases/diagnosis , Amyotrophic Lateral Sclerosis/blood , Amyotrophic Lateral Sclerosis/diagnosis , Biomarkers/blood , Guillain-Barre Syndrome/blood , Guillain-Barre Syndrome/diagnosis , Humans , Polyneuropathies/blood , Polyneuropathies/diagnosis
14.
Pediatr Blood Cancer ; 67(1): e28031, 2020 01.
Article in English | MEDLINE | ID: mdl-31612589

ABSTRACT

BACKGROUND: GD2 is a ganglioside that is ubiquitously expressed in the plasma membrane of neuroblastoma and is shed into the circulation. PROCEDURE: GD2 was measured with a high-pressure liquid chromatography/tandem mass spectrometry assay in serum or plasma from 40 children without cancer (controls) and in biobanked samples from 128 (73 high-risk) children with neuroblastic tumors at diagnosis, 56 children with relapsed neuroblastoma, 14 children with high-risk neuroblastoma after treatment, and 8 to 12 children each with 10 other common childhood cancers at diagnosis. RESULTS: The C18 (18 carbon fatty acid) lipoform was the predominant circulating form of GD2 in controls and in patients with neuroblastoma. The median concentration of GD2 in children with high-risk neuroblastoma at diagnosis was 167 nM (range, 16.1-1060 nM), which was 30-fold higher than the median concentration (5.6 nM) in controls. GD2 was not elevated in serum from children with the differentiated neuroblastic tumors, ganglioneuroma (n = 10) and ganglioneuroblastoma-intermixed subtype (n = 12), and in children with 10 other childhood cancers. GD2 concentrations were significantly higher in serum from children with MYCN-amplified tumors (P = 0.0088), high-risk tumors (P < 0.00001), International Neuroblastoma Staging System (INSS) stage 4 tumors (P < 0.00001), and in children who died (P = 0.034). CONCLUSIONS: Circulating GD2 appears to be a specific and sensitive tumor biomarker for high-risk/high-stage neuroblastoma and may prove to be clinically useful as a diagnostic or prognostic circulating tumor biomarker. GD2 will be measured prospectively and longitudinally in children enrolled on a high-risk neuroblastoma treatment trial to assess its ability to measure response to treatment and predict survival.


Subject(s)
Biomarkers, Tumor/blood , Gangliosides/blood , Neuroblastoma/diagnosis , Case-Control Studies , Child , Follow-Up Studies , Humans , Neuroblastoma/blood , Prognosis , Retrospective Studies
15.
Neurology ; 93(11): e1085-e1092, 2019 09 10.
Article in English | MEDLINE | ID: mdl-31399495

ABSTRACT

OBJECTIVES: To delineate the clinical features and ocular motor findings in acute vestibular syndrome (AVS) associated with anti-GQ1b antibodies. METHODS: We reviewed 90 patients with positive serum anti-GQ1b antibody in association with various neurological syndromes at Seoul National University Bundang Hospital from 2004 to 2018. The diagnoses included typical Miller Fisher syndrome (n = 31), acute ophthalmoplegia without ataxia (n = 27), Guillain-Barre syndrome with ophthalmoplegia (n = 18), AVS (n = 11), and Bickerstaff brainstem encephalitis (n = 3). Of them, the 11 patients with AVS formed the basis of this study. We also conducted a systematic review on AVS reported in association with anti-GQ1b antibody. RESULTS: Patients with AVS showed various ocular motor findings that included head-shaking nystagmus (n = 6), spontaneous nystagmus (n = 5), gaze-evoked nystagmus (n = 5), central positional nystagmus (n = 3), canal paresis (n = 2), and abnormal head-impulse tests (n = 1) without any internal or external ophthalmoplegia. Compared to those with other subtypes, patients with AVS mostly showed normal deep tendon reflexes (8 of 11 [73%], p = 0.002) and normal results on nerve conduction studies (4 of 4 [100%], p = 0.010). The clinical and laboratory findings resolved or improved markedly in all patients within 6 months of symptom onset. Systematic review further identified 7 patients with AVS and positive serum anti-GQ1b antibody who showed various ocular motor findings, including gaze-evoked nystagmus, saccadic dysmetria, central positional nystagmus, and ocular flutter or opsoclonus. CONCLUSION: Anti-GQ1b antibody may cause acute vestibulopathy by involving either the central or peripheral vestibular structures. AVS may constitute a subtype of anti-GQ1b antibody syndrome.


Subject(s)
Autoantibodies/blood , Gangliosides/blood , Vestibular Diseases/blood , Vestibular Diseases/diagnosis , Acute Disease , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Child , Female , Follow-Up Studies , Humans , Male , Middle Aged , Young Adult
16.
Glycoconj J ; 36(5): 419-428, 2019 10.
Article in English | MEDLINE | ID: mdl-31297734

ABSTRACT

Gangliosides altered during the pathological conditions and particularly in cancers. Here, we aimed to profile the gangliosides in breast cancer serum and propose potential biomarkers. LC-FTMS method was first used to identify all the ganglioside species in serum, then LC-MS/MS-MRM method was employed to quantitate the levels of gangliosides in serum from healthy volunteers and patients with benign breast tumor or breast cancer. 49 ganglioside species were determined, including GM1, GM2, GM3, GD1, GD3 and GT1 species. Compared to healthy volunteers, the levels of GM1, GM2, GM3, GD1 and GD3 displayed a rising trend in breast cancer patients. In particular, as the major glycosphingolipid component, GM3 showed excellent diagnostic accuracy in cancer serum (AUC > 0.9). PCA profile of the GM3 species showed clear distinction between normal and cancer serum. What's more, ROC curve proved great diagnostic accuracy of GM3 between cancer and benign serum. In addition, GM3 was discovered as a diagnostic marker to differentiate luminal B subtype from other subtypes. Furthermore, a positive correlation between GM3 and Ki-67 status of patients was identified. In conclusion, our results introduced the alteration patterns of serum gangliosides in breast cancer and suggested serum GM3 as a potential diagnostic biomarker in breast cancer diagnosis and luminal B subtype distinction.


Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/diagnosis , G(M3) Ganglioside/blood , Neoplasms/diagnosis , Adult , Aged , Area Under Curve , Breast Neoplasms/blood , Breast Neoplasms/pathology , Case-Control Studies , Chromatography, Liquid , Diagnosis, Differential , Female , Gangliosides/blood , Gangliosides/classification , Humans , Ki-67 Antigen/blood , Middle Aged , Neoplasms/blood , Neoplasms/pathology , Principal Component Analysis , Prognosis , ROC Curve , Tandem Mass Spectrometry
17.
Mol Genet Metab ; 128(1-2): 68-74, 2019.
Article in English | MEDLINE | ID: mdl-31104888

ABSTRACT

Sanfilippo syndrome or mucopolysaccharidosis type III (MPS III) is a childhood metabolic disorder marked by neuropathology arising due to impaired heparan sulphate (HS) catabolism. Consequently, partially degraded HS accumulates in the lysosomes of affected cells and is excreted in the urine. The measurement of HS in urine has long been considered a biomarker of Sanfilippo syndrome although it is largely non-specific. Using blood, urine and CSF collected from a cohort of Sanfilippo patients we investigated the utility of primary and secondary biomarkers to inform on disease activity. These included enzyme activity, specific oligosaccharides with non-reducing end residues reflective of the enzyme deficiency, and gangliosides. The diagnostic oligosaccharides - a HS disaccharide and tetrasaccharide - were elevated in the urine, plasma and CSF of all MPS IIIA and IIIB patients, respectively. There was no correlation between the concentrations in any of the matrices suggesting they reflect specific tissues and not overall disease burden. Enzyme activity did not inform on disease severity, with no measurable activity in CSF and activity approaching normal in MPS IIIA plasma. The concentration of gangliosides, GM2 and GM3, were significantly higher in the CSF of all MPS III subjects when compared to controls and correlated with the age of onset of first symptoms. Given that these gangliosides reflect delayed brain development they may be useful measures of disease burden, within the limitations of the clinical surrogates. Observation of these biochemical measurements in MPS III patients enrolled in clinical trials may determine whether they represent true pharmacodynamics biomarkers.


Subject(s)
Biomarkers/analysis , Gangliosides/analysis , Mucopolysaccharidosis III/diagnosis , Oligosaccharides/analysis , Child, Preschool , Gangliosides/blood , Gangliosides/cerebrospinal fluid , Gangliosides/urine , Heparitin Sulfate/metabolism , Humans , Infant , Mucopolysaccharidosis III/blood , Mucopolysaccharidosis III/cerebrospinal fluid , Mucopolysaccharidosis III/urine , Oligosaccharides/blood , Oligosaccharides/cerebrospinal fluid , Oligosaccharides/urine
18.
J Neuroimmunol ; 330: 170-173, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30642576

ABSTRACT

Anti-GQ1b antibody syndrome encompasses Miller Fisher syndrome and its related disorders. We retrospectively identified 11 pediatric patients (5.4-18 years old) with anti-GQ1b antibody syndrome. Diagnoses of patients included acute ophthalmoparesis (n = 6), classical Miller Fisher syndrome (n = 2), Miller Fisher syndrome/Guillain-Barré syndrome (n = 1), acute ataxic neuropathy (n = 1), and pharyngeal-cervical-brachial weakness (n = 1). Nine patients (81.8%) fully recovered. Maturational change in GQ1b antigen expression and the accessibility of anti-GQ1b antibodies might be the cause of the difference of clinical manifestations in children with anti-GQ1b antibody syndrome.


Subject(s)
Autoantibodies/blood , Gangliosides/blood , Miller Fisher Syndrome/blood , Miller Fisher Syndrome/epidemiology , Ophthalmoplegia/blood , Ophthalmoplegia/epidemiology , Adolescent , Child , Child, Preschool , Female , Humans , Male , Miller Fisher Syndrome/diagnostic imaging , Ophthalmoplegia/diagnostic imaging , Republic of Korea/epidemiology , Retrospective Studies , Syndrome
19.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1102-1103: 60-65, 2018 Dec 01.
Article in English | MEDLINE | ID: mdl-30368044

ABSTRACT

GD2 is a ganglioside found in the plasma membrane of the neural crest-derived cancer, neuroblastoma. GD2 is shed into the circulation of patients with neuroblastoma and could serve as a tumor biomarker to monitor tumor burden or response to treatment. We developed and validated a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method to quantify the D18:1-18:0 (C18) and the D18:1-20:0 (C20) lipoforms of GD2 in human plasma and serum. Human brain derived GD2 containing a mixture of C18 and C20 was used as the analytical standard. Samples were extracted with methanol containing dueterated-GM1 (internal standard), and analytes were separated on a Phenomenex Kinetex C18 column eluted with a gradient mobile phase composed of ammonium acetate buffer, methanol and isopropanol. An AB Sciex 4500 QTRAP mass spectrometer in negative ion mode was used to quantify the doubly charged GD2 C18 and C20 lipoform precursor ions (m/z 836.8 and m/z 850.8) that both yield a product ion of m/z 290.0. The calibration curves were linear from 4-1000 ng/mL and 6-1500 ng/mL for GD2 C18 and C20 lipoforms respectively. Inter-day and intra-day accuracy were within the acceptable validation range in plasma and serum.


Subject(s)
Chromatography, High Pressure Liquid/methods , Gangliosides/blood , Tandem Mass Spectrometry/methods , Humans , Limit of Detection , Linear Models , Reproducibility of Results
20.
Anal Chem ; 90(22): 13193-13199, 2018 11 20.
Article in English | MEDLINE | ID: mdl-30335964

ABSTRACT

Sialic acids occur widely as glycoconjugates at the nonreducing ends of glycans. Glycosphingolipids (GSLs) include a large number of sialyl-linked glycan isomers with α2,3-, α2,6-, and α2,8-linked polysialic acids. Thus, it is difficult to distinguish structural isomers with the same mass by mass spectrometry. The sialic acid linkage specific alkylamidation (SALSA) method has been developed for discriminating between α2,3- and α2,6-linked isomers, but sequential amidation of linkage-specific sialic acids is generally complicated and time-consuming. Moreover, analysis of GSL-glycans containing α2,8-linked polysialic acids using solid-phase SALSA has not been reported. Herein, we report a novel SALSA method focused on ring-opening aminolysis (aminolysis-SALSA), which shortens the reaction time and simplifies the experimental procedures. We demonstrate that aminolysis-SALSA can successfully distinguish serum GSL-glycan isomers by mass spectrometry. In addition, ring-opening aminolysis can easily be applied to amine and hydrazine derivatives.


Subject(s)
Gangliosides/blood , Glycomics/methods , Lactones/chemistry , Polysaccharides/blood , Sialic Acids/chemistry , Animals , Cattle , Chemical Phenomena , Gangliosides/chemistry , Isomerism , Polysaccharides/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
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