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1
Rai, Seema, Gurmeet Kaur Sethi, Rama Kumari, and Varun Kaul. "Gaucher disease: masquerading as chronic malaria." International Journal of Contemporary Pediatrics 5, no. 4 (June 22, 2018): 1688. http://dx.doi.org/10.18203/2349-3291.ijcp20182588.
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Gaucher disorder s rare lysosomal disorder characterized by glycolipid laden lysosomes leading to hepatosplenomegaly, bone marrow involvement. Three types of Gaucher disease have been described based on the clinical features, ethnicity and the natural history of the disease. Gaucher disease Type 1 (GD1) occurs mainly in infancy to adulthood and is the commonest lysosomal storage disorder. Gaucher Disease Type II (GD2) and Gaucher disease type III (GD3) patients have onset at less than 1 year, and 2-20 years, respectively.1 GD1 patients do not have neurological involvement. GD2 is the acute neuronopathic and GD3 is the chronic neuronopathic type.
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Awasthi, Sita, Gregory G. Mahairas, Carolyn E. Shaw, Meei-Li Huang, David M. Koelle, Christine Posavad, Lawrence Corey, and Harvey M. Friedman. "A Dual-Modality Herpes Simplex Virus 2 Vaccine for Preventing Genital Herpes by Using Glycoprotein C and D Subunit Antigens To Induce Potent Antibody Responses and Adenovirus Vectors Containing Capsid and Tegument Proteins as T Cell Immunogens." Journal of Virology 89, no. 16 (June 3, 2015): 8497–509. http://dx.doi.org/10.1128/jvi.01089-15.
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ABSTRACTWe evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4+and CD8+T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model.IMPORTANCEHSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.
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Vladimirova, Liubov Yu, Natalya A. Abramova, and Oleg Ivanovich Kit. "Treatment for RAS wild-type (wt) metastatic colorectal cancer (mCRC): Continuation of anti-EGFR therapy while switching chemotherapy regimen." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 744. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.744.
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744 Background: The purpose of the study was to assess the effeciency and safety of continuing of EGFR-inhibition while switching the chemotherapy (CT) from FOLFOX+Cetuximab (C) as the 1st-line to FOLFIRI+С as the 2nd-line treatment for pts with RAS wt mCRC. Methods: Pts with RAS wt mCRC were enrolled to the pilot study according to inclusion criteria: ECOG≤2, normal bone marrow, liver and kidney functions, no brain metastases, measurable metastatic lesions. The therapy included: the 1st-line with FOLFOX-6+C until progression, then FOLFIRI+C as the 2nd-line therapy. The treatment continued until progression or unacceptable toxicity. Response rate (RR), PFS after the 1st and the 2ndlines of treatment as well as toxicity were evaluated. Results: 20 pts (11 men, 9 women), 38-58 years old, mean age 48.3±1.3 years, were recruited. All pts had multiple visceral metastases: to the liver –30.0%(6), lungs and pleura – 20.0%(4), liver and lungs – 50.0%(10), including the bone metastases – 15.0%(3). The RR was 85.0 %(17), including PR - 4(20.0%) and SD - 13(65.5%). Median PFS after the 1st-line therapy was 12.3±2.6 months, median PFS after the 2nd-line therapy - 6.5±2.8 months. Median OS was not reached yet. Adverse events included: neutropenia Gd2 – 30.0%(6), Gd3 – 20.0%(4), anemia Gd2 – 10.0%(2), stomatitis Gd2-3 – 20.0%(4), diarrhea Gd2 - 55.0%(11), thrombophlebitis – 10.0%(2). C-associated dermatologic toxicity: acneiform rash Gd2-3 – 85.0%(17), skin itching Gd2 - 30.0%(6), panaritium Gd1-2 -30.0%(6), blepharitis Gd1-2 – 10.0%(2), hypertrichosis – 20.0%(4). Conclusions: Continuing EGFR-inhibition with C while switching CT regimens beyond progression provided significant tumor control and was not accompanied by unacceptable toxicity. This strategy deserves futher evaluation in randomized studies in EGFR-dependent mCRC pts.
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Anya, D. K., and K. I. Eghianruwa. "Concurrent administration of methanolic extract of Zingiber officinale Roscoe (Zingiberales: Zingiberaceae) and diminazene aceturate enhanced survival rate and reduced parasitaemia in experimental murine Trypanosoma brucei Plimmer & Bradford, 1899 (Kinetoplastea: Trypanosomatida) infection." Brazilian Journal of Biological Sciences 5, no. 9 (2018): 95–104. http://dx.doi.org/10.21472/bjbs.050910.
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The efficacy of concurrent diminazene and Zingiber officinale Roscoe (Zingiberales: Zingiberaceae) extract in murine Trypanosoma brucei Plimmer & Bradford, 1899 (Kinetoplastea: Trypanosomatida) infection was evaluated. Two infected groups were treated with extract at 400 mg.kg-1 (G1) and 800 mg.kg-1 (G2) alone while another two groups received 400 mg.kg-1 (GD1) and 800 mg.kg-1 (GD2) of extract concurrently with diminazene 3.5 mg.kg-1 intraperitoneally. One infected group received diminazene 3.5 mg.kg-1 only (D) while another received 1 mg.kg-1 Tween 80 (C1) orally. The seventh group was uninfected and untreated (C2). Survival rate, parasitemia, liver weight, spleen weight, haematological indices were evaluated. Survival rates were 0% in C1, G1 and G2, 20% in D, 40% in GD2, 60% in GD1 and 100% in C2. Animals in groups G1, G2 and C1 died between 6 and 8 days pt. Parasitemia levels were significantly (P < 0.05) higher in D1 than in GD1 and GD2 by day 16 post treatment. PCV and RBC counts were significantly (P < 0.05) lower in GD1, GD2 and D than in C2. Liver and spleen weights increased significantly (P < 0.05) due to infection and never fully recovered in all treatment options. Ginger (Z. officinale) extract enhanced diminazene efficacy by increasing survival rates and lowering parasitemia.
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Kasprowicz, Angelina, Groux-Degroote Sophie, Chann Lagadec, and Philippe Delannoy. "Role of GD3 Synthase ST8Sia I in Cancers." Cancers 14, no. 5 (March 3, 2022): 1299. http://dx.doi.org/10.3390/cancers14051299.
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GD3 synthase controls the biosynthesis of complex gangliosides, bearing two or more sialic acid residues. Disialylated gangliosides GD3 and GD2 are tumor-associated carbohydrate antigens (TACA) in neuro–ectoderm-derived cancers, and are directly involved in cell malignant properties, i.e., migration, invasion, stemness, and epithelial–mesenchymal transition. Since GD3 and GD2 levels are directly linked to GD3 synthase expression and activity, targeting GD3 synthase appears to be a promising strategy through which to interfere with ganglioside-associated malignant properties. We review here the current knowledge on GD3 synthase expression and regulation in cancers, and the consequences of complex ganglioside expression on cancer cell signaling and properties, highlighting the relationships between GD3 synthase expression and epithelial–mesenchymal transition and stemness. Different strategies were used to modulate GD3 synthase expression in cancer cells in vitro and in animal models, such as inhibitors or siRNA/lncRNA, which efficiently reduced cancer cell malignant properties and the proportion of GD2 positive cancer stem cells, which are associated with high metastatic properties, resistance to therapy, and cancer relapse. These data show the relevance of targeting GD3 synthase in association with conventional therapies, to decrease the number of cancer stem cells in tumors.
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Cheresh, D. A., M. D. Pierschbacher, M. A. Herzig, and K. Mujoo. "Disialogangliosides GD2 and GD3 are involved in the attachment of human melanoma and neuroblastoma cells to extracellular matrix proteins." Journal of Cell Biology 102, no. 3 (March 1, 1986): 688–96. http://dx.doi.org/10.1083/jcb.102.3.688.
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Human melanoma cells express relatively large amounts of the disialogangliosides GD3 and GD2 on their surface whereas neuroblastoma cells express GD2 as a major ganglioside. Monoclonal antibodies (Mabs) directed specifically to the carbohydrate moiety of GD3 and GD2 inhibit melanoma and neuroblastoma cell attachment to various substrate adhesive proteins, e.g. collagen, vitronectin, laminin, fibronectin, and a heptapeptide, glycyl-L-arginyl-glycyl-L-aspartyl-L-seryl-L-prolyl-L-cysteine, which constitutes the cell attachment site of fibronectin. Cells that are preattached to a fibronectin substrate can also be induced to detach and round up in the presence of purified anti-ganglioside Mab. Moreover, when melanoma cells that contain both GD2 and GD3 are incubated with Mabs directed to both of these molecules an additive inhibition is observed. The specificity of this inhibition is demonstrated since Mabs of various isotypes directed to either protein or carbohydrate epitopes on a number of other major melanoma or neuroblastoma cell surface antigens have no effect on cell attachment. A study of the kinetics involved in this inhibition indicates that significant effects occur during the first 5 min of cell attachment, suggesting an important role for GD2 and GD3 in the initial events of cell-substrate interactions. The role of gangliosides in cell attachment apparently does not directly involve a strong interaction with fibronectin since we could not observe any binding of radiolabeled fibronectin or fragments of the molecule known to contain the cell attachment site to melanoma gangliosides separated on thin-layer chromatograms. An alternative explanation would be that gangliosides may play a role in the electrostatic requirements for cell-substrate interactions. In this regard, controlled periodate oxidation of terminal, unsubstituted sialic acid residues on the cell surface not only specifically destroys the antigenic epitopes on GD2 and GD3 recognized by specific Mabs but also inhibits melanoma cell and neuroblastoma cell attachment. In fact, the periodate-induced ganglioside oxidation and the inhibition of cell attachment are equally dose dependent. These data suggest that cell-substratum interactions may depend in part on the electrostatic environment provided by terminal sialic acid residues of cell surface gangliosides and possibly other anionic glycoconjugates.
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Zhao, X. J., and N. K. Cheung. "GD2 oligosaccharide: target for cytotoxic T lymphocytes." Journal of Experimental Medicine 182, no. 1 (July 1, 1995): 67–74. http://dx.doi.org/10.1084/jem.182.1.67.
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Carbohydrate antigens rarely provide target epitopes for cytotoxic T lymphocytes (CTL). Disialoganglioside GD2 is a glycolipid expressed at high levels in human tumors and a small group of murine lymphomas (EL4, RBL5, RMA, RMA-S, A13, and BALBRVE). Immunization of C57B1/6 mice with irradiated EL4 cells stimulated a specific CTL response and protected these animals from engraftment of EL4 lymphoma. The CTL activity resided in the CD4-CD8+ population, was dependent on T cell receptor alpha/beta, and was not removed by anti-natural killer cell immunoabsorption, but was restricted to GD2 and H-2b bearing targets. CTL activity could be completely inhibited by GD2-oligosaccharide-specific monoclonal antibodies and their F(ab')2 fragments, but not by immunoglobulin G3 myelomas or antibodies against GD3 or GM2. Soluble GD2 did not inhibit specific tumor lysis. RMA-S lymphoma cells (GD2+H-2b-TAP2 deficient) were resistant to GD2-specific CTL. Sialic acid-containing peptides eluted from EL4 lymphoma cells could (a) stabilize H-2 molecules on RMA-S cells and (b) sensitize them for GD2-specific CTL. Control peptides (derived from vesicular stomatitis virus nucleoprotein peptide and GD2-negative lymphomas) could also stabilize H-2 on RMA-S, but were resistant to GD2-specific CTL. These H-2-binding peptides could be purified by anti-GD2 affinity chromatography. We postulate a new class of naturally occurring epitopes for T cells where branched-chain oligosaccharides are linked to peptides with anchoring motifs for the major histocompatibility complex class I pocket. While analogous to the haptens trinitrophenyl and O-beta-linked acetyl-glucosamine, the potential implications of natural carbohydrates as antigenic epitopes for CTL in biology are considerable.
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Chan, Godfrey Chi-Fung, and Carol Matias Chan. "Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma." Biomolecules 12, no. 3 (February 24, 2022): 358. http://dx.doi.org/10.3390/biom12030358.
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Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in normal tissue, such as peripheral afferent nerves. Monoclonal antibodies targeting GD2 have been applied clinically to high-risk neuroblastoma with significant success. However, there are different anti-GD2 products and administration regimens. For example, anti-GD2 has been used in combination with chemotherapy during the induction phase or with retinoic acid during the maintenance stage. Regimens also vary in the choice of whether to add cytokines (i.e., IL-2, GMCSF, or both). Furthermore, the addition of an immune enhancer, such as β-glucan, or allogeneic natural killer cells also becomes a confounder in the interpretation. The question concerning which product or method of administration is superior remains to be determined. So far, most studies agree that adding anti-GD2 to the conventional treatment protocol can achieve better short- to intermediate-term event-free and overall survival, but the long-term efficacy remains to be verified. How to improve its efficacy is another challenge. Late relapse and central nervous system metastasis have emerged as new problems. The methods to overcome the mechanisms related to immune evasion or resistance to immunotherapy represent new challenges to be resolved. The newer anti-GD2 strategies, such as bispecific antibody linking of anti-GD2 with activated T cells or chimeric antigen receptor T cells, are currently under clinical trials, and they may become promising alternatives. The use of anti-GD2/GD3 tumor vaccine is a novel and potential approach to minimizing late relapse. How to induce GD2 expression from tumor cells using the epigenetic approach is a hot topic nowadays. We expect that anti-GD2 treatment can serve as a model for the use of monoclonal antibody immunotherapy against cancers in the future.
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Wei, Jianshe, Yoshiki Takamatsu, Ryoko Wada, Masayo Fujita, Gilbert Ho, Eliezer Masliah, and Makoto Hashimoto. "Therapeutic Potential of αS Evolvability for Neuropathic Gaucher Disease." Biomolecules 11, no. 2 (February 15, 2021): 289. http://dx.doi.org/10.3390/biom11020289.
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Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.
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Li, Yuexi, Sumei Li, Yong Qi, Tingting Xu, Jiameng Li, Ying Pan, and Suqin Li. "Eucaryotic expression of HSV glycoproteins gC2, gD1, gD2 and immunogenicity analysis." New Biotechnology 33 (July 2016): S75. http://dx.doi.org/10.1016/j.nbt.2016.06.977.
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Cheresh, D. A., R. Pytela, M. D. Pierschbacher, F. G. Klier, E. Ruoslahti, and R. A. Reisfeld. "An Arg-Gly-Asp-directed receptor on the surface of human melanoma cells exists in an divalent cation-dependent functional complex with the disialoganglioside GD2." Journal of Cell Biology 105, no. 3 (September 1, 1987): 1163–73. http://dx.doi.org/10.1083/jcb.105.3.1163.
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The disialogangliosides GD2 and GD3 play a major role in the ability of human melanoma cells to attach to Arg-Gly-Asp-containing substrates such as fibronectin and vitronectin, since pretreatment of these cells with monoclonal antibodies to the oligosaccharide of GD2 and GD3 can inhibit their attachment and spreading on such adhesive proteins. This report demonstrates that human melanoma cells (M21) synthesize and express a glycoprotein receptor that shares antigenic epitopes with the vitronectin receptor on human fibroblasts and is capable of specifically recognizing the Gly-Arg-Gly-Asp-Ser-Pro sequence. In the presence of calcium, GD2, the major ganglioside of M21 cells, colocalized with this receptor on the surface of human melanoma cells and their focal adhesion plaques as demonstrated by double-label transmission immunoelectron microscopy and indirect immunofluorescence. Biochemical evidence is presented indicating that the vitronectin receptor on M21 human melanoma cells contains associated calcium and GD2. This ganglioside copurified with the glycoprotein receptor for vitronectin on affinity columns containing either an Arg-Gly-Asp-containing peptide, concanavalin A, or lentil lectin. This major Arg-Gly-Asp-directed receptor on M21 cells could be metabolically labeled with 45Ca2+. Chelation of this ion with EDTA caused the dissociation of GD2 from the receptor and rendered the remaining glycoprotein incapable of binding to an Arg-Gly-Asp-containing peptide. Reconstitution experiments demonstrated a requirement for calcium, and not magnesium, for receptor binding to Arg-Gly-Asp and indicated that addition of ganglioside can enhance this interaction.
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Marconi, S., M. Acler, L. Lovato, L. De Toni, E. Tedeschi, E. Anghileri, S. Romito, C. Cordioli, and B. Bonetti. "Anti-GD2-like IgM autoreactivity in multiple sclerosis patients." Multiple Sclerosis Journal 12, no. 3 (June 2006): 302–8. http://dx.doi.org/10.1191/135248506ms1279oa.
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Seric IgM autoreactivity in 100 multiple sclerosis (MS) and 106 control (70 of whom had other neurological diseases) patients was assessed either by immunohistochemistry on normal human CNS tissue or to GD2, GD1a, GD3 by ELISA and thin layer chromatography (TLC) techniques. By double immunohistochemistry, we found that 44% of the total MS population showed seric IgM reactivity to oligodendrocytes and myelin, this finding being particularly frequent in patients with secondary progressive MS. In the non-MS cohort, positive signals were seen only in one patient. In all cases, extraction of lipids from CNS sections abolished the immunoreactivity. Among the gangliosides investigated by ELISA, anti-GD2-like IgM autoantibodies were detected in the serum of 30% of MS patients, a subgroup of whom (below 10%) reacted also with GD1a and/or GD3. More than 85% of MS cases with anti-GD2-like IgM immunoreactivity by ELISA showed also IgM anti-oligodendrocyte/myelin staining by immunohistochemistry. However, no immunostaining in MS sera was observed when gangliosides were resolved by TLC. A positive correlation with neurological disability was observed, as the Expanded Disability Status Scale of MS patients with anti-GD2-like IgM autoreactivity by ELISA was significantly worse than seronegative MS cases. The results of the present study enforce the role of glycolipids as potential autoantigens and of IgM autoantibodies in MS pathogenesis.
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Giona, Fiorina, Carlo Di Bonaventura, Patrizia Mancini, Gianmarco Tessari, Turchetta Rosaria, Emanuele Cerulli Irelli, Stefano Ferracuti, et al. "Multidisciplinary Study Based on Clinical, Electrophysiological and Psycological Evaluations Combined with Advanced Neuroimaging in Gaucher Disease Patients." Blood 134, Supplement_1 (November 13, 2019): 2185. http://dx.doi.org/10.1182/blood-2019-128143.
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Gaucher Disease (GD) is an autosomal recessive metabolic disorder due to glucocerebrosidase deficit. There are three main clinical phenotypes: type I (GD1: non-neuronopathic form), characterized by a visceral involvement that can mimic a hematologic disease; type II (GD2: acute neuropathic form) and type III (GD3) characterized by a slower and progressive neurological involvement. Hematologists have often involved in diagnosis and management of the GD1 patients. Increasing data and our experience show that patients with GD1 may present manifestations of Parkinson's disease or Parkinsonism symptoms (tremor, bradykinesia and rigidity), frequently combined with cognitive impairment and behavioral alterations. The aim of this study is to deeply investigate the neurological and neuropsychiatric aspects in GD1 patients in order to identify clinical and subclinical neurological manifestations, including cognitive impairment and behavioral alterations in this category of patients. This observational, monocentric, and prospective study is planned to enroll 22 GD patients (19 GD1 patients and 3 GD3 patients with or without active neurological signs) aged >12 years. Neurological assessments include: clinical evaluation including Severity Scoring Tool Unified Parkinson's Disease Rating scale and Epworth Sleepiness scale, psycho-diagnostic tests and psychiatric evaluation using cognitive test battery and two psychiatric (BPRS) and psychological (CBA 2.0) questionnaires, Somatosensory and Motors Evoked Potentials, Electroencephalography (EEG) and magnetic resonance (MR) 3Tesla, at baseline, after 12 months and 24 months. Preliminary results concerning the baseline evaluation of first cohort of patients are here reported. Since June 2019, 11 patients (10 GD1 and 1 symptomatic GD3) have been enrolled. Neurological impairment according to the major features (Gaucher severity score tool) was found in 4/11 patients: signs of Parkinson disease in 1 GD1 patient, motoneuron disease in 1 GD3 patients, abnormalities in ocular motility and psycho-cognitive disturbances in 2 GD1 patients. Minor features of a neurological impairment was found as follows: bradykinesia in 5 GD1 patients, excessive daytime sleepiness in 5 GD1 patients, and saccadic slowness in 1 GD1 patient. EEG revealed focal or diffuse slow waves in 6 patien patients (5 GD1 and 1 GD3). Cognitive and psychological evaluations revealed the presence of significant psychiatric symptoms such as depression, anxiety, and physical concerns. Six patients (5 GD1and 1 GD3) surprisingly had sensorineural hearing loss. Auditory Brainstem Response revealed abnormal disyncrony-like morphology and central speech processing in noise in 3 GD1 and in 4 (3 GD1 and 1 GD3) patients, respectively. Ophthalmological evaluation highlighted a normal visus and intraocular pressure in all patients. Moderate alterations of the fundus were present in 2 patients (1 GD1 and 1 GD3) and superficial corneal dystrophies in 3 (2 GD1 and 1 GD3) patients. An increased latency and moderate reduction in the amplitudes of optic nerve function were found in all tested patients. The retinal responses to the Electroretinogram exam were of excellent quality in all but one GD1 patient, who showed slightly reduced responses. The spectral domain-optical coherence tomography (SD-OCT) examination showed posterior pole alterations in 3 patients (2 GD1 and 1 GD3) and borderline nerve fiber layers of the optic nerve (RNFL) in 3 (2 GD1 and 1 GD3) cases. Our clinical study represents quite an innovative one, since neurological investigations are focused on GD2 and GD3 phenotypes. Neurological involvement with different phenotypical aspects were also found in GD1 patients. Sensorineural hearing loss and central alteration of auditory processing were present in higher incidence compared to the unaffected population. Psychological data din't show significant cognitive impairments, but pointed out some psychiatric aspects, such as anxiety, depression and somatic concerns. MR 3Tesla can be an important tool to better understand these data. Evaluation of the remaining cohort of patients and longer follow-up could confirm that neurological involvement is not exclusive of the type 3 GD. Disclosures No relevant conflicts of interest to declare.
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Anand, Vivek, Fouad El-Dana, Stanley Ly, Michael Andreeff, and Venkata Lokesh Battula. "Abstract P5-06-10: Tumor microenvironment modulates ganglioside expression leading to immunosuppression in triple negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–06–10—P5–06–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-06-10.
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Abstract Triple-negative breast cancer (TNBC) is one of the most aggressive human malignancies, characterized by a strikingly poor prognosis linked to high rates of distant metastases and disease relapse. Among several mechanisms that contribute to TNBC aggressiveness is the ability of TNBC cells to evade the anti-tumor immune response. Numerous efforts have been directed to identify and target molecules and signaling pathways that contribute to TNBC immune evasion. A considerable proportion of TNBCs are resistant to immune-checkpoint therapy, implying that additional molecules are involved in immune suppression in these malignancies. We have previously reported that ganglioside GD2 identifies breast cancer stem-like cells (BCSCs) and promotes tumorigenesis. GD3 synthase (GD3S), a key enzyme that regulates GD2 biosynthesis, is significantly upregulated in TNBCs. Gangliosides have been found to promote an immunosuppressive tumor microenvironment. In this study, we hypothesize that tumor-microenvironment influences expression of gangliosides downstream of GD3S, including GD2/GD3, suppressing the anti-tumor immune response while inhibiting GD3S expression enhances immune-mediated killing of TNBC cells. We performed immunohistochemistry (IHC) on primary TNBC patient samples (N=89) and measured GD2 expression using an automated imaging system (Vectra-Polaris). Immunohistochemistry analysis revealed that approximately 60% of samples had detectable GD2 expression of different intensity and was associated with poor overall survival of patients with TNBC (p=0.002). Our IHC data also demonstrated that GD2 is expressed not only in tumors but also in the tumor-associated stroma in ~60% of TNBC samples, suggesting the effect of crosstalk between TME and TNBC cells on GD2 expression. Additionally, to substantiate the role of TME on GD2 expression, we cultured bone marrow-derived mesenchymal stromal cell (BM-MSCs) with MDA-MB-231 cells and found a 2-fold increase in GD2 expression in BM-MSC and MDA-MB-231 cells (p<0.001), suggesting microenvironmental factors contribute to GD2 expression on both tumor and stromal cells. To examine the immunomodulatory role of gangliosides we used the TCGA dataset to analyze the co-expression of GD3S mRNA with T-cell exhaustion markers in all breast cancer patients. We found a significant (p<0.001) positive correlation between ST8SIA1 and CTLA-4 (pearson= 0.4), LAG-3 (pearson= 0.33), and PD1 (pearson=0.3) in breast cancer patients. Furthermore, we overexpressed GD3S in TNBC and non-TNBC cells and observed its effect on T-cell mediated killing of breast cancer (BC) cells by a live-cell imaging system (IncuCyte). Overexpression of GD3S caused upregulation of GD2 in BT549, HIM3 (TNBC), and MCF7 (non-TNBC) cells, and their co-culture with T-cells resulted in a significant reduction (p<0.001) in cell death compared to the controls. In conclusion, GD2 is a tumor-specific marker in patients with TNBC and that GD3S overexpression is associated with T-cell exhaustion and maintenance of an immunosuppressive microenvironment in breast cancer. This immunosuppressive microenvironment in TNBCs fostered by gangliosides downstream of GD3S is also a manifestation of the cross-talk between tumor and tumor-associated stromal cells. Citation Format: Vivek Anand, Fouad El-Dana, Stanley Ly, Michael Andreeff, Venkata Lokesh Battula. Tumor microenvironment modulates ganglioside expression leading to immunosuppression in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-10.
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Saraswati, Allysa Puspa, S. Sutopo, and Syahrul Kurniawan. "Effect of Organic Fertilizer Form and Dosage on Soil Chemical Properties, Leaf Macro Nutrient Content and Vegetative Growth of Siamese Orange (Citrus nobilis Lour) seedlings." Jurnal Tanah dan Sumberdaya Lahan 9, no. 1 (January 1, 2022): 29–36. http://dx.doi.org/10.21776/ub.jtsl.2022.009.1.4.
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Orange is a national superior commodity that has an important role in increasing foreign exchange for the country. However, the development of citrus cultivation in Indonesia is still relatively low, probably due to soil fertility degradation. Therefore, this study aimed to analyze the effect of differences in the application of organic fertilizer (form and dose) and their interaction on soil chemical properties, nutrient concentration in the leaf (i.e. N, P, K), and growth in Siamese citrus seedlings. The treatments included the application of a combination of forms and doses of organic fertilizer, namely SD1 (powder dose 2 t ha-1), SD2 (powder dose 4 t ha-1), SD3 (powder dose 6 t ha-1), SD4 (powder dose 8 t ha-1), SD5 (powder dose 10 t/ha), GD1 (granule dose 2 t ha-1), GD2 (granule dose 4 t ha-1), GD3 (granule dose 6 t/ha), GD4 (granule dose 8 t ha-1) and GD5 (granule dose 10 t ha-1). The results showed that there was a significant difference in the interaction between form and dose of organic fertilizer only in the number of primary branches at 4 WAP (weeks after application) with the highest values was found in powder organic fertilizer at a dose of 8 t ha-1 and granules organic fertilizer at a dose 10 t ha-1. In addition, the application of powder organic fertilizer application had a higher plant height at 10-12 WAP as compared to the application of granule organic fertilizer.
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Hidari, K. I.-P. J., S. Ichikawa, K. Furukawa, M. Yamasaki, and Y. Hirabayashi. "β1-4N-acetylgalactosaminyltransferase can synthesize both asialoglycosphingolipid GM2 and glycosphingolipid GM2in vitro and in vivo: isolation and characterization of a β1-4N-acetylgalactosaminyltransferase cDNA clone from rat ascites hepatoma cell line AH7974F." Biochemical Journal 303, no. 3 (November 1, 1994): 957–65. http://dx.doi.org/10.1042/bj3030957.
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We have cloned a cDNA encoding beta 1-4N-acetylgalactosaminyltransferase (EC 2.4.1.92) (GalNAc-T) from rat ascites hepatoma of the free-cell type AH7974F. The cell line only expressed asialo-series glycosphingolipids (GSLs) including asialo-GM2 [Taki, T., Hirabayashi, Y., Ishiwata, Y., Matsumoto, M., and Kojima, K. (1979) Biochim. Biophys. Acta 572, 113-120]. The cDNA, pGNA56, was isolated by screening AH7974F cDNA library in lambda gt10 with a probe. The probe was obtained from AH7974F cDNA by PCR using primers with the nucleotide sequence of the human GalNAc-T cDNA. The amino acid sequence deduced from the nucleotide sequence of pGNA56 exhibited 88% similarity to the human GalNAc-T sequence. The enzyme was a typical type II membrane protein, which consisted of a short N-terminal residue, a transmembrane region, and a long C-terminal residue, including the catalytic domain. The substrate specificity of rat GalNAc-T was determined using homogenates from cells into which the cDNA clone was transfected. The enzyme catalysed not only the formation of GM2 and GD2 from GM3 and GD3 respectively, but also asialo-GM2 from CDH. It also acted on GSL substrates, including GM1b, sialylparagloboside and GD1 alpha. On the other hand, the enzyme did not transfer GalNAc to soluble substrates such as glycoproteins and oligosaccharide. The GSL compositional and immunocytochemical analyses of stable transfectants obtained by transfection of the cDNA showed simultaneous expression of asialo-GM2 and GM2 on the plasma membrane. Therefore, we concluded that the formation of asialo-GM2, GM2 and GD2 was catalysed by the single GalNAc-T. Northern-blot hybridization showed that the GalNAc-T mRNA was strongly expressed in rat brain, testis, and spleen. The gene was also expressed in rat normal liver to a lesser extent. We found the GSLs in asialo- and alpha-pathways such as asialo-GM1 and GD1 alpha in the rat tissues by using a sensitive t.l.c.-immunostaining method. These observations also supported our conclusion that the single GalNAc-T synthesizes asialo-GM2, GM2 and GD2 in vivo.
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Byun, H. S., S. H. Ko, G. S. Lee, S. H. Hyun, and E. B. Jeung. "115 RAT EPIDERMAL GROWTH FACTOR GENE EXPRESSION CONTROLLED BY PROGESTERONE DURING PREGNANCY." Reproduction, Fertility and Development 20, no. 1 (2008): 138. http://dx.doi.org/10.1071/rdv20n1ab115.
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The implantation of the developing blastocyst into the uterine wall is regulated by a precisely timed interplay of the ovarian hormones estrogen and progesterone, which control a set of regulatory factors that make the uterus receptive to implantation. These factors include EGF receptor (Egfr) and members of the epidermal growth factor (Egf) family, namely, EGF, heparin-binding EGF (Hbegf), transforming growth factor-alpha (Tgfa), and amphiregulin (Areg). However, the exact role(s) these factors play in pregnancy remain unclear. To address this, a group of three rats was euthanized every day from gestation day (GD) 0 through to GD21. The uterus, attached uterus (these tissues are mostly composed of stromal cells), and placenta were rapidly excised and used directly for total RNA. We used real-time PCR with the TaqMan system (Applied Biosystems, Foster City, CA, ISA) to examine the uterine expression patterns of these factors in rats during the entire pregnancy. Data were analyzed by nonparametric one-way analysis of variance using the Kruskal-Wallis test, followed by Dunnett's test for multiple comparisons. Egf and Egfr mRNA levels increased significantly at implantation, especially on GD3 and GD6, after which their expression gradually decreased. Hbegf and Tgfa showed a modest spike of transcription around the implantation period (GD4 and GD3, respectively) but were much more strongly expressed at mid-pregnancy, which is when progesterone is secreted at high levels. Areg expression peaked strongly around implantation (GD4) and at mid-pregnancy (GD12). Treatment of pregnant rats on GD5 or GD8 with the progesterone receptor antagonist RU486 (2.5 mg per rat) blocked the expression of all of the genes on the days of treatment. Moreover, injection of immature rats with progesterone induced the uterine expression of all of the genes except Hbegf, while injection with estrogen or estrogen plus progesterone had no effect. Taken together, all genes tested may be assumed to regulate the implantation process. Moreover, Hbegf, Tgfa, and Areg may participate during mid-pregnancy. In addition, all of these activities are likely to be controlled by progesterone in the uterus of rats during pregnancy.
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Shlapobersky, Mark, Joshua O. Marshak, Lichun Dong, Meei-li Huang, Qun Wei, Alice Chu, Alain Rolland, Sean Sullivan, and David M. Koelle. "Vaxfectin-adjuvanted plasmid DNA vaccine improves protection and immunogenicity in a murine model of genital herpes infection." Journal of General Virology 93, no. 6 (June 1, 2012): 1305–15. http://dx.doi.org/10.1099/vir.0.040055-0.
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The herpes simplex type 2 (HSV-2) envelope glycoprotein (gD2) was evaluated as a potential antigen candidate for a plasmid DNA (pDNA)-based HSV-2 vaccine. The pDNA was formulated with Vaxfectin, a cationic lipid-based adjuvant, and tested in a murine HSV-2 lethal challenge model. gD2 was expressed as full-length (FL) and secreted (S) gD2 forms. A 0.1 µg pDNA dose was tested to distinguish treatment conditions for survival and a 100 µg pDNA dose was tested to distinguish treatment conditions for reduction in vaginal and latent HSV-2 copies. Vaxfectin-formulated gD2 pDNA significantly increased serum IgG titres and survival for both FL gD2 and S gD2 compared with gD2 pDNA alone. Mice immunized with FL gD2 formulated with Vaxfectin showed reduction in vaginal and dorsal root ganglia (DRG) HSV-2 copies. The stringency of this protection was further evaluated by testing Vaxfectin-formulated FL gD2 pDNA at a high 500 LD50 inoculum. At this high viral challenge, the 0.1 µg dose of FL gD2 Vaxfectin-formulated pDNA yielded 80 % survival compared with no survival for FL gD2 pDNA alone. Vaxfectin-formulated FL gD2 pDNA, administered at a 100 µg pDNA dose, significantly reduced HSV-2 DNA copy number, compared with FL gD2 DNA alone. In addition, 40 % of mice vaccinated with adjuvanted FL pDNA had no detectable HSV-2 viral genomes in the DRG, whereas all mice vaccinated with gD2 pDNA alone were positive for HSV-2 viral genomes. These results show the potential contribution of Vaxfectin-gD2 pDNA to a future multivalent HSV-2 vaccine.
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Erber, Ramona, Sareetha Kailayangiri, Hanna Huebner, Matthias Ruebner, Arndt Hartmann, Lothar Häberle, Julia Meyer, et al. "Variable Expression of the Disialoganglioside GD2 in Breast Cancer Molecular Subtypes." Cancers 13, no. 21 (November 8, 2021): 5577. http://dx.doi.org/10.3390/cancers13215577.
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The disialoganglioside GD2 is a tumor-associated antigen that may allow for the application of targeted immunotherapies (anti-GD2 antibodies, GD2 CAR T cells) in patients with neuroblastoma and other solid tumors. We retrospectively investigated GD2 expression in a breast cancer cohort, using immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays (TMAs), and its impact on survival. GD2 expression on IHC (n = 568) and IF (n = 503) was investigated in relation to subtypes and patient outcome. Overall, 50.2% of the 568 IHC-assessed samples and 69.8% of the 503 IF-assessed samples were GD2-positive. The highest proportion of GD2-positive tumors was observed in luminal tumors. Significantly fewer GD2-positive cases were detected in triple-negative breast cancer (TNBC) compared with other subtypes. The proportion of GD2-expressing tumors were significantly lower in HER2-positive breast cancer in comparison with luminal tumors on IF staining (but not IHC). GD2 expression of IHC or IF was not significantly associated with disease-free or overall survival, in either the overall cohort or in individual subtypes. However, GD2 expression can be seen in more than 50% of breast cancer cases, with the highest frequency in hormone receptor-positive tumors. With this high expression frequency, patients with GD2-positive advanced breast cancer of all subtypes may benefit from GD2-targeting immunotherapies, which are currently subject to clinical testing.
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Cavdarli, Sumeyye, Nao Yamakawa, Charlotte Clarisse, Kazuhiro Aoki, Guillaume Brysbaert, Jean-Marc Le Doussal, Philippe Delannoy, Yann Guérardel, and Sophie Groux-Degroote. "Profiling of O-acetylated Gangliosides Expressed in Neuroectoderm Derived Cells." International Journal of Molecular Sciences 21, no. 1 (January 6, 2020): 370. http://dx.doi.org/10.3390/ijms21010370.
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The expression and biological functions of oncofetal markers GD2 and GD3 were extensively studied in neuroectoderm-derived cancers in order to characterize their potential as therapeutic targets. Using immunological approaches, we previously identified GD3, GD2, and OAcGD2 expression in breast cancer (BC) cell lines. However, antibodies specific for O-acetylated gangliosides are not exempt of limitations, as they only provide information on the expression of a limited set of O-acetylated ganglioside species. Consequently, the aim of the present study was to use structural approaches in order to apprehend ganglioside diversity in melanoma, neuroblastoma, and breast cancer cells, focusing on O-acetylated species that are usually lost under alkaline conditions and require specific analytical procedures. We used purification and extraction methods that preserve the O-acetyl modification for the analysis of native gangliosides by MALDI-TOF. We identified the expression of GM1, GM2, GM3, GD2, GD3, GT2, and GT3 in SK-Mel28 (melanoma), LAN-1 (neuroblastoma), Hs 578T, SUM 159PT, MDA-MB-231, MCF-7 (BC), and BC cell lines over-expressing GD3 synthase. Among O-acetylated gangliosides, we characterized the expression of OAcGM1, OAcGD3, OAcGD2, OAcGT2, and OAcGT3. Furthermore, the experimental procedure allowed us to clearly identify the position of the sialic acid residue that carries the O-acetyl group on b- and c-series gangliosides by MS/MS fragmentation. These results show that ganglioside O-acetylation occurs on both inner and terminal sialic acid residue in a cell type-dependent manner, suggesting different O-acetylation pathways for gangliosides. They also highlight the limitation of immuno-detection for the complete identification of O-acetylated ganglioside profiles in cancer cells.
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Yesmin, Farhana, Robiul H. Bhuiyan, Yuhsuke Ohmi, Satoko Yamamoto, Kei Kaneko, Yuki Ohkawa, Pu Zhang, et al. "Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins." International Journal of Molecular Sciences 23, no. 1 (December 31, 2021): 423. http://dx.doi.org/10.3390/ijms23010423.
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Gangliosides have been considered to modulate cell signals in the microdomain of the cell membrane, lipid/rafts, or glycolipid-enriched microdomain/rafts (GEM/rafts). In particular, cancer-associated gangliosides were reported to enhance the malignant properties of cancer cells. In fact, GD2-positive (GD2+) cells showed increased proliferation, invasion, and adhesion, compared with GD2-negative (GD2−) cells. However, the precise mechanisms by which gangliosides regulate cell signaling in GEM/rafts are not well understood. In order to analyze the roles of ganglioside GD2 in the malignant properties of melanoma cells, we searched for GD2-associating molecules on the cell membrane using the enzyme-mediated activation of radical sources combined with mass spectrometry, and integrin β1 was identified as a representative GD2-associating molecule. Then, we showed the physical association of GD2 and integrin β1 by immunoprecipitation/immunoblotting. Close localization was also shown by immuno-cytostaining and the proximity ligation assay. During cell adhesion, GD2+ cells showed multiple phospho-tyrosine bands, i.e., the epithelial growth factor receptor and focal adhesion kinase. The knockdown of integrin β1 revealed that the increased malignant phenotypes in GD2+ cells were clearly cancelled. Furthermore, the phosphor-tyrosine bands detected during the adhesion of GD2+ cells almost completely disappeared after the knockdown of integrin β1. Finally, immunoblotting to examine the intracellular distribution of integrins during cell adhesion revealed that large amounts of integrin β1 were localized in GEM/raft fractions in GD2+ cells before and just after cell adhesion, with the majority being localized in the non-raft fractions in GD2− cells. All these results suggest that GD2 and integrin β1 cooperate in GEM/rafts, leading to enhanced malignant phenotypes of melanomas.
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Fleurence, Julien, Sophie Fougeray, Meriem Bahri, Denis Cochonneau, Béatrice Clémenceau, François Paris, Andras Heczey, and Stéphane Birklé. "TargetingO-Acetyl-GD2 Ganglioside for Cancer Immunotherapy." Journal of Immunology Research 2017 (2017): 1–16. http://dx.doi.org/10.1155/2017/5604891.
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Target selection is a key feature in cancer immunotherapy, a promising field in cancer research. In this respect, gangliosides, a broad family of structurally related glycolipids, were suggested as potential targets for cancer immunotherapy based on their higher abundance in tumors when compared with the matched normal tissues. GD2 is the first ganglioside proven to be an effective target antigen for cancer immunotherapy with the regulatory approval of dinutuximab, a chimeric anti-GD2 therapeutic antibody. Although the therapeutic efficacy of anti-GD2 monoclonal antibodies is well documented, neuropathic pain may limit its application.O-Acetyl-GD2, theO-acetylated-derivative of GD2, has recently received attention as novel antigen to target GD2-positive cancers. The present paper examines the role ofO-acetyl-GD2 in tumor biology as well as the available preclinical data of anti-O-acetyl-GD2 monoclonal antibodies. A discussion on the relevance ofO-acetyl-GD2 in chimeric antigen receptor T cell therapy development is also included.
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Koh, Yasuhiro, Takuya Tsunoda, Makoto Iwahashi, Hiroki Yamaue, Kiwao Ishimoto, Hiroshi Tanimura, Hisao Fukumoto, et al. "Decreased Expression of α2,8 Sialyltransferase and Increased Expression of β1,4 N-Acetylgalactosaminyltransferase in Gastrointestinal Cancers." Experimental Biology and Medicine 227, no. 3 (March 2002): 196–200. http://dx.doi.org/10.1177/153537020222700307.
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Gangliosides such as GD3, GM2, and GD2 are abundantly expressed on the cell surfaces of various malignant cells, suggesting the potential for anti-ganglioside antibody therapy for tumors. Anti-ganglioside GD2 antibody treatment is currently undergoing clinical trials for melanoma and neuroblastoma. We previously reported high in vivo antitumor effects of anti-GM2 ganglioside antibody against lung cancer. To determine whether anti-GM2 antibody may be clinically indicated for gastrointestinal cancers, we evaluated the mRNA expression of α2,8 sialyltransferase, a GD3 synthase, and β1,4 N-acetylgalactosaminyltransferase (β1,4 GalNAc-T), a GM2/GD2 synthase, in gastrointestinal cancers. We performed modified semi-quantitative RT-PCR, which reduces complexity incidental to radiolabeling on samples taken from small surgically removed clinical specimens. Stomach (19/22) and colorectal (21/30) cancers showed decreased expression of α2,8 sialyltransferase as compared with respective normal tissues (P < 0.05). In contrast, increased expression of β1,4 GalNAc-T was detected in both types of tumors. Clinicopathological analysis revealed significantly higher expression level of α2,8 sialyltransferase in the poorly differentiated than in the well-differentiated stomach cancer group (P < 0.05). Furthermore, the expression level of α2,8 sialyltransferase was significantly decreased in male as compared with female colorectal cancer patients (P < 0.05). These results suggest that expression level of GM2 ganglioside is elevated in gastrointestinal cancer, and that anti-GM2 antibody may be applicable to its treatment.
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Nesburn, Anthony B., Susan Slanina, Rae Lyn Burke, Homayon Ghiasi, S. Bahri, and Steven L. Wechsler. "Local Periocular Vaccination Protects against Eye Disease More Effectively Than Systemic Vaccination following Primary Ocular Herpes Simplex Virus Infection in Rabbits." Journal of Virology 72, no. 10 (October 1, 1998): 7715–21. http://dx.doi.org/10.1128/jvi.72.10.7715-7721.1998.
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ABSTRACT Vaccination of experimental animals can provide efficient protection against ocular herpes simplex virus type 1 (HSV-1) challenge. Although it is suspected that local immune responses are important in protection against ocular HSV-1 infection, no definitive studies have been done to determine if local ocular vaccination would produce more efficacious protection against HSV-1 ocular challenge than systemic vaccination. To address this question, we vaccinated groups of rabbits either systemically or periocularly with recombinant HSV-2 glycoproteins B (gB2) and D (gD2) in MF59 emulsion or with live KOS (a nonneurovirulent strain of HSV-1). Three weeks after the final vaccination, all eyes were challenged with McKrae (a virulent, eye disease-producing strain of HSV-1). Systemic vaccination with either HSV-1 KOS or gB2/gD2 in MF59 did not provide significant protection against any of the four eye disease parameters measured (conjunctivitis, iritis, epithelial keratitis, and corneal clouding). In contrast, periocular vaccination with gB2/gD2 in MF59 provided significant protection against conjunctivitis and iritis, while ocular vaccination with live HSV-1 KOS provided significant protection against all four parameters. Thus, local ocular vaccination provided better protection than systemic vaccination against eye disease following ocular HSV-1 infection. Since local vaccination should produce a stronger local immune response than systemic vaccination, these results suggest that the local ocular immune response is very important in protecting against eye disease due to primary HSV-1 infection. Thus, for clinical protection against primary HSV-1-induced corneal disease, a local ocular vaccine may prove more effective than systemic vaccination.
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Reppel, Loïc, Ourania Tsahouridis, Jason Akulian, Ian J. Davis, Hong Lee, Giovanni Fucà, Jared Weiss, Gianpietro Dotti, Chad V. Pecot, and Barbara Savoldo. "Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003897. http://dx.doi.org/10.1136/jitc-2021-003897.
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BackgroundWe explored whether the disialoganglioside GD2 (GD2) is expressed in small cell lung cancer (SCLC) and non-SCLC (NSCLC) and can be targeted by GD2-specific chimeric antigen receptor (CAR) T cells.MethodsGD2 expression was evaluated in tumor cell lines and tumor biopsies by flow cytometry and immunohistochemistry. We used a GD2.CAR that coexpress the IL-15 to promote T-cell proliferation and persistence, and the inducible caspase 9 gene safety switch to ablate GD2.CAR-T cells in case of unforeseen toxicity. The antitumor activity of GD2.CAR-T cells was evaluated using in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. The modulation of the GD2 expression in tumor cell lines in response to an epigenetic drug was also evaluated.ResultsGD2 was expressed on the cell surface of four of fifteen SCLC and NSCLC cell lines (26.7%) tested by flow cytometry, and in 39% of SCLC, 72% of lung adenocarcinoma and 56% of squamous cell carcinoma analyzed by immunohistochemistry. GD2 expression by flow cytometry was also found on the cell surface of tumor cells freshly isolated from tumor biopsies. GD2.CAR-T cells exhibited antigen-dependent cytotoxicity in vitro and in vivo in xenograft models of GD2-expressing lung tumors. Finally, to explore the applicability of this approach to antigen low expressing tumors, we showed that pretreatment of GD2low/neg lung cancer cell lines with the Enhancer of zeste homolog 2 inhibitor tazemetostat upregulated GD2 expression at sufficient levels to trigger GD2.CAR-T cell cytotoxic activity.ConclusionsGD2 is a promising target for CAR-T cell therapy in lung cancer. Tazemetostat treatment could be used to upregulate GD2 expression in tumor cells, enhancing their susceptibility to CAR-T cell targeting.
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Zhang, Min, Chunyan Cao, Zijun Chen, Nihui Huang, Bihai Bai, Yuechan Li, and An Xie. "Synthesis and Comparison of Eu3+ Doped M-Gd2(MoO4)3 and O-Gd2(MoO4)3 Phosphors." Science of Advanced Materials 14, no. 1 (January 1, 2022): 62–66. http://dx.doi.org/10.1166/sam.2022.4171.
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The Eu3+ doped monoclinic phase of Gd2(MoO4)3 (M-Gd2(MoO4)3) and the Eu3+ doped orthorhombic phase of Gd2(MoO4)3 (O-Gd2(MoO4)3) red phosphors were synthesized by adjusting the synthesis temperatures. The XRD (X-ray diffraction) patterns, the EDS (energy-dispersive spectra), and the FE-SEM (field emission scanning electron microscope) images were used to comparatively study crystalline structures, compositions, and morphologies of the two materials. The DRS (diffuse reflection spectra), the room and high temperature PL (photoluminescence) spectra, and the fluorescence decay curves were recorded to compare the PL properties of the two phosphors. The characterization results suggest that the M-Gd2(MoO4)3 phosphor has lower synthesis temperature, while the O-Gd2(MoO4)3 phosphor has bigger particles, larger energy band gap value, stronger PL intensities, longer lifetimes, and better thermal stabilities. For Eu3+, the research results prove that the O-Gd2(MoO4)3 is a better host material choice than that of the M-Gd2(MoO4)3.
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Wan, J., H. U. Saragovi, H. Conway, and L. Ivanisevic. "Investigation of peptomimetics of GD2 antibodies as targeted therapy against human small cell lung cancer in-vitro." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13128. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13128.
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13128 Background: GD2 is a well-established target that has been validated for neuroblastoma and small cell lung cancer. The therapeutic and diagnostic use of monoclonal antibodies directed to GD2 in small cell lung cancer is well documented. It has been shown that the binding of GD2 monoclonal antibodies alone can induce growth suppression and cell death of small cell lung cancer cells in-vitro. Our laboratory has developed synthetic small molecule peptomimetics as ligands of GD2. Peptomimetics have favorable in-vivo pharmacological properties compared to antibodies with no immunogenicity, longer half-lives, low toxicity, good tissue penetration, biodistribution and high target selectivity. This study proposed to determine the efficacy of peptomimetics of GD2 antibodies against small cell lung cancer cells in-vitro. Methods: 2 human cell lines were studied. H69 is a classic small cell lung cancer and H82 is a morphological variant small cell lung cancer both of which have been reported in the literature to express GD2. Cell surface expression of ganglioside GD2 was analyzed by flow cytometry (FACScan, BD Biosciences) using GD2 mAB 3F8 and GD2 mAB ME361. Cell proliferation was assessed using standard MTT assays with serum containing medium and cultured for approximately 3 doubling times for each cell line. The cell lines were exposed to increasing doses of GD2 specific peptomimetic to a maximum of 25 uM with controls including serum containing media with and without a GD2 negative peptomimetic and assessed for cell proliferation. Results: GD2 expression was confirmed for both cell lines- H69 and H82 using FACs. Exposure of the GD2 specific peptomimetic clearly caused growth suppression on the range of 35–40% when compared to controls. A dose response relationship was demonstrated with a plateau beyond 10 uM concentrations. Each experiment repeated ≥ 3 occasions. Conclusions: We have shown that attachment of GD2 specific peptomimetics can cause decreased cell proliferation in 2 small cell lung cancer cell lines H69 and H82. We have shown that there is a dose response relationship by which these compounds reduce cell viability. Peptomimetics of GD2 antibodies show promise as a targeted therapy for small cell lung cancer in-vitro and warrant further study. [Table: see text]
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Lo Piccolo, Maria Serena, Nai Kong V. Cheung, and Irene Y. Cheung. "GD2 synthase." Cancer 92, no. 4 (2001): 924–31. http://dx.doi.org/10.1002/1097-0142(20010815)92:4<924::aid-cncr1402>3.0.co;2-o.
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Ferreira, Sandra Patrícia Ataíde, and Maria da Graça Bompastor Borges Dias. "Compreensão de leitura: estratégias de tomar notas e da imagem mental." Psicologia: Teoria e Pesquisa 18, no. 1 (April 2002): 51–62. http://dx.doi.org/10.1590/s0102-37722002000100007.
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Objetivou-se verificar e comparar o efeito do treinamento das estratégias de Tomar Notas e da Imagem Mental sobre a compreensão de leitura entre crianças de oito a 14 anos com dificuldades nesta área, de escolas públicas e particulares. Primeiramente, foram classificadas nos Grupos de Pouca e Muita Dificuldade de Compreensão (GD1 e GD2) e distribuídas em três grupos: dois grupos experimentais (GE1 e GE2) e um grupo controle (GC). Depois, o GE1 utilizou a atividade de Tomar Notas e o GE2, a estratégia da Imagem Mental. O GC não recebeu treinamento, mas realizou a mesma tarefa que os grupos experimentais. Os resultados demonstram um desempenho significativamente melhor do GE1 frente ao GE2 e ao GC. Verificou-se que o GD1 progrediu mais sobre as questões inferenciais do que o GD2. As crianças das escolas públicas foram as mais beneficiadas. Ambas estratégias possibilitaram a emergência de respostas às questões literais e inferenciais.
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Navid, F., V. M. Santana, and R. C. Barfield. "Anti-GD2 Antibody Therapy for GD2-Expressing Tumors." Current Cancer Drug Targets 10, no. 2 (March 1, 2010): 200–209. http://dx.doi.org/10.2174/156800910791054167.
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Brämswig, K. H., A. B. Riemer, E. Förster-Waldl, A. Pollak, C. C. Zielinski, H. Pehamberger, H. N. Lode, O. Scheiner, and E. Jensen-Jarolim. "Mimotopes of the disialoganglioside GD2 elicit anti-GD2 antibodies recognising GD2 on melanoma cells." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 12505. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.12505.
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12505 Background: The disialoganglioside GD2, a carbohydrate antigen, is expressed on all tumors of neuroectodermal origin, including melanoma, sarcoma, neuroblastoma and small cell lung cancer. Due to its specific expression on tumor surfaces, GD2 is an attractive target for immunotherapy. The mouse/human chimeric antibody form ch14.18 was already applied in melanoma and neuroblastoma trials as passive immunotherapy. We aimed to replace the poorly immunogenic ganglioside with highly immunogenic peptides, in order to establish an active immunotherapy. Methods: We used the ch14.18 antibody to select GD2 mimotopes. In the present study, two mimics of the ch14.18 epitope were chosen for immunogenicity evaluation. The mimics were coupled to KLH (keyhole limpet hemocyanin) in order make them more immunogenic. Three groups of BALB/c mice were immunized i.p with the mimotope conjugates (GRL-KLH or DGG-KLH), or the carrier protein KLH alone. Results: BALB/c mice immunized with the mimotope conjugates indeed showed a specific humoral immune response towards the purified original antigen GD2 in ELISA, and also against the natural GD2 melanoma cell lysate in Western Blots. As the elicited antibodies were of the IgG isotype, the mimotope conjugates are capable of recruiting T cell help and inducing memory phenomena. Conclusion: We are able to show that an epitope of the carbohydrate antigen GD2 can successfully be translated into immunogenic peptide epitope mimics. Moreover, immunizations with these mimics induced IgG antibodies again recognizing the original antigen. We thus provide evidence that GD2 mimotopes are suitable candidates for active immunotherapy of GD2 expressing tumors. The work was supported by BioLife Science GmbH, Vienna, Austria; by project grant #10965 of the Austrian National Bank Science Fund; and by the Center of Excellence in Clinical and Experimental Oncology (CLEXO), Austrian Federal Ministry of Education, Science and Culture (GZ200.062/2-VI/1/2002). A.B. Riemer and K.H. Brämswig are recipients of Hans & Blanca Moser Fund scholarships. The work was also supported by DFG (Lo635–2) and Fördergesellschaft Kinderkrebs-Neuroblastomforschung to H.N.Lode. [Table: see text]
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Park, Jeong A., Hong fen Guo, Hong Xu, and Nai-Kong V. Cheung. "PD-L1 Checkpoint Blockade Augments Anti-Tumor Immune Response of GD2 or HER2-Bsab Ex Vivo Armed T-Cells (EVAT) Therapy in Osteosarcoma." Blood 134, Supplement_1 (November 13, 2019): 1959. http://dx.doi.org/10.1182/blood-2019-131325.
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Background Ex Vivo Armed T-cells (EVAT) carrying zeptomoles (10-21M) of T-cell engaging GD2-bispecific antibody (GD2-EVAT) or HER2-bispecific antibodies (HER2-EVAT) have potent anti-tumor activity against GD2(+) and/or HER2(+) solid tumors. Strategies to further optimize this approach are highly relevant. PD-1 is a key immune checkpoint receptor expressed mainly by activated T-cells and mediates immune suppression by binding to its ligands PD-L1 or PD-L2. Upregulation of PD-L1 has been found in many cancers including osteosarcoma and associated with aggressive disease and poor outcome. While the use of immune checkpoint inhibitors (ICIs) seems logical, the ideal timing when combined with T-cell engaging bispecific antibody (T-BsAb) or EVAT has yet to be defined. Here, we described the effects of anti-PD-1 or anti-PD-L1 antibodies on GD2-EVAT or HER2-EVAT therapy and explored the impact of its timing in the treatment of osteosarcoma which is GD2(+), HER2(+) and PD-L1(+). Methods GD2-BsAb and HER-BsAb were built using the IgG(L)-scFv format (Can Immunol Res, 3:266, 2015, Oncoimmunology, PMID:28405494). T-cells from healthy volunteer donors were isolated, and cultured ex vivo in the presence of CD3/CD28 beads plus 30 IU/mL of interleukin 2 (IL-2). Between day 7 and day 14, activated T-cells (ATCs) were harvested and armed for 20 minutes at room temperature with GD2-BsAb or HER2-BsAb. In vivo anti-tumor activity against GD2(+), HER2(+), and PD-L1(+) osteosarcoma cell line xenografts was tested in BALB-Rag2-/-IL-2R-γc-KO mice. Anti-human PD-1 antibody (pembrolizumab, anti-PD-1) or anti-human PD-L1 antibody (atezolizumab, anti-PD-L1) were tested for synergy with GD2-EVAT or HER2-EVAT therapy. Results The PD-1 expression increased among T-cells that circulated in the blood, that infiltrated the spleen or the tumor after EVAT therapy. While anti-PD-L1 combination therapy with GD2-EVAT or HER2-EVAT improved anti-tumor response against osteosarcoma (P=0.0123 and P=0.0004), anti-PD-1 did not (all P>0.05). The addition of anti-PD-L1 significantly increased T-cell survival in blood and T-cell infiltration of tumor when compared to GD2-EVAT or HER2-EVAT alone (all P<0.0001). Treatment of GD2-EVAT or anti-PD-L1 plus GD2-EVAT downregulated GD2 expression on tumors, but anti-PD-1 plus GD2-EVAT did not. For the next step we tested the impact of different combination schedules of ICIs on GD2-EVAT therapy. Concurrent anti-PD-1 (6 doses along with GD2-EVAT therapy) interfered with GD2-EVAT, while sequential anti-PD-1 (6 doses after GD2-EVAT) did not make a significant effect (P>0.05). On the other hand, while the concurrent use of anti-PD-L1 did not show benefit on GD2-EVAT, sequentially administered anti-PD-L1 produced a significant improvement in tumor control when compared to anti-PD-L1 or GD2-EVAT alone (P=0.002 and P=0.018). When anti-PD-L1 treatment was extended (12 doses after GD2-EVAT), the anti-tumor effect was most pronounced compared to GD2-EVAT alone (P <0.0001), which translated into improved survival (P=0.0057). These in vivo anti-tumor responses were associated with increased CD8(+) tumor infiltrating lymphocytes (TILs) of tumor. Conclusion In the arming platform, large numbers of target-specific T-cells can be generated, and this EVAT therapy is a highly effective cellular treatment with high potency in preclinical models. In addition, the advantage of ex vivo cytokine release following T-cell arming and activation could reduce or avoid life threatening cytokine storm if such activation was to proceed in vivo. Adoptive T-cell therapy induced immune response upregulates the inhibitory immune checkpoint PD-1/PD-L1 pathway, and combination treatment with anti-PD-L1 antibody, especially when combined as sequential therapy and continuously treated, significantly improved anti-tumor effect of EVAT, partly through increase in CD8(+) TILs infiltration. Disclosures Xu: MSK: Other: co-inventors in patents on GD2 bispecific antibody and HER2 bispecific antibody. Cheung:Ymabs: Patents & Royalties, Research Funding.
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Demakov, Pavel A., Alena A. Vasileva, Vladimir A. Lazarenko, Alexey A. Ryadun, and Vladimir P. Fedin. "Crystal Structures, Thermal and Luminescent Properties of Gadolinium(III) Trans-1,4-cyclohexanedicarboxylate Metal-Organic Frameworks." Crystals 11, no. 11 (November 11, 2021): 1375. http://dx.doi.org/10.3390/cryst11111375.
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Four new gadolinium(III) metal-organic frameworks containing 2,2′-bipyridyl (bpy) or 1,10-phenanthroline (phen) chelate ligands and trans-1,4-cyclohexanedicarboxylate (chdc2−) were synthesized. Their crystal structures were determined by single-crystal X-ray diffraction analysis. All four coordination frameworks are based on the binuclear carboxylate building units. In the compounds [Gd2(bpy)2(chdc)3]·H2O (1) and [Gd2(phen)2(chdc)3]·0.5DMF (2), the six-connected {Ln2(L)2(OOCR)6} blocks form a 3D network with the primitive cubic (pcu) topology. In the compounds [Gd2(NO3)2(phen)2(chdc)2]·2DMF (3) and [Gd2Cl2(phen)2(chdc)2]·0.3DMF·2.2dioxane (4), the four-connected {Ln2(L)2(X)2OOCR)4} units (where X = NO3− for 3 or Cl− for 4) form a 2D square-grid (sql) network. The solid-state luminescent properties were investigated for the synthesized frameworks. Bpy-containing compound 1 shows no luminescence, possibly due to the paramagnetic quenching by Gd3+ cation. In contrast, the phenathroline-containing MOFs 2–4 possess yellow emission under visible excitation (λex = 460 nm) with the tuning of the characteristic wavelength by the coordination environment of the metal center.
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Sorokin, Maxim, Irina Kholodenko, Daniel Kalinovsky, Tatyana Shamanskaya, Igor Doronin, Dmitry Konovalov, Aleksei Mironov, et al. "RNA Sequencing-Based Identification of Ganglioside GD2-Positive Cancer Phenotype." Biomedicines 8, no. 6 (May 30, 2020): 142. http://dx.doi.org/10.3390/biomedicines8060142.
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The tumor-associated ganglioside GD2 represents an attractive target for cancer immunotherapy. GD2-positive tumors are more responsive to such targeted therapy, and new methods are needed for the screening of GD2 molecular tumor phenotypes. In this work, we built a gene expression-based binary classifier predicting the GD2-positive tumor phenotypes. To this end, we compared RNA sequencing data from human tumor biopsy material from experimental samples and public databases as well as from GD2-positive and GD2-negative cancer cell lines, for expression levels of genes encoding enzymes involved in ganglioside biosynthesis. We identified a 2-gene expression signature combining ganglioside synthase genes ST8SIA1 and B4GALNT1 that serves as a more efficient predictor of GD2-positive phenotype (Matthews Correlation Coefficient (MCC) 0.32, 0.88, and 0.98 in three independent comparisons) compared to the individual ganglioside biosynthesis genes (MCC 0.02–0.32, 0.1–0.75, and 0.04–1 for the same independent comparisons). No individual gene showed a higher MCC score than the expression signature MCC score in two or more comparisons. Our diagnostic approach can hopefully be applied for pan-cancer prediction of GD2 phenotypes using gene expression data.
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Theruvath, Johanna, Christopher Mount, Michelle Monje, Crystal Mackall, and Robbie Majzner. "IMMU-55. GD2 IS A MACROPHAGE CHECKPOINT MOLECULE AND COMBINED GD2/CD47 BLOCKADE RESULTS IN SYNERGISTIC EFFECTS AGAINST GD2 POSITIVE MALIGNANCIES." Neuro-Oncology 22, Supplement_2 (November 2020): ii116. http://dx.doi.org/10.1093/neuonc/noaa215.484.
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Abstract GD2 is a disialoganglioside expressed on a variety of tumors including DIPG, neuroblastoma and osteosarcoma. Anti-GD2 antibodies have demonstrated some success in neuroblastoma and they have either not proven to be effective or have not been evaluated in other GD2 positive malignancies. CD47 is the dominant “Don’t Eat Me” signal expressed by cancer cells to inhibit macrophages and blocking CD47 leads to phagocytosis of tumor cells. We hypothesized that CD47 blockade synergizes with anti-GD2. We measured in vitro phagocytosis of DIPG and NBL cells and observed a synergy of anti-GD2/CD47 compared to the single agents. In vivo, this combination led to the complete clearance of both orthotopic and metastatic models of NBL. Additionally, the combination significantly enhanced survival of OS xenografts. Finally, in a murine model of metastatic pulmonary OS, the combination led to a near elimination of all metastatic burden. To understand the underlying biologic basis, we studied the effects of GD2 crosslinking on tumor cells and the effects of GD2 blockade on macrophages. A portion of DIPG or NBL cells die when treated with dinutuximab, and those that survive upregulate surface calreticulin, an important pro-phagocytic (“Eat Me”) signal. Additionally, we have identified the ligand for GD2, a molecule expressed on macrophages known to inhibit phagocytosis. In summary, we have identified a novel combination of anti-GD2 and anti-CD47 antibodies that is highly effective in preclinical models and will soon be tested in children. Furthermore, we have shown that GD2 itself is a macrophage checkpoint or “Don’t Eat Me” signal.
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Wingerter, Arthur, Khalifa El Malki, Roger Sandhoff, Larissa Seidmann, Daniel-Christoph Wagner, Nadine Lehmann, Nadine Vewinger, et al. "Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma." Cancers 13, no. 3 (January 29, 2021): 520. http://dx.doi.org/10.3390/cancers13030520.
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The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing’s sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood–brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher’s disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.
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Martinez, Caridad, Ted J. Hofmann, Roberta Marino, Massimo Dominici, and Edwin M. Horwitz. "GD2+ Selected Mesenchymal Stromal Cells (MSCs) Demonstrate a More Robust Proliferation and Differentiation Potential Compared to Unselected Cells." Blood 110, no. 11 (November 16, 2007): 1919. http://dx.doi.org/10.1182/blood.v110.11.1919.1919.
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Abstract Human mesenchymal stromal cells (MSCs) are spindle-shape, plastic-adherent cells with capacity to differentiate to bone, cartilage, and fat. MSCs express fibroblast, endothelial, and lymphocyte antigens, e.g. CD105, CD73, CD90, and CD166 which are the cornerstone of phenotypic characterization of these cells. We recently showed that MSCs are the only bone marrow cell to express GD2, a neural ganglioside. Now, for the first time we show that GD2 may serve as the single, unique, and definitive marker of marrow and adipose derived MSCs that can be used to isolate GD2+ MSCs, which possess important biologic properties justifying prospective isolation. MSCs expression of GD2 is uniformly high on freshly isolated and culture-expanded cells. Using the Miltenyi AutoMACS® device and a monoclonal antibody recognizing GD2 (clone 14.G2A) we prospectively isolated a highly enriched MSC population from bone marrow MNCs. The selected fraction was >98% pure for GD2+ cells determined by flow cytometry. Light microscopy showed that the GD2-selected cells were smaller, thinner, and more spindle-like when attached to plastic compared to unselected MSCs which spread wider along the surface of the culture flask, the so-called “fried egg” appearance. The doubling time of GD2-selected MSCs was 30 hrs compared to 90 hrs for unselected cells representing a 3-fold greater growth rate. Cell cycle analysis by flow cytometry showed ∼80% of cells were in G0/G1 and ∼20% were in S/G2/M phases of the cell cycle in both populations. With the shorter doubling time, this data indicates that GD2-selected MSCs move through the cell cycle more rapidly than unselected cells. In accordance with this finding, electron microscopy showed few organelles in the GD2-selected cells, but increase lamellar bodies indicating overall less complexity, but consistent with a greater membrane turnover rate (cell division) than unselected MSCs. Moreover, flow cytometric analysis revealed an increased expression of receptors for bFGF and EFG, known mitogenic factor receptors for MSCs, compared to unselected MSCs. In vitro differentiation of GD2-selected MSCs showed a more robust osteoid matrix formation (osteoblast) and proteoglycan formation (chondroblast) assayed by semi-quantitative Alizarin Red and Alcian blue staining, respectively. Additionally, more GD2-selected MSCs differentiated to adipocytes than among unselected cells. Surprisingly, GD2 expression persisted on the in vitro human MSC-differentiated osteoblasts, chondroblasts, and adipocytes, in contrast to human bone-derived osteoblasts, adipose tissue, and cartilage which lacked GD2 expression. We conclude that GD2 is a unique, stably expressed surface MSC marker which can be used to prospectively isolate MSCs from marrow, GD2-selcted cells have a more robust in vitro proliferation and differentiation potential which may be valuable for cell therapy, and biologically, in vitro isolated MSCs may not represent the in vivo progenitor for bone, fat, or cartilage.
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Balis, Frank M., Cynthia Lester McCully, Christine M. Busch, Elizabeth Fox, and Katherine E. Warren. "Pharmacokinetics of the disialoganglioside, GD2, a circulating tumor biomarker for neuroblastoma, in nonhuman primates." Journal of Circulating Biomarkers 10 (December 3, 2021): 26–29. http://dx.doi.org/10.33393/jcb.2021.2329.
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Background: The ganglioside GD2 is a potential circulating tumor biomarker for the childhood cancer, neuroblastoma. Interpreting the levels of a circulating tumor biomarker depends in part on a knowledge of the biomarker’s clinical pharmacology. Background: The ganglioside GD2 is a potential circulating tumor biomarker for the childhood cancer neuroblastoma. Interpreting the levels of a circulating tumor biomarker depends in part on a knowledge of the biomarker’s clinical pharmacology. Methods: We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of the C18 lipoform of GD2 in two nonhuman primates with indwelling subcutaneous CSF lateral ventricular reservoir systems. GD2 was quantified with a validated high-performance liquid chromatography (HPLC)/tandem mass spectrometry assay. GD2 was administered as a short intravenous infusion and frequent plasma and CSF samples were drawn over 72 hours. Results: GD2 plasma concentration declined monoexponentially with a half-life of 16 hours. Clearance was 0.0136 and 0.0131 L/h and volume of distribution (Vd) was 0.035 and 0.038 L/kg in the two animals. Vd was equivalent to plasma volume. Greater than 98% of GD2 in plasma is in a bound form consistent with its known association with lipoproteins and accounting for its limited volume of distribution. GD2 did not cross over from plasma into the CSF. Conclusions: The pharmacokinetic profile of GD2 is favorable for a circulating tumor biomarker. This study demonstrates the value of characterizing the clinical pharmacology of circulating biomarkers to better understand their clinical behavior.
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Kholodenko, Irina V., Daniel V. Kalinovsky, Elena V. Svirshchevskaya, Igor I. Doronin, Maria V. Konovalova, Alexey V. Kibardin, Tatyana V. Shamanskaya, Sergey S. Larin, Sergey M. Deyev, and Roman V. Kholodenko. "Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies." Molecules 24, no. 21 (October 24, 2019): 3835. http://dx.doi.org/10.3390/molecules24213835.
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Antigen-binding fragments of antibodies specific to the tumor-associated ganglioside GD2 are well poised to play a substantial role in modern GD2-targeted cancer therapies, however, rapid elimination from the body and reduced affinity compared to full-length antibodies limit their therapeutic potential. In this study, scFv fragments of GD2-specific antibodies 14.18 were produced in a mammalian expression system that specifically bind to ganglioside GD2, followed by site-directed pegylation to generate mono-, di-, and tetra-scFv fragments. Fractionated pegylated dimers and tetramers of scFv fragments showed significant increase of the binding to GD2 which was not accompanied by cross-reactivity with other gangliosides. Pegylated multimeric di-scFvs and tetra-scFvs exhibited cytotoxic effects in GD2-positive tumor cells, while their circulation time in blood significantly increased compared with monomeric antibody fragments. We also demonstrated a more efficient tumor uptake of the multimers in a syngeneic GD2-positive mouse cancer model. The findings of this study provide the rationale for improving therapeutic characteristics of GD2-specific antibody fragments by multimerization and propose a strategy to generate such molecules. On the basis of multimeric antibody fragments, bispecific antibodies and conjugates with cytotoxic drugs or radioactive isotopes may be developed that will possess improved pharmacokinetic and pharmacodynamic properties.
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Terzic, Tatjana, Martine Cordeau, Sabine Herblot, Pierre Teira, Sonia Cournoyer, Mona Beaunoyer, Michel Peuchmaur, Michel Duval, and Herve Sartelet. "Expression of Disialoganglioside (GD2) in Neuroblastic Tumors: A Prognostic Value for Patients Treated With Anti-GD2 Immunotherapy." Pediatric and Developmental Pathology 21, no. 4 (October 25, 2017): 355–62. http://dx.doi.org/10.1177/1093526617723972.
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Neuroblastoma, a malignant neoplasm of the sympathetic nervous system, is one of the most aggressive pediatric cancers. Patients with stage IV high-risk neuroblastoma receive an intensive multimodal therapy ending with an immunotherapy based on a chimeric monoclonal antibody ch14.18. Although the use of ch14.18 monoclonal antibody has significantly increased the survival rate of high-risk neuroblastoma patients, about 33% of these patients still relapse and die from their disease. Ch14.18 targets the disialoganglioside, GD2, expressed on neuroblastic tumor (NT) cells. To better understand the causes of tumor relapse following ch14.18 immunotherapy, we have analyzed the expression of GD2 in 152 tumor samples from patients with NTs using immunohistochemical stainings. We observed GD2 expression in 146 of 152 samples (96%); however, the proportion of GD2-positive cells varied among samples. Interestingly, low percentage of GD2-positive cells before immunotherapy was associated with relapse in patients receiving ch14.18 immunotherapy. In addition, we demonstrated in vitro that the sensitivity of neuroblastoma cell lines to natural killer-mediated lysis was dependent on the proportion of GD2-positive cells, in the presence of ch14.18 antibody. In conclusion, our results indicate that the proportion of tumor cells expressing GD2 in NTs should be taken in consideration, as a prognostic marker, for high-risk neuroblastoma patients receiving anti-GD2 immunotherapy.
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Evers, Mitchell, Marjolein Stip, Kaylee Keller, Hanneke Willemen, Maaike Nederend, Marco Jansen, Chilam Chan, et al. "Anti-GD2 IgA kills tumors by neutrophils without antibody-associated pain in the preclinical treatment of high-risk neuroblastoma." Journal for ImmunoTherapy of Cancer 9, no. 10 (October 2021): e003163. http://dx.doi.org/10.1136/jitc-2021-003163.
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BackgroundThe addition of monoclonal antibody therapy against GD2 to the treatment of high-risk neuroblastoma led to improved responses in patients. Nevertheless, administration of GD2 antibodies against neuroblastoma is associated with therapy-limiting neuropathic pain. This severe pain is evoked at least partially through complement activation on GD2-expressing sensory neurons.MethodsTo reduce pain while maintaining antitumor activity, we have reformatted the approved GD2 antibody ch14.18 into the IgA1 isotype. This novel reformatted IgA is unable to activate the complement system but efficiently activates leukocytes through the FcαRI (CD89).ResultsIgA GD2 did not activate the complement system in vitro nor induced pain in mice. Importantly, neutrophil-mediated killing of neuroblastoma cells is enhanced with IgA in comparison to IgG, resulting in efficient tumoricidal capacity of the antibody in vitro and in vivo.ConclusionsOur results indicate that employing IgA GD2 as a novel isotype has two major benefits: it halts antibody-induced excruciating pain and improves neutrophil-mediated lysis of neuroblastoma. Thus, we postulate that patients with high-risk neuroblastoma would strongly benefit from IgA GD2 therapy.
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Ly, Stanley, Vivek Anand, Fouad El-Dana, Khoa Nguyen, Yiming Cai, Shirong Cai, Helen Piwnica-Worms, et al. "Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2+ breast cancer stem-like cells." Journal for ImmunoTherapy of Cancer 9, no. 3 (March 2021): e001197. http://dx.doi.org/10.1136/jitc-2020-001197.
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BackgroundTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no effective standard therapy. Breast cancer stem-like cells (BCSCs) in primary TNBCs are reported to be responsible for metastatic spread of the disease and resistance to chemotherapy, but no available therapeutic tools target BCSCs. We previously reported that the ganglioside GD2 is highly expressed on BCSCs and that inhibition of its expression hampers TNBC growth. We therefore hypothesized that the anti-GD2 antibody dinutuximab (ch14.18) targets GD2+ BCSCs and inhibits TNBC growth.MethodTo test our hypothesis, we first determined GD2 expression via immunohistochemistry in frozen primary tumor samples from patients with TNBC (n=89). Then, we examined the effects of dinutuximab on TNBC cell adhesion, migration, and mammosphere formation in vitro and on tumor growth in vivo using TNBC cell-line and patient-derived xenograft (PDX) models.ResultsWe found that GD2 was expressed in around 60% of primary TNBC tumors at variable levels and was associated with worse overall survival of patients with TNBC (p=0.002). GD2 was found to be expressed in tumors and stroma, but normal ducts and lobules in adjacent tissues have shown low or no GD2 staining, indicating that GD2 is potentially a novel biomarker for tumor and its microenvironment. Treatment with dinutuximab significantly decreased adhesion and migration of MDA-MB-231 and SUM159 TNBC cells. Moreover, dinutuximab treatment inhibited mTOR signaling, which has been shown to be regulated by GD2 in BCSCs. Dinutuximab also reduced tumor growth in nude mice bearing TNBC cell-line xenografts. Finally, dinutuximab in combination with activated natural killer cells inhibited tumor growth in a TNBC PDX model and improved overall survival of tumor-bearing mice.ConclusionsDinutuximab successfully eliminated GD2+ cells and reduced tumor growth in both in vivo models. Our data provide proof-of-concept for the criticality of GD2 in BCSCs and demonstrate the potential of dinutuximab as a novel therapeutic approach for TNBC.
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Long, Adrienne H., Rimas J. Orentas, and Crystal L. Mackall. "Synthetic Chimeric Antigen Receptors (CARs) Rapidly Induce Exhaustion and Augmented Glycolytic Metabolism In Human T Cells and Implicate Persistent CD28 Signaling As a Driver Of Exhaustion In Human T Cells." Blood 122, no. 21 (November 15, 2013): 192. http://dx.doi.org/10.1182/blood.v122.21.192.192.
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Abstract Introduction Chimeric antigen receptors (CARs) provide a promising new approach for the adoptive immunotherapy of cancer. Though impressive antitumor activity has been observed with some CAR T cells, other CAR T cells demonstrate poor antitumor efficacy in vivo despite high cytolytic capacity in vitro due to poor expansion and persistence. Whether exhaustion of CAR T cells mirrors exhaustion that occurs naturally in chronically stimulated human T cells has not yet been studied. Here, we report that expression of select CD28 containing CARs in normal human T cells rapidly induces an exhausted state characterized by high PD-1 expression, poor persistence and poor antitumor efficacy, whereas other CARs do not induce this phenotype. Results Human T cells were expanded with anti-CD3/CD28 beads, and then transduced with a second-generation (CD28-CD3ζ) disialoganglioside 2 (GD2) specific CAR or a second-generation (CD28-CD3ζ) CD19 specific CAR. By day 7 of in vitro expansion, GD2 CAR T cells developed a metabolism more highly dependent on glycolysis compared to CD19 CAR T cells or untransduced controls. Neither CAR population was exposed to antigen during this expansion period. Using a Seahorse Extracellular Flux Analyzer, the ratio of glycolysis to oxidative phosphorylation rates (ECAR:OCR ratio) of GD2 CAR T cells was found to be double that of CD19 CAR T cells or controls on day 7. The highly glycolytic metabolism of GD2 CAR T cells was associated with an exhausted phenotype. GD2 CAR T cells expressed higher levels of PD-1, TIM-3 and LAG-3, and transcription repressor BLIMP-1, compared to CD19 CAR T cells or untransduced controls. Additionally, GD2 CAR T cells were poor cytokine producers, generating <10x lower levels of IL2, TNFα and IFNγ than CD19 CAR T cells upon in vitro co-incubation with a GD2+CD19+ osteosarcoma line (143B-CD19), despite maintaining comparable in vitro cytolytic ability. GD2 CAR T cells showed poor in vitro expansion and increased rates of apoptosis compared to controls. GD2 CAR T cells also did not persist and did not mediate antitumor effects against GD2+CD19+ tumors in a murine xenograft model in vivo, whereas CD19 CAR T cells completely eradicated CD19+ tumors and persisted in both the spleen and tumor compartments. To rule out the possibility that diminished cytokine production and in vivo efficacy was related to antigen specific effects, T cells were co-transduced with both the GD2 and CD19 CARs. Though single-transduced CD19 CAR T cells show no signs of an altered metabolism or exhaustion and have strong antitumor efficacy, CD19 CAR T cells co-transduced with the GD2 CAR demonstrate an exhausted phenotype and diminished antitumor efficacy similar to that of single-transduced GD2 CAR T cells. Thus, expression of the GD2 CAR confers a dominant exhausted phenotype in T cells, and prevents otherwise efficacious CARs from mediating strong antitumor effects. We hypothesized that chronic signaling of CD3ζ and CD28 via the GD2 CAR results in exhaustion. Interestingly, however, we did not identify GD2 expression in the culture system. Point mutations in the CAR antigen-binding site, though abrogating GD2 binding, did not prevent the development of exhaustion. Thus, we postulate that constitutive receptor signaling may occur via interactions between the framework regions of the CAR receptors. Importantly however, substitution of 4-1BB for the CD28 domain in the GD2 CAR substantially diminished PD-1 expression, one of the hallmark features of exhausted T cells. Conclusions We report that expression of a CD28 containing GD2 CAR induces both an altered metabolism and an exhausted state in human T cells, resulting in poor in vivo persistence and antitumor efficacy. We hypothesize that tonic signaling through the GD2 CAR induces this phenotype and have identified the CD28 domain as an important component contributing to this phenotype. Rapid induction of exhaustion mediated via a synthetic receptor provides a novel model system to identify mechanistic factors required for this phenotype in human T cells. Work is currently underway to molecularly define the basis for the exhaustion of GD2 CAR T cells and to probe a potential role for altered T cell metabolism as a contributor to T cell exhaustion in human T cells. Disclosures: No relevant conflicts of interest to declare.
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Hummel, Hans-Ulrich, and Petra Joerg. "Zur Kenntnis von Gadolinium(III)-sulfit Dihydrat Gd2(SO3)3· 2 H2O/ On the Existance of Gadolinium (III)-sulfite Dihydrate Gd2(SO3)3 · 2H2O." Zeitschrift für Naturforschung B 48, no. 1 (January 1, 1993): 82–84. http://dx.doi.org/10.1515/znb-1993-0118.
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Different hydrates of Gd2(SO3)3 are obtained depending on preparation conditions. For preparation of Gd2(SO3)3, gaseous SO2 is passed through a suspension of Gd2O3 in H2O at room temperature until a clear solution is formed. Upon immediate heating to about 100 °C a mixture of Gd2(SO3)3 · 2H2O and Gd2(SO3)3 · 3H2O is formed. If the boiling procedure is performed after 6 days, a pure product consisting of the trihydrate is obtained. The different phases are identified by REM, DTA -TG -investigation and X-ray powder analysis. The X-ray powder pattern of Gd2(SO3)3 · 2H2O is consistent with patterns of isotype Ln2(SO3)3 · H2O were Ln = Pr, Nd, Sm and Eu.
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Soman, Gopalan, Xiaoyi Yang, Hengguang Jiang, Steve Giardina, and Gautam Mitra. "Comparison of GD2 binding capture ELISA assays for anti-GD2-antibodies using GD2-coated plates and a GD2-expressing cell-based ELISA." Journal of Immunological Methods 373, no. 1-2 (October 2011): 181–91. http://dx.doi.org/10.1016/j.jim.2011.08.016.
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Martinez, Caridad, Ted J. Hofmann, Roberta Marino, Massimo Dominici, and Edwin M. Horwitz. "Human bone marrow mesenchymal stromal cells express the neural ganglioside GD2: a novel surface marker for the identification of MSCs." Blood 109, no. 10 (January 30, 2007): 4245–48. http://dx.doi.org/10.1182/blood-2006-08-039347.
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Abstract Mesenchymal stromal cells (MSCs) have enormous potential for the regeneration of bone, cartilage, and other tissues derived from primitive mesoderm. Despite extensive research, there is still no single marker that reliably identifies MSCs within the bone marrow. Using immunocytochemistry and flow cytometry, we demonstrate here that the neural ganglioside GD2 is expressed by MSCs either newly isolated from bone marrow or expanded in tissue culture; this finding was supported by reverse transcriptase–polymerase chain reaction (RT-PCR) analysis showing expression of the mRNA for GD2 synthase, an essential enzyme for GD2 biosynthesis. GD2 was also expressed on MSCs isolated from adipose tissue, but not on foreskin fibroblasts. Importantly, MSCs were the only cells within normal marrow that expressed this marker. Thus, GD2 appears to be the first reported single surface marker that uniquely distinguishes MSCs from other marrow elements. GD2 may prove valuable to study MSC biology and for the preparation of MSCs for clinical applications.
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Cavdarli, Sumeyye, Larissa Schröter, Malena Albers, Anna-Maria Baumann, Dorothée Vicogne, Jean-Marc Le Doussal, Martina Mühlenhoff, Philippe Delannoy, and Sophie Groux-Degroote. "Role of Sialyl-O-Acetyltransferase CASD1 on GD2 Ganglioside O-Acetylation in Breast Cancer Cells." Cells 10, no. 6 (June 11, 2021): 1468. http://dx.doi.org/10.3390/cells10061468.
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The O-acetylated form of GD2, almost exclusively expressed in cancerous tissues, is considered to be a promising therapeutic target for neuroectoderm-derived tumors, especially for breast cancer. Our recent data have shown that 9-O-acetylated GD2 (9-OAcGD2) is the major O-acetylated ganglioside species in breast cancer cells. In 2015, Baumann et al. proposed that Cas 1 domain containing 1 (CASD1), which is the only known human sialyl-O-acetyltransferase, plays a role in GD3 O-acetylation. However, the mechanisms of ganglioside O-acetylation remain poorly understood. The aim of this study was to determine the involvement of CASD1 in GD2 O-acetylation in breast cancer. The role of CASD1 in OAcGD2 synthesis was first demonstrated using wild type CHO and CHOΔCasd1 cells as cellular models. Overexpression using plasmid transfection and siRNA strategies was used to modulate CASD1 expression in SUM159PT breast cancer cell line. Our results showed that OAcGD2 expression was reduced in SUM159PT that was transiently depleted for CASD1 expression. Additionally, OAcGD2 expression was increased in SUM159PT cells transiently overexpressing CASD1. The modulation of CASD1 expression using transient transfection strategies provided interesting insights into the role of CASD1 in OAcGD2 and OAcGD3 biosynthesis, and it highlights the importance of further studies on O-acetylation mechanisms.
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Fest, Stefan, Kerstin Hilt, Nicole Huebener, Yan Zeng, Anne Strandsby, Silke Weixler, Gerhard Gaedicke, et al. "GD2 Peptide Mimotope DNA Vaccines for Anti-Neuroblastoma Immunotherapy." Blood 104, no. 11 (November 16, 2004): 1350. http://dx.doi.org/10.1182/blood.v104.11.1350.1350.
Full textAbstract:
Abstract The tumor-associated antigen disialoganglioside-GD2 is expressed on neuroblastoma and melanoma and is an established target for passive immunotherapy. The aim of this study was to develop an active immunization strategy leading to the induction of a humoral anti-GD2 immune response. However, carbohydrates and glycolipids are T cell-independent antigens (TI) and usually evoke a poor immune response in tumor-bearing hosts. Here, we describe the identification, characterization and in vivo efficacy of cyclic peptides mimicking the structure of glycolipid GD2, i.e. GD2 mimotopes, in order to overcome T-cell independency. First, GD2 peptide mimotopes were identified by biopanning experiments of a phage-display library displaying circular decapeptides against the human/mouse chimeric anti-GD2 antibody (Ab) ch14.18. Thirteen independent phage clones were isolated which bind to ch14.18 with high specificity. Competitive binding of phages expressing GD2 peptide mimotopes to ch14.18 antibody revealed two superior peptide candidates, mimotope A (MA) and and mimotope D (MD), which were subjected to further evaluation. Second, two plasmid DNA minigene vaccines were generated by overlapping PCR encoding for MA and MD, respectively. The plasmids were based on pSecTag2-A also including a kappa leader sequence, a T-cell helper epitope from HIV-1 gp 120 (T1) and a myc-tag. Minigene expression was demonstrated following transfection of COS-7 cells in western-blots and GD2 mimikry was determined in solid phase ELISA experiments. Third, the efficacy of these mimotope DNA vaccines to induce a tumor protective anti-GD2 immune response was tested in the syngeneic NXS2 model of neuroblastoma expressing ganglioside GD2. The DNA vaccination was accomplished with attenuated Salmonella typhimurium (SL 7207) used as an oral vaccine carrier. Only mice receiving the mimotope DNA vaccines revealed a decrease in primary tumor growth by 50% and a dramatic reduction of spontaneous liver metastases with a mean liver weight of 1g in both groups (MA and MD) in contrast to negative controls (3g). Interestingly, mice immunized with KLH conjugated peptide mimotopes A and D revealed an increased rate of s.c. tumor growth and spontaneous liver metastasis with average liver weights of 5 (MA) and 7 (MD), respecively, suggesting the induction of tolerance using this peptide vaccine approach. Finally the highest anti-GD2 humoral immune response was observed in sera of mice from both GD2 mimotope DNA vaccine groups, consistent with the anti-tumor reponse observed in vivo. Based on these data, we belive that GD2 mimotope DNA vaccines may provide a useful strategy for active immunization against neuroblastoma.
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Hook, Lauren M., Sita Awasthi, Tina M. Cairns, Mohamad-Gabriel Alameh, Bernard T. Fowler, Kevin P. Egan, Molly M. H. Sung, Drew Weissman, Gary H. Cohen, and Harvey M. Friedman. "Antibodies to Crucial Epitopes on HSV-2 Glycoprotein D as a Guide to Dosing an mRNA Genital Herpes Vaccine." Viruses 14, no. 3 (March 5, 2022): 540. http://dx.doi.org/10.3390/v14030540.
Full textAbstract:
The toxicity of mRNA-lipid nanoparticle (LNP) vaccines depends on the total mRNA-LNP dose. We established that the maximum tolerated dose of our trivalent mRNA-LNP genital herpes vaccine was 10 μg/immunization in mice. We then evaluated one of the mRNAs, gD2 mRNA-LNP, to determine how much of the 10 μg total dose to assign to this immunogen. We immunized mice with 0.3, 1.0, 3.0, or 10 μg of gD2 mRNA-LNP and measured serum IgG ELISA, neutralizing antibodies, and antibodies to six crucial gD2 epitopes involved in virus entry and spread. Antibodies to crucial gD2 epitopes peaked at 1 μg, while ELISA and neutralizing titers continued to increase at higher doses. The epitope results suggested no immunologic benefit above 1 μg of gD2 mRNA-LNP, while ELISA and neutralizing titers indicated higher doses may be useful. We challenged the gD2 mRNA-immunized mice intravaginally with HSV-2. The 1-μg dose provided total protection, confirming the epitope studies, and supported assigning less than one-third of the trivalent vaccine maximum dose of 10 μg to gD2 mRNA-LNP. Epitope mapping as performed in mice can also be accomplished in phase 1 human trials to help select the optimum dose of each immunogen in a multivalent vaccine.
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ji, Cheng, Fengtao You, Tingting Zhang, Shuangshuang Fan, Zhichao Han, Shufen Xiang, Yinyan Wang, et al. "Novel anti-GD2 CAR-T cells exhibit superior cytotoxicity against neuroblastoma." European Journal of Inflammation 18 (January 2020): 205873922096119. http://dx.doi.org/10.1177/2058739220961193.
Full textAbstract:
Treatment of high-risk paediatric neuroblastoma represents an unmet clinical need. Chimeric antigen receptor-modified T cell (CAR-T) therapy is a promising treatment option, but there exist some challenges regarding specificity and potency. The current study used ganglioside GD2 as a target for CAR-T construction because of its selective overexpression in neuroblastoma cells. We engineered a GD2-based CAR-T construct, including ICOS and 4-1BB co-stimulatory domains for better persistence. The cytotoxicity of the generated CAR-T cells (PG3-GD2-CAR-T) was verified using in vitro and in vivo assays. PG3-GD2-CAR-T cells exerted potent anti-tumour activity in vitro and in vivo, with minimal effects on peripheral blood cells. PG3-GD2-CAR-T cells exhibited encouraging specificity for and potency against neuroblastoma.