398 results on '"Gornall H"'
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2. Familial Aicardi–Goutières syndrome due to SAMHD1mutations is associated with chronic arthropathy and contracturesNo authors describe a conflict of interest.The clinical phenomenology was defined by R.C.D., D.SG. and M.A. The genetic studies were performed by H.G., G.I.R. and Y.J.C. R.C.D. and Y.J.C. wrote the first drafts of the article, and all authors were involved in writing the final drafts of the article.How to cite this article: Dale RC, Gornall H, SinghGrewal D, Alcausin M, Rice GI, Crow YJ. 2010. Familial Aicardi–Goutières syndrome due to SAMHD1mutations is associated with chronic arthropathy and contractures. Am J Med Genet Part A 152A:938–942.
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Dale, Russell C., Gornall, Hannah, SinghGrewal, Davinder, Alcausin, Melanie, Rice, Gillian I., and Crow, Yanick J.
- Abstract
We report on two siblings doubly heterozygous for null mutations in the recently identified AGS5gene SAMHD1. The older female child showed mild intellectual disability with microcephaly. Her brother demonstrated a significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains, and recurrent mouth ulcers. One child had a chronic progressive deforming arthropathy of the small and large joints, with secondary contractures. This family illustrate the remarkable phenotypic diversity accruing from mutations in genes associated with Aicardi–Goutières syndrome AGS. The association of arthropathy with SAMHD1mutations highlights a phenotypic overlap of AGS with familial autoinflammatory disorders such as chronic infantile neurological cutaneous and articular syndrome CINCA. This family therefore illustrate the need to consider mutation analysis of SAMHD1in nonspecific inflammatory phenotypes of childhood. We propose that arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi–Goutières syndrome because of SAMHD1mutations. © 2010 WileyLiss, Inc.
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- 2010
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3. Lung ART: phase III study comparing post-operative conformal radiotherapy to no post-operative radiotherapy in patients with completely resected non-small cell lung cancer and mediastinal N2 involvement
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Faivre-Finn, C., primary, Le Péchoux, C., additional, Edwards, J.G., additional, Chappell, B.E., additional, Gornall, H., additional, and Lubiatowska, R., additional
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- 2018
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4. 169: Lung ART: Phase III study comparing post-operative conformal radiotherapy to no post-operative radiotherapy in patients with completely resected non-small cell lung cancer and mediastinal N2 involvement
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Faivre-Finn, C., primary, Le Pechoux, C., additional, Edwards, J., additional, Chappel, B., additional, and Gornall, H., additional
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- 2017
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5. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis
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Ramesh, V, Bernardi, B, Stafa, A, Garone, Caterina, Franzoni, E, Abinun, M, Mitchell, P, Mitra, D, Friswell, M, Nelson, J, Shalev, Sa, Rice, Gi, Gornall, H, Szynkiewicz, M, Aymard, F, Ganesan, V, Prendiville, J, Livingston, Jh, Crow, Yj, Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
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Male ,DNA Mutational Analysis ,Infant ,Proteins ,Phosphoproteins ,SAM Domain and HD Domain-Containing Protein 1 ,Exodeoxyribonucleases ,Child, Preschool ,Homeostasis ,Humans ,Point Mutation ,Carotid Stenosis ,Female ,Cerebral Arterial Diseases ,Child ,Monomeric GTP-Binding Proteins - Abstract
AIM: To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. METHOD: We used clinical and radiological description and molecular analysis. RESULTS: Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. INTERPRETATION: Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1
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- 2010
6. Chilblains as a Diagnostic Sign of Aicardi-Goutières Syndrome
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Abdel-Salam, G. M. H., primary, El-Kamah, G. Y., additional, Rice, G. I., additional, EL-Darouti, M., additional, Gornall, H., additional, Szynkiewicz, M., additional, Aymard, F., additional, Zaki, M. S., additional, Abdel-Aleem, A. K., additional, Lebon, P., additional, and Crow, Y. J., additional
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- 2010
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7. P270 Moyamoya syndrome and peripheral vascular disease due to mutation in newly described Aicardi Goutieres syndrome 5 gene SAMHD1
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Ramesh, V., primary, Abinun, M., additional, Mitchell, P., additional, Mitra, D., additional, Friswell, M., additional, Rice, G.L., additional, Gornall, H., additional, and Crow, Y.J., additional
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- 2009
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8. SAMHD1 compound heterozygous rare variants associated with moyamoya and mitral valve disease in the absence of other features of Aicardi-Goutières syndrome.
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Karla AR, Pinard A, Boerio ML, Hemelsoet D, Tavernier SJ, De Pauw M, Vereecke E, Fraser S, Bamshad MJ, Guo D, Callewaert B, and Milewicz DM
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- Male, Humans, Child, Adult, SAM Domain and HD Domain-Containing Protein 1 genetics, Mitral Valve pathology, Mutation, Moyamoya Disease complications, Nervous System Malformations diagnostic imaging, Nervous System Malformations genetics, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System genetics, Autoimmune Diseases of the Nervous System pathology, Brain Diseases complications
- Abstract
Aicardi-Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early-onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in nine genes: TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1. Diagnosis is established by clinical findings (encephalopathy and acquired microcephaly, intellectual and physical impairments, dystonia, hepatosplenomegaly, sterile pyrexia, and/or chilblains), characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), or the identification of pathogenic/likely pathogenic variants in the known genes. One of the genes associated with AGS, SAMHD1, has also been associated with a spectrum of cerebrovascular diseases, including moyamoya disease (MMD). In this report, we describe a 31-year-old male referred to genetics for MMD since childhood who lacked the hallmark features of AGS patients but was found to have compound heterozygous SAMHD1 variants. He later developed mitral valve insufficiency due to recurrent chordal rupture and ultimately underwent a heart transplant at 37 years of age. Thus, these data suggest that SAMHD1 pathogenic variants can cause MMD without typical AGS symptoms and support that SAMHD1 should be assessed in MMD patients even in the absence of AGS features., (© 2023 Wiley Periodicals LLC.)
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- 2024
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9. CCR7 + selected gene-modified T cells maintain a central memory phenotype and display enhanced persistence in peripheral blood in vivo.
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Kueberuwa G, Gornall H, Alcantar-Orozco EM, Bouvier D, Kapacee ZA, Hawkins RE, and Gilham DE
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- Animals, Humans, Immunologic Memory, K562 Cells, Mice, Phenotype, Immunotherapy, Adoptive, Receptors, CCR7 immunology, T-Lymphocytes immunology, T-Lymphocytes transplantation
- Abstract
Background: Adoptive T cell immunotherapy (ATCT) for cancer entails infusing patients with T cells that recognise and destroy tumour cells. Efficient engraftment of T cells and persistence in the circulation correlate with favourable clinical outcomes. T cells of early differentiation possess an increased capacity for proliferation and therefore persistence, using these cells for ATCT could therefore lead to improved clinical outcomes., Method: We describe a method to enrich T cells of early differentiation status using paramagnetic beads and antibodies targeting cells expressing C-C motif chemokine receptor 7 (CCR7)., Results: Selection of cells expressing CCR7 enriches T cells of bearing markers of early differentiation status. This was validated through analysis of an array of surface markers and an observed reduction in effector cell functions ex vivo. CCR7 selection resulted in dramatic 83.6 and 137 fold increases in circulating levels of CD4 and CD8 T cells respectively compared to non-sorted T cells 3 weeks after adoptive transfer to NSG mice. We observed no significant difference in the engraftment levels of CCR7 or CD62L selected cells in the NSG mouse model. Comparison of cells ex vivo, however, suggests CCR7 selection is superior to CD62L selection in enriching T cells of early differentiation status., Conclusions: CCR7 selection offers a means to enrich T cells of early differentiation status for ACTC. Together our data suggests that these T cells are likely to display enhanced engraftment and persistence in patients in vivo and could therefore improve therapeutic efficacy of ACTC.
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- 2017
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10. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.
- Author
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Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
- Abstract
Aim To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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- View/download PDF
11. Monogenic lupus – from gene to targeted therapy.
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Menzel, Katharina, Novotna, Kateryna, Jeyakumar, Nivya, Wolf, Christine, and Lee-Kirsch, Min Ae
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TYPE I interferons ,SYSTEMIC lupus erythematosus ,NUCLEIC acids ,AUTOIMMUNE diseases ,IMMUNE complexes - Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by loss of tolerance to nuclear antigens. The formation of autoantibodies and the deposition of immune complexes trigger inflammatory tissue damage that can affect any part of the body. In most cases, SLE is a complex disease involving multiple genetic and environmental factors. Despite advances in the treatment of SLE, there is currently no cure for SLE and patients are treated with immunosuppressive drugs with significant side effects. The elucidation of rare monogenic forms of SLE has provided invaluable insights into the molecular mechanisms underlying systemic autoimmunity. Harnessing this knowledge will facilitate the development of more refined and reliable biomarker profiles for diagnosis, therapeutic monitoring, and outcome prediction, and guide the development of novel targeted therapies not only for monogenic lupus, but also for complex SLE. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Cell-Based Treatment in Acute Myeloid Leukemia Relapsed after Allogeneic Stem Cell Transplantation.
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Canichella, Martina and de Fabritiis, Paolo
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ACUTE myeloid leukemia ,STEM cell transplantation ,CHIMERIC antigen receptors ,HEMATOPOIETIC stem cells ,CELLULAR therapy - Abstract
Allogeneic stem cell transplant (ASCT) remains the only treatment option for patients with high-risk acute myeloid leukemia (AML). Recurrence of leukemic cells after ASCT represents a dramatic event associated with a dismal outcome, with a 2-year survival rate of around 20%. Adoptive cell therapy (ACT) is a form of cell-based strategy that has emerged as an effective therapy to treat and prevent post-ASCT recurrence. Lymphocytes are the principal cells used in this therapy and can be derived from a hematopoietic stem cell donor, the patient themselves, or healthy donors, after being engineered to express the chimeric antigen receptor (CAR-T and UniCAR-T). In this review, we discuss recent advances in the established strategy of donor lymphocyte infusion (DLI) and the progress and challenges of CAR-T cells. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Definition and application of good manufacturing process-compliant production of CEA-specific chimeric antigen receptor expressing T-cells for phase I/II clinical trial.
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Guest RD, Kirillova N, Mowbray S, Gornall H, Rothwell DG, Cheadle EJ, Austin E, Smith K, Watt SM, Kühlcke K, Westwood N, Thistlethwaite F, Hawkins RE, and Gilham DE
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- Humans, Immunophenotyping, Interferon-gamma biosynthesis, Adoptive Transfer, Carcinoembryonic Antigen immunology, Chimerin Proteins biosynthesis, Receptors, Antigen, T-Cell biosynthesis, T-Lymphocytes immunology
- Abstract
Adoptive cell therapy employing gene-modified T-cells expressing chimeric antigen receptors (CARs) has shown promising preclinical activity in a range of model systems and is now being tested in the clinical setting. The manufacture of CAR T-cells requires compliance with national and European regulations for the production of medicinal products. We established such a compliant process to produce T-cells armed with a first-generation CAR specific for carcinoembryonic antigen (CEA). CAR T-cells were successfully generated for 14 patients with advanced CEA(+) malignancy. Of note, in the majority of patients, the defined procedure generated predominantly CD4(+) CAR T-cells with the general T-cell population bearing an effector-memory phenotype and high in vitro effector function. Thus, improving the process to generate less-differentiated T-cells would be more desirable in the future for effective adoptive gene-modified T-cell therapy. However, these results confirm that CAR T-cells can be generated in a manner compliant with regulations governing medicinal products in the European Union.
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- 2014
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14. CAR T cells: driving the road from the laboratory to the clinic.
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Cheadle EJ, Gornall H, Baldan V, Hanson V, Hawkins RE, and Gilham DE
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- Animals, Cancer Vaccines genetics, Cancer Vaccines immunology, Cell Culture Techniques, Gene Transfer Techniques, Genetic Engineering, Humans, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Leukemia, B-Cell immunology, Leukemia, B-Cell therapy, Lymphoma, B-Cell immunology, Lymphoma, B-Cell therapy, Antigens, CD19 immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
Blockbuster antibody therapies have catapulted immune-based approaches to treat cancer into the consciousness of mainstay clinical research. On the back of this, other emerging immune-based therapies are providing great promise. T-cell therapy is one such area where recent trials using T cells genetically modified to express an antibody-based chimeric antigen receptor (CAR) targeted against the CD19 antigen have demonstrated impressive responses when adoptively transferred to patients with advanced chronic lymphocytic leukemia. The general concept of the CAR T cell was devised some 20 years ago. In this relatively short period of time, the technology to redirect T-cell function has moved at pace facilitating clinical translation; however, many questions remain with respect to developing the approach to improve CAR T-cell therapeutic activity and also to broaden the range of tumors that can be effectively targeted by this approach. This review highlights some of the underlying principles and compromises of CAR T-cell technology using the CD19-targeted CAR as a paradigm and discusses some of the issues that relate to targeting solid tumors with CAR T cells., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2014
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15. Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for cancer.
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Alcantar-Orozco EM, Gornall H, Baldan V, Hawkins RE, and Gilham DE
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- Animals, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Humans, Interleukins genetics, Interleukins metabolism, MART-1 Antigen genetics, MART-1 Antigen metabolism, Melanoma therapy, Mice, Mice, Inbred NOD, Mice, SCID, Models, Animal, Skin Neoplasms therapy, T-Lymphocytes metabolism, T-Lymphocytes physiology, Immunotherapy, Adoptive methods, T-Lymphocytes transplantation, Xenograft Model Antitumor Assays methods
- Abstract
The genetic modification of peripheral blood lymphocytes using retroviral vectors to redirect T cells against tumor cells has been recently used as a means to generate large numbers of antigen-specific T cells for adoptive cell therapy protocols. However, commonly used retroviral vector-based genetic modification requires T cells to be driven into cell division; this potent mitogenic stimulus is associated with the development of an effector phenotype that may adversely impact upon the long-term engraftment potential and subsequent antitumor effects of T cells. To investigate whether the cytokines used during culture impact upon the engraftment potential of gene-modified T cells, a humanized model employing T cells engrafted with a MART-1-specific T cell receptor adoptively transferred into NOD/Shi-scid IL-2rγ(-/-) (NSG) immune-deficient mice bearing established melanoma tumors was used to compare the effects of the common γ chain cytokines IL-2, IL-7, and IL-15 upon gene-modified T cell activity. MART-1-specific T cells cultured in IL-7 and IL-15 demonstrated greater relative in vitro proliferation and viability of T cells compared with the extensively used IL-2. Moreover, the IL-15 culture prolonged the survival of animals bearing melanoma tumors after adoptive transfer. However, the combination of IL-7 and IL-15 produced T cells with improved engraftment potential compared with IL-15 alone; however, a high rate of xenogeneic graft-versus-host disease prevented the identification of a clear improvement in antitumor effect of these T cells. These results clearly demonstrate modulation of gene-modified T cell engraftment in the NSG mouse, which supports the future testing of the combination of IL-7 and IL-15 in adoptive cell therapy protocols; however, this improved engraftment is also associated with the long-term maintenance of xenoreactive T cells, which limits the ultimate usefulness of the NSG mouse model in this situation.
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- 2013
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16. Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome.
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Rice GI, Reijns MA, Coffin SR, Forte GM, Anderson BH, Szynkiewicz M, Gornall H, Gent D, Leitch A, Botella MP, Fazzi E, Gener B, Lagae L, Olivieri I, Orcesi S, Swoboda KJ, Perrino FW, Jackson AP, and Crow YJ
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- Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System enzymology, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Nervous System Malformations diagnosis, Nervous System Malformations enzymology, Ribonuclease H metabolism, Autoimmune Diseases of the Nervous System genetics, Nervous System Malformations genetics, Point Mutation, RNA Splice Sites, Ribonuclease H genetics
- Abstract
Aicardi-Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families., (© 2013 WILEY PERIODICALS, INC.)
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- 2013
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17. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
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Briggs TA, Rice GI, Daly S, Urquhart J, Gornall H, Bader-Meunier B, Baskar K, Baskar S, Baudouin V, Beresford MW, Black GC, Dearman RJ, de Zegher F, Foster ES, Francès C, Hayman AR, Hilton E, Job-Deslandre C, Kulkarni ML, Le Merrer M, Linglart A, Lovell SC, Maurer K, Musset L, Navarro V, Picard C, Puel A, Rieux-Laucat F, Roifman CM, Scholl-Bürgi S, Smith N, Szynkiewicz M, Wiedeman A, Wouters C, Zeef LA, Casanova JL, Elkon KB, Janckila A, Lebon P, and Crow YJ
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- Animals, Autoimmunity, Bone Diseases, Developmental enzymology, Cattle, Chromosomes, Human, Pair 19, Female, Humans, Inflammation, Lupus Erythematosus, Systemic metabolism, Male, Models, Molecular, Mutation, Mutation, Missense, Phenotype, Sclerosis pathology, Tartrate-Resistant Acid Phosphatase, Acid Phosphatase deficiency, Acid Phosphatase genetics, Bone Diseases, Developmental genetics, Bone Diseases, Developmental pathology, Gene Expression Regulation, Interferon Type I metabolism, Isoenzymes deficiency, Isoenzymes genetics
- Abstract
We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.
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- 2011
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18. Familial Aicardi-Goutières syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures.
- Author
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Dale RC, Gornall H, Singh-Grewal D, Alcausin M, Rice GI, and Crow YJ
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- Child, Child, Preschool, Chronic Disease, Contracture complications, DNA Mutational Analysis, Family, Female, Humans, Infant, Infant, Newborn, Joint Diseases complications, Male, Pedigree, Pregnancy, SAM Domain and HD Domain-Containing Protein 1, Syndrome, Urticaria complications, Urticaria genetics, Abnormalities, Multiple genetics, Contracture genetics, Genetic Predisposition to Disease, Joint Diseases genetics, Monomeric GTP-Binding Proteins genetics, Mutation genetics
- Abstract
We report on two siblings doubly heterozygous for null mutations in the recently identified AGS5 gene SAMHD1. The older female child showed mild intellectual disability with microcephaly. Her brother demonstrated a significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains, and recurrent mouth ulcers. One child had a chronic progressive deforming arthropathy of the small and large joints, with secondary contractures. This family illustrate the remarkable phenotypic diversity accruing from mutations in genes associated with Aicardi-Goutières syndrome (AGS). The association of arthropathy with SAMHD1 mutations highlights a phenotypic overlap of AGS with familial autoinflammatory disorders such as chronic infantile neurological cutaneous and articular syndrome (CINCA). This family therefore illustrate the need to consider mutation analysis of SAMHD1 in non-specific inflammatory phenotypes of childhood. We propose that arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi-Goutières syndrome because of SAMHD1 mutations., ((c) 2010 Wiley-Liss, Inc.)
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- 2010
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19. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response.
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Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, and Crow YJ
- Subjects
- Amino Acid Substitution, Brain Diseases, Metabolic, Inborn immunology, Humans, Monomeric GTP-Binding Proteins immunology, SAM Domain and HD Domain-Containing Protein 1, Brain Diseases, Metabolic, Inborn genetics, Immunity, Innate, Monomeric GTP-Binding Proteins genetics
- Abstract
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
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- 2009
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20. Recent advances in CAR‐T cell therapy for acute myeloid leukaemia.
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Gao, Chi, Li, Xin, Xu, Yao, Zhang, Tongcun, Zhu, Haichuan, and Yao, Di
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ACUTE myeloid leukemia ,CELLULAR therapy ,HEMATOPOIETIC stem cell transplantation ,CHIMERIC antigen receptors ,BONE marrow cells - Abstract
Acute myeloid leukaemia (AML) is a fatal and refractory haematologic cancer that primarily affects adults. It interferes with bone marrow cell proliferation. Patients have a 5 years survival rate of less than 30% despite the availability of several treatments, including chemotherapy, allogeneic haematopoietic stem cell transplantation (Allo‐HSCT), and receptor antagonist drugs. Allo‐HSCT is the mainstay of acute myeloid leukaemia treatment. Although it does work, there are severe side effects, such as graft‐versus‐host disease (GVHD). In recent years, chimeric antigen receptor (CAR)‐T cell therapies have made significant progress in the treatment of cancer. These engineered T cells can locate and recognize tumour cells in vivo and release a large number of effectors through immune action to effectively kill tumour cells. CAR‐T cells are among the most effective cancer treatments because of this property. CAR‐T cells have demonstrated positive therapeutic results in the treatment of acute myeloid leukaemia, according to numerous clinical investigations. This review highlights recent progress in new targets for AML immunotherapy, and the limitations, and difficulties of CAR‐T therapy for AML. [ABSTRACT FROM AUTHOR]
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- 2024
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21. CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy.
- Author
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Jiawen Huang, Qian Yang, Wen Wang, and Juan Huang
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CHIMERIC antigen receptors ,MAJOR histocompatibility complex ,IMMUNOTHERAPY ,MANUFACTURING cells - Abstract
Chimeric antigen receptor (CAR) T cell therapy has transformed cancer immunotherapy. However, significant challenges limit its application beyond B cell-driven malignancies, including limited clinical efficacy, high toxicity, and complex autologous cell product manufacturing. Despite efforts to improve CAR T cell therapy outcomes, there is a growing interest in utilizing alternative immune cells to develop CAR cells. These immune cells offer several advantages, such as major histocompatibility complex (MHC)-independent function, tumor microenvironment (TME) modulation, and increased tissue infiltration capabilities. Currently, CAR products from various T cell subtypes, innate immune cells, hematopoietic progenitor cells, and even exosomes are being explored. These CAR products often show enhanced antitumor efficacy, diminished toxicity, and superior tumor penetration. With these benefits in mind, numerous clinical trials are underway to access the potential of these innovative CAR cells. This review aims to thoroughly examine the advantages, challenges, and existing insights on these new CAR products in cancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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22. Genetic interrogation for sequence and copy number variants in systemic lupus erythematosus.
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Kim-Wah Yeo, Nicholas, Che Kang Lim, Nay Yaung, Katherine, Kim Huat Khoo, Nicholas, Thaschawee Arkachaisri, Albani, Salvatore, and Joo Guan Yeo
- Subjects
SYSTEMIC lupus erythematosus ,DNA copy number variations ,EXOMES ,NUCLEOTIDE sequencing ,LUPUS erythematosus - Abstract
Early-onset systemic lupus erythematosus presents with a more severe disease and is associated with a greater genetic burden, especially in patients from Black, Asian or Hispanic ancestries. Next-generation sequencing techniques, notably whole exome sequencing, have been extensively used in genomic interrogation studies to identify causal disease variants that are increasingly implicated in the development of autoimmunity. This Review discusses the known casual variants of polygenic and monogenic systemic lupus erythematosus and its implications under certain genetic disparities while suggesting an age-based sequencing strategy to aid in clinical diagnostics and patient management for improved patient care. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Particularități clinico-genetice și neuro-imagistice în sindromul Aicardi-Goutières.
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Hadjiu, Svetlana, Calistru, Iulia, Sprîncean, Mariana, Capestru, Elena, Istratuc, Irina, Constantin, Olga, Calcîi, Cornelia, and Ina, Palii
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NEURONS ,GENETIC disorders ,MYELIN sheath ,SPINAL cord ,WHITE matter (Nerve tissue) ,LEUKODYSTROPHY - Abstract
Copyright of Journal for Neurology & Psychiatry of Child & Adolescent in Romania is the property of Romanian Society of Child & Adolescent Neurology & Psychiatry and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
24. Vasculitis and vasculopathy associated with inborn errors of immunity: an overview.
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Federici, Silvia, Cinicola, Bianca Laura, La Torre, Francesco, Castagnoli, Riccardo, Lougaris, Vassilios, Giardino, Giuliana, Volpi, Stefano, Caorsi, Roberta, Leonardi, Lucia, Corrente, Stefania, Soresina, Annarosa, Cancrini, Caterina, Insalaco, Antonella, Gattorno, Marco, De Benedetti, Fabrizio, Marseglia, Gian Luigi, Del Giudice, Michele Miraglia, and Cardinale, Fabio
- Published
- 2024
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25. Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition.
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Gernez, Yael, Narula, Mansi, Cepika, Alma-Martina, Camacho, Juanita Valdes, Hoyte, Elisabeth G., Mouradian, Kirsten, Glader, Bertil, Singh, Deepika, Sathi, Bindu, Rao, Latha, Tolin, Ana L., Weinberg, Kenneth I., Lewis, David B., Bacchetta, Rosa, and Weinacht, Katja G.
- Subjects
LITERATURE reviews ,SKELETAL dysplasia ,BONE marrow ,MULTIPLE myeloma ,DEVELOPMENTAL delay ,SPASTICITY - Abstract
Biallelic mutations in the ACP5 gene cause spondyloenchondrodysplasia with immune dysregulation (SPENCDI). SPENCDI is characterized by the phenotypic triad of skeletal dysplasia, innate and adaptive immune dysfunction, and variable neurologic findings ranging from asymptomatic brain calcifications to severe developmental delay with spasticity. Immune dysregulation in SPENCDI is often refractory to standard immunosuppressive treatments. Here, we present the cases of two patients with SPENCDI and recalcitrant autoimmune cytopenias who demonstrated a favorable clinical response to targeted JAK inhibition over a period of more than 3 years. One of the patients exhibited steadily rising IgG levels and a bone marrow biopsy revealed smoldering multiple myeloma. A review of the literature uncovered that approximately half of the SPENCDI patients reported to date exhibited increased IgG levels. Screening for multiple myeloma in SPENCDI patients with rising IgG levels should therefore be considered. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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26. Intracerebral large artery disease in Aicardi-Goutières syndrome with TREX1 mutation: a case report.
- Author
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Wu, Chang-Chun, Peng, Steven Shinn-Forng, and Lee, Wang-Tso
- Subjects
ARTERIAL diseases ,MAGNETIC resonance angiography ,GENETIC mutation ,SYNDROMES ,GASTROINTESTINAL system - Abstract
We report a patient diagnosed with Aicardi-Goutières syndrome (AGS) with homozygous TREX1 gene mutation. Her magnetic resonance angiography (MRA) showed intracerebral large artery disease, which was rarely reported in the past in TREX1 AGS patients. Her younger sister also had homozygous TREX1 gene mutation and died of necrotizing enterocolitis. Intracerebral large artery involvement has been seen as a particular feature of SAMHD1-related disease. Our patient also had arthropathy, which is a finding more commonly mentioned in SAMHD1-related diseases. The observations in our case may contribute to our understanding of the pathogenetic mechanism of TREX1 AGS, involving the intracerebral large arteries, arthropathy, and possibly the gastrointestinal tract. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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27. Molecular phylogenetics, character evolution and systematics of the genus Micranthes ( Saxifragaceae).
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Tkach, Natalia, Röser, Martin, and Hoffmann, Matthias H.
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MOLECULAR phylogeny ,SAXIFRAGA ,PLANT evolution ,PLANT morphology ,NUCLEOTIDE sequence ,PLANT classification - Abstract
With c. 85 species, the genus Micranthes is among the larger genera of the Saxifragaceae. It is only distantly related to the morphologically similar genus Saxifraga, in which it has frequently been included as Saxifraga section Micranthes. To study the molecular evolution of Micranthes, we analysed nuclear ribosomal (internal transcribed spacer, ITS) and plastid ( trn L- trn F) DNA sequences in a comprehensive set of taxa comprising c. 75% of the species. The molecular phylogenetic tree from the combined dataset revealed eight well-supported clades of Micranthes. These clades agree in part with previously acknowledged subsections or series of Saxifraga section Micranthes. As these eight groups can also be delineated morphologically, we suggest that they should be recognized as sections of Micranthes. New relationships were also detected for some species and species groups, e.g. section Davuricae sister to sections Intermediae and Merkianae, and M. micranthidifolia as a member of section Micranthes. Species proposed to be excluded from the genus Micranthes for morphological reasons were resolved in the molecular tree in Saxifraga. Many morphological characters surveyed were homoplasious to varying extents. Micromorphological characters support comparatively well the clades in the phylogenetic tree. An updated nomenclature and a taxonomic conspectus of sections and species of Micranthes are provided. © 2015 The Linnean Society of London, Botanical Journal of the Linnean Society, 2015, 178, 47-66. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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28. Chimeric Antigen Receptor T-Cell Therapy in Acute Myeloid Leukemia: State of the Art and Recent Advances.
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Canichella, Martina, Molica, Matteo, Mazzone, Carla, and de Fabritiis, Paolo
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CLINICAL drug trials ,CELLULAR therapy ,CELL receptors ,B cell lymphoma ,TREATMENT effectiveness ,CELL lines ,BONE marrow ,DRUG development ,DIFFUSION of innovations ,DISEASE management - Abstract
Simple Summary: Compared to the resounding success demonstrated in the field of B-cell leukemia, lymphoma, and multiple myeloma, in the field of acute myeloid leukemia, CAR-T-cell-therapy slows down its application in clinical practice. Yet, immunotherapy and/or cell therapy could be curative in certain high-risk AML subtypes refractory to classical chemotherapy approaches. Several CAR-T constructs targeting different antigens have been tested and have shown promising results. This review illustrates the main results obtained with the use of CAR-T in AML. Chimeric antigen receptors (CAR)-T-cell therapy represents the most important innovation in onco-hematology in recent years. The progress achieved in the management of complications and the latest generations of CAR-T-cells have made it possible to anticipate in second-line the indication of this type of treatment in large B-cell lymphoma. While some types of B-cell lymphomas and B-cell acute lymphoid leukemia have shown extremely promising results, the same cannot be said for myeloid leukemias—in particular, acute myeloid leukemia (AML), which would require innovative therapies more than any other blood disease. The heterogeneities of AML cells and the immunological complexity of the interactions between the bone marrow microenvironment and leukemia cells have been found to be major obstacles to the clinical development of CAR-T in AML. In this review, we report on the main results obtained in AML clinical trials, the preclinical studies testing potential CAR-T constructs, and future perspectives. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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29. T-Rex escaped from the cytosolic park: Re-thinking the impact of TREX1 exonuclease deficiencies on genomic stability.
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Técher H
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- Humans, Animals, DNA Damage, Cytosol metabolism, Immunity, Innate genetics, Inflammation genetics, DNA Repair genetics, Exodeoxyribonucleases metabolism, Exodeoxyribonucleases genetics, Genomic Instability, Phosphoproteins metabolism, Phosphoproteins genetics
- Abstract
The Three Prime Repair Exonuclease 1 (TREX1) has been implicated in several pathologies characterized by chronic and inborn inflammation. Aberrant innate immunity caused by DNA sensing through the cGAS-STING pathway has been proposed to play a major role in the etiology of these interferonopathies. However, the molecular source of this DNA sensing and the possible involvement of TREX1 in genome (in)stability remains poorly understood. Recent findings reignite the debate about the cellular functions performed by TREX1 nuclease, notably in chromosome biology and stability. Here I put into perspective recent findings that suggest that TREX1 is at the crossroads of DNA damage response and inflammation in different pathological contexts., (© 2024 The Author(s). BioEssays published by Wiley Periodicals LLC.)
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- 2024
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30. Leveraging iPSC technology to assess neuro-immune interactions in neurological and psychiatric disorders.
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Michalski, Christina and Zhexing Wen
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NEUROLOGICAL disorders ,INDUCED pluripotent stem cells ,MENTAL illness ,CENTRAL nervous system ,NEURODEGENERATION - Abstract
Communication between the immune and the nervous system is essential for human brain development and homeostasis. Disruption of this intricately regulated crosstalk can lead to neurodevelopmental, psychiatric, or neurodegenerative disorders. While animal models have been essential in characterizing the role of neuroimmunity in development and disease, they come with inherent limitations due to species specific differences, particularly with regard to microglia, the major subset of brain resident immune cells. The advent of induced pluripotent stem cell (iPSC) technology now allows the development of clinically relevant models of the central nervous system that adequately reflect human genetic architecture. This article will review recent publications that have leveraged iPSC technology to assess neuro-immune interactions. First, we will discuss the role of environmental stressors such as neurotropic viruses or pro-inflammatory cytokines on neuronal and glial function. Next, we will review how iPSC models can be used to study genetic risk factors in neurological and psychiatric disorders. Lastly, we will evaluate current challenges and future potential for iPSC models in the field of neuroimmunity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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31. Non‐coding RNAs in cancer immunotherapy: Predictive biomarkers and targets.
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Alahdal, Murad and Elkord, Eyad
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NON-coding RNA ,T cell receptors ,NON-small-cell lung carcinoma ,BIOMARKERS ,CHIMERIC antigen receptors - Abstract
Background: To date, standardising clinical predictive biomarkers for assessing the response to immunotherapy remains challenging due to variations in personal genetic signatures, tumour microenvironment complexities and epigenetic onco‐mechanisms. Main body: Early monitoring of key non‐coding RNA (ncRNA) biomarkers may help in predicting the clinical efficacy of cancer immunotherapy and come up with standard predictive ncRNA biomarkers. For instance, reduced miR‐125b‐5p level in the plasma of non‐small cell lung cancer patients treated with anti‐PD‐1 predicts a positive outcome. The level of miR‐153 in the plasma of colorectal cancer patients treated with chimeric antigen receptor T lymphocyte (CAR‐T) cell therapy may indicate the activation of T‐cell killing activity. miR‐148a‐3p and miR‐375 levels may forecast favourable responses to CAR‐T‐cell therapy in B‐cell acute lymphoblastic leukaemia. In cancer patients treated with the GPC3 peptide vaccine, serum levels of miR‐1228‐5p, miR‐193a‐5p and miR‐375‐3p were reported as predictive biomarkers of good response and improved overall survival. Therefore, there is a critical need for further studies to elaborate on the key ncRNA biomarkers that have the potential to predict early clinical responses to immunotherapy. Conclusion: This review summarises important predictive ncRNA biomarkers that were reported in cancer patients treated with different immunotherapeutic modalities, including monoclonal antibodies, small molecule inhibitors, cancer vaccines and CAR‐T cells. In addition, a concise discussion on forthcoming perspectives is provided, outlining technical approaches for the optimal utilisation of immunomodulatory ncRNA biomarkers as predictive tools and therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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32. RNASEH2C c.194G>A is a Chinese‐specific founder mutation in three unrelated patients with Aicardi‐Goutières syndrome 3.
- Author
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Wang, Qingming, Han, Ye, Zhou, Xinlong, Cheng, ShuangXi, Wang, Xin, Chen, Xiaoli, and Yuan, Haiming
- Subjects
FAMILIAL spastic paraplegia ,MISSENSE mutation ,SYMPTOMS ,MALARIA ,SYNDROMES ,MOUTH ulcers - Abstract
Biallelic pathogenic variants in RNASEH2C cause Aicardi‐Goutières syndrome 3 (AGS3, MIM #610329), a rare early‐onset encephalopathy characterized by intermittent unexplained fever, chilblains, irritability, progressive microcephaly, dystonia, spasticity, severe psychomotor retardation and abnormal brain imaging. Currently, approximately 50 individuals with AGS3 and 19 variants in RNASEH2C have been revealed. Here, we reported the novel clinical manifestations and genotypic information of three unrelated Chinese patients with AGS3 caused by pathogenic variants in RNASEH2C. In addition to three novel missense variants (c.101G>A, p.Cys34Tyr; c.401T>A, p.Leu134Gln and c.434G>T, p.Arg145Leu), one missense variant (c.194G>A, p.Gly65Asp) reoccurred in all patients but was completely absent in South Asian and other ethnicities. Our study expanded the variant spectrum of RNASEH2C and identified RNASEH2C c.194G>A as a Chinese‐specific founder mutation. The novel phenotypes, including mouth ulcers, hip dysplasia, retarded dentition and hypogonadism, observed in our patients greatly enriched the clinical characteristics of AGS3. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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- View/download PDF
33. Exploration of Gross Motor Function in Aicardi-Goutières Syndrome.
- Author
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Gavazzi, Francesco, Glanzman, Allan M., Woidill, Sarah, Formanowski, Brielle, Dixit, Agrani, Isaacs, David, Kornafel, Tracy, Ballance, Elizabeth, Pierce, Samuel R., Modesti, Nicholson, Barcelos, Isabella, Cusack, Stacy V., Jan, Amanda K., Flores, Zaida, Sherbini, Omar, Vincent, Ariel, D'Aiello, Russell, Lorch, Scott A., DeMauro, Sara B., and Jawad, Abbas
- Subjects
GROSS motor ability ,HEALTH outcome assessment ,MOTOR ability ,SYNDROMES - Abstract
Background: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. While the Aicardi-Goutières syndrome severity score favors severely impacted individuals, there is an unmet need to define tools measuring function across the Aicardi-Goutières syndrome spectrum as potential outcome assessments for future clinical trials. Methods: Gross Motor Function Measure–88 (GMFM-88) and AGS Severity Scale were administered in individuals affected by Aicardi-Goutières syndrome (n = 71). We characterized the performance variability by genotype. Derived versions of the GMFM-88, including the GMFM-66, GMFM-66 item set (GMFM-66IS), and GMFM-66 Basal&Ceiling (GMFM-66BC) were calculated. The Aicardi-Goutières syndrome cohort was divided into severe (AGS Severity Scale score <4) or attenuated (≥4). Performance on the AGS Severity Scale highly correlated with total GMFM-88 scores (Spearman Correlation: R = 0.91). To assess variability of the GMFM-88 within genotypic subcohorts, interquartile ranges (IQRs) were compared. Results : GMFM-88 performance in the TREX1 cohort had least variability while the SAMHD1 cohort had the largest IQR (4.23 vs 81.8). Floor effect was prominent, with most evaluations scoring below 20% (n = 46, 64.79%), particularly in TREX1 - and RNASEH2- cohorts. Performance by the GMFM-66, GMFM-66IS, and GMFM-66BC highly correlated with the full GMFM-88. The Aicardi-Goutières syndrome population represents a broad range of gross motor skills. Conclusions: This work identified the GMFM-88 as a potential clinical outcome assessment in subsets of the Aicardi-Goutières syndrome population but underscores the need for additional validation of outcome measures reflective of the diverse gross motor function observed in this population, including low motor function. When time is limited by resources or patient endurance, shorter versions of the GMFM-88 may be a reasonable alternative. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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34. JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences.
- Author
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Ott, Nils, Faletti, Laura, Heeg, Maximilian, Andreani, Virginia, and Grimbacher, Bodo
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GAIN-of-function mutations ,CELLULAR signal transduction ,STAT proteins ,TRANSCRIPTION factors ,INDIVIDUALIZED medicine ,AUTOIMMUNE diseases - Abstract
The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway's architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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35. TREX-1 related Aicardi-Goutières syndrome improved by Janus kinase inhibitor.
- Author
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Ryckmans C, Donge M, Marchèse A, Mastouri M, Thomee C, Stouffs K, Lieser SL, and Scalais E
- Subjects
- Male, Pregnancy, Female, Humans, Infant, Atrophy, Janus Kinase Inhibitors, Lymphocytosis cerebrospinal fluid, Lymphocytosis genetics, Nervous System Malformations drug therapy, Nervous System Malformations genetics, Basal Ganglia Diseases diagnosis, Basal Ganglia Diseases drug therapy, Basal Ganglia Diseases genetics, Autoimmune Diseases of the Nervous System drug therapy, Autoimmune Diseases of the Nervous System genetics, Calcinosis genetics, Azetidines, Purines, Pyrazoles, Sulfonamides
- Abstract
Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy classically characterized by early onset of severe neurologic injury with basal ganglia calcifications, white matter abnormalities, and progressive cerebral atrophy, along with lymphocytosis and raised interferon alpha (INFα) in the cerebrospinal fluid (CSF). Here, we report a 3
1/2 year-old patient born with prenatal onset AGS, first manifesting as intra-uterine growth retardation. Cranial ultrasonography and cerebral MRI revealed ventriculomegaly and periventricular and basal ganglia calcifications, along with cerebral atrophy. Perinatal infections and known metabolic disorders were excluded. Both CSF lymphocytosis and raised INFα were present. Molecular analysis disclosed two already described compound heterozygous pathogenic variants in TREX1 (c. 309dup, p.(Thr104Hisfs*53) and c. 506G > A, p.(Arg169His)). The evolution was marked by severe global developmental delay with progressive microcephaly. Promptly, the patient developed irritability, quadri-paretic dyskinetic movements, and subsequently tonic seizures. Sensorineural hearing loss was detected as well as glaucoma. Initially, he was symptomatically treated with trihexyphenidyl followed by levetiracetam and topiramate. At age 22 months, baricitinib (0.4 mg/kg/day) was introduced, leading to normal serum INFα levels. Clinically, dyskinetic movements significantly decreased as well as irritability and sleep disturbance. We confirmed that baricitinib was a useful treatment with no major side effect., (© 2023 Wiley Periodicals LLC.)- Published
- 2024
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36. Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy.
- Author
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Tise CG, Morales JA, Lee AS, Velez-Bartolomei F, Floyd BJ, Levy RJ, Cusmano-Ozog KP, Feigenbaum AS, Ruzhnikov MRZ, Lee CU, and Enns GM
- Subjects
- Adrenoleukodystrophy complications, Adrenoleukodystrophy genetics, Adrenoleukodystrophy pathology, Autoimmune Diseases of the Nervous System complications, Autoimmune Diseases of the Nervous System genetics, Autoimmune Diseases of the Nervous System pathology, Dried Blood Spot Testing, Female, Genetic Diseases, X-Linked complications, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked pathology, Humans, Infant, Infant, Newborn, Lysophosphatidylcholines blood, Male, Nervous System Malformations complications, Nervous System Malformations genetics, Nervous System Malformations pathology, Tandem Mass Spectrometry, Adrenoleukodystrophy blood, Autoimmune Diseases of the Nervous System blood, Genetic Diseases, X-Linked blood, Neonatal Screening, Nervous System Malformations blood
- Abstract
We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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37. Early lymphocyte collection for anti‐CD19 CART production improves T‐cell fitness in patients with relapsed/refractory diffuse large B‐cell lymphoma.
- Author
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Dubnikov Sharon, T., Assayag, M., Avni, B., Kfir‐Erenfeld, S., Lebel, E., Gatt, M. E., Goldschmidt, N., Stepensky, P., Asherie, N., and Grisariu, S.
- Subjects
DIFFUSE large B-cell lymphomas ,T cells ,LYMPHOCYTES ,CD19 antigen ,CHIMERIC antigen receptors - Abstract
Summary: Background: Chimeric antigen receptor (CAR) T cells targeted to the CD19 B‐cell antigen form an approved treatment for patients with relapsed/refractory diffuse large B‐cell lymphoma (r/r DLBCL). However, since this therapy is administered after multiple lines of treatment and exposure to lymphotoxic agents, there is an urgent need to optimize this modality of treatment. Methods: To circumvent the difficulties of harvesting adequate and optimal T cells from DLBCL patients and improve CART therapy, we suggest an earlier lymphopheresis (i.e. at first relapse, before salvage treatment). We conducted a prospective study and evaluated the potential benefit of an earlier lymphopheresis (early group, n = 22) on the clinical outcome of CD19‐CART infused DLBCL patients, in comparison with standard lymphopheresis (i.e. at second relapse and beyond; standard group, n = 23). Results: An increased percentage of naïve T cells and increased in vitro T‐cell functionality were observed in the early group. Additionally, these cells exhibit a lower exhaustion profile than T cells collected in the standard group. Conclusion: While improved T‐cell phenotype and function in the lymphopheresis product did not translate into significantly improved clinical outcomes, a trend towards better overall survival (OS) and progression‐free survival (PFS) was observed. Early lymphopheresis maximizes the potential of salvage therapies, without compromising CAR T‐cell quality. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
38. Clinical spectrum and currently available treatment of type I interferonopathy Aicardi–Goutières syndrome.
- Author
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Dell'Isola, Giovanni Battista, Dini, Gianluca, Culpepper, Kaleb Logan, Portwood, Katherin Elizabeth, Ferrara, Pietro, Di Cara, Giuseppe, Verrotti, Alberto, and Lodolo, Mauro
- Abstract
Background: Aicardi–Goutières syndrome (AGS) is a genetically determined disorder with a variable phenotype. Since the original description of AGS, advances in gene sequencing techniques have resulted in a significant broadening of the phenotypic spectrum associated with AGS genes, and new clinical pictures have emerged beyond the classic presentation. The aim of this review is to provide a comprehensive analysis of the clinical spectrum of AGS and report currently available treatments and new immunosuppressive strategies. Data sources: Literature reviews and original research articles were collected from databases, including PubMed and ClinicalTrials.gov. Relevant articles about AGS were included. Results: The involvement of the nervous system certainly represents the major cause of mortality and morbidity in AGS patients. However, other clinical manifestations, such as chilblains, hepatosplenomegaly, and hematological disturbances, may lead to the diagnosis and considerably impact the prognosis and overall quality of life of these patients. Therapeutic approaches of AGS are limited to interventions aimed at specific symptoms and the management of multiple comorbidities. However, advances in understanding the pathogenesis of AGS could open new and more effective therapies. Conclusions: The over-activation of innate immunity due to upregulated interferon production plays a critical role in AGS, leading to multi-organ damage with the main involvement of the central nervous system. To date, there is no specific and effective treatment for AGS. New drugs specifically targeting the interferon pathway may bring new hope to AGS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
39. Juvenile Dermatomyositis and Infantile Cerebral Palsy: Aicardi-Gouteres Syndrome, Type 5, with a Novel Mutation in SAMHD1—A Case Report.
- Author
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Sorokina, Lubov S., Raupov, Rinat K., and Kostik, Mikhail M.
- Subjects
CEREBRAL palsy ,DISABILITIES ,SYNDROMES ,CORPUS callosum ,DERMATOMYOSITIS ,BASAL ganglia - Abstract
Introduction: Aicardi-Gouteres syndrome (AGS) is a monogenic interferonopathy characterized by early onset, dysregulation of skin (chilblain lesions), brain, and immune systems (fever, hepatomegaly, glaucoma, arthritis, myositis, and autoimmune activity). The disease looks like TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes) infection with early-onset encephalopathy resulting in severe neuropsychological disability. Case description: A six-year-old girl has been suffering from generalized seizures, fever episodes, severe psychomotor development delay, and spastic tetraparesis since the first year of her life. Her two elder brothers died at a young age from suspected infantile cerebral palsy (ICP). Other siblings (younger brother and two elder sisters) are as healthy as their parents. The girl was diagnosed with juvenile dermatomyositis at 5.5 years. Basal ganglia, periventricular, and cerebellum calcifications; hypoplasia of the corpus callosum; and leukodystrophy were detected on CT. The IFN-I score was 12 times higher than normal. The previously not described nucleotide variant c.434G > C (chr 20:36935104C > G; NM_015474) was detected in exon 4 of the SAMHD1 gene in the homozygous state, leading to amino acid substitution p.R145P. Aicardi-Goutières syndrome 5 was diagnosed. Her treatment included corticosteroids, methotrexate, and tofacitinib 5 mg twice a day and it contributed to health improvements. The following brain CT depicted the previously discovered changes without the sign of calcification spreading. Conclusions: Early diagnosis of AGS is highly important as it allows starting treatment in a timely manner. Timely treatment, in return, can help avoid the development/progression of end-organ damage, including severe neurological complications and early death. It is necessary to spread information about AGS among neurologists, neonatologists, infectious disease specialists, and pediatricians. A multidisciplinary team approach is required. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
40. Biomaterials promote in vivo generation and immunotherapy of CAR-T cells.
- Author
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Ya-Ting Qin, Ya-Ping Li, Xi-Wen He, Xi Wang, Wen-You Li, and Yu-Kui Zhang
- Subjects
BIOMATERIALS ,IMMUNOTHERAPY ,MANUFACTURING processes ,CYTOLOGY ,TREATMENT effectiveness - Abstract
Chimeric antigen receptor-T (CAR-T) cell therapy based on functional immune cell transfer is showing a booming situation. However, complex manufacturing processes, high costs, and disappointing results in the treatment of solid tumors have limited its use. Encouragingly, it has facilitated the development of new strategies that fuse immunology, cell biology, and biomaterials to overcome these obstacles. In recent years, CAR-T engineering assisted by properly designed biomaterials has improved therapeutic efficacy and reduced side effects, providing a sustainable strategy for improving cancer immunotherapy. At the same time, the low cost and diversity of biomaterials also offer the possibility of industrial production and commercialization. Here, we summarize the role of biomaterials as gene delivery vehicles in the generation of CAR-T cells and highlight the advantages of in-situ construction in vivo. Then, we focused on how biomaterials can be combined with CAR-T cells to better enable synergistic immunotherapy in the treatment of solid tumors. Finally, we describe biomaterials' potential challenges and prospects in CAR-T therapy. This review aims to provide a detailed overview of biomaterial-based CAR-T tumor immunotherapy to help investigators reference and customize biomaterials for CAR-T therapy to improve the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
41. Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5 variants with variable neurological presentations.
- Author
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Elhossini, Rasha M., Elbendary, Hasnaa M., Rafat, Karima, Ghorab, Raghda M., and Abdel-Hamid, Mohamed S.
- Subjects
PITUITARY dwarfism ,PHENOTYPIC plasticity ,EGYPTIANS ,SOMATOTROPIN ,BASAL ganglia ,HORMONE therapy - Abstract
Spondyloenchondrodysplasia (SPENCD) is an immune-osseous disorder caused by biallelic variants in ACP5 gene and is less commonly associated with neurological abnormalities such as global developmental delay, spasticity and seizures. Herein, we describe five new patients from four unrelated Egyptian families with complex clinical presentations including predominant neurological presentations masking the skeletal and immunological manifestations. All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia. One patient had an associated growth hormone deficiency with fair response to growth hormone therapy (GH) where the height improved from −3.0 SD before GH therapy to −2.35 SD at presentation. Patients had different forms of immune dysregulation. All patients except for one had either cellular immunodeficiency (3 patients) or combined immunodeficiency (1 patient). Whole exome sequencing was performed and revealed four ACP5 variants: c.629C > T (p.Ser210Phe), c.526C > T (p.Arg176Ter), c.742dupC (p.Gln248ProfsTer3) and c.775G > A (p.Gly259Arg). Of them, three variants were not described before. Our study reinforces the striking phenotypic variability associated with SPENCD and expands the mutational spectrum of this rare disorder. Further, it documents the positive response to growth hormone therapy in the studied patient. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
42. Type I Interferonopathies in Childhood.
- Author
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Haşlak, Fatih, Könte, Elif Kılıç, Aslan, Esma, Şahin, Sezgin, and Kasapçopur, Özgür
- Subjects
SEQUENCE analysis ,GENETIC mutation ,GENETIC testing ,AICARDI-Goutieres syndrome ,GENETIC techniques ,SYSTEMIC lupus erythematosus ,AUTOINFLAMMATORY diseases - Abstract
Type 1 interferonopathy is a novel context reflecting a group of inborn disorders sharing common pathway disturbances. This group of diseases is characterized by autoimmunity and autoinflammation caused by an upregulation of type 1 interferons (IFN)s due to certain genetic mutations. Several features are common in most of the diseases in this group, such as vasculitic skin changes, including chilblains, panniculitis, interstitial lung disease, basal ganglion calcifications, neuromotor impairments, epilepsy, stroke, and recurrent fever. Family history and consanguineous marriage are also common. IFN signature is a useful diagnostic tool and is positive in almost all patients with type 1 interferonopathies. Although IFN signature is a sensitive test, its specificity is relatively low. It can also be positive in viral infections and several connective tissue diseases. Therefore, next-generation sequence methods, whole exome sequencing (WES) in particular, are required for the ultimate diagnosis. The optimal treatment regime is still under debate due to a lack of clinical trials. Although high-dose steroids, anti-IL-1 and anti-IL-6 treatments, and reverse transcriptase inhibitors are used, JAK inhibitors are highly promising. Additionally, monoclonal antibodies against IFN-alpha and interferon-α receptor (IFNAR) are currently underway. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
43. Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond.
- Author
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Caielli, Simone, Wan, Zurong, and Pascual, Virginia
- Abstract
Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
44. CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity.
- Author
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Gupta, Sasha, Simic, Milos, Sagan, Sharon A., Shepherd, Chanelle, Duecker, Jason, Sobel, Raymond A., Dandekar, Ravi, Wu, Gregory F., Wu, Wesley, Pak, John E., Hauser, Stephen L., Lim, Wendell, Wilson, Michael R., and Zamvil, Scott S.
- Published
- 2023
- Full Text
- View/download PDF
45. A re‐examination of the circumscription of Saxifraga mengtzeana (Saxifragaceae).
- Author
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Zhang, Xin‐Jian, Gornall, Richard J., Zhang, Zhuo‐Xin, Chen, Jun‐Tong, Sun, Hang, and Deng, Tao
- Subjects
BOTANY ,PHENOTYPES ,SYNONYMS ,PETIOLES ,COLLECTIONS - Abstract
In the Flora of China account of Saxifraga mengtzeana Engl. & Irmsch., eight synonyms were attributed to it and one variant, recognized as Saxifraga epiphylla Gornall & Ohba, was split from it. This study reevaluates the taxonomic status of some of the synonyms and of the segregated species in light of new evidence presented here. Morphological and molecular evidence demonstrate that collections from northwestern Yunnan and Sichuan are genetically differentiated from those in southeastern Yunnan and neighboring Guangxi. Observations in the field and in cultivation show that the peltate petiole attachment diagnostic of S. mengtzeana var. peltifolia Engl. & Irmsch. is developmentally labile. Similar observations combined with molecular data show that viviparous phenotypes, formerly treated as S. epiphylla, although largely under genetic control, occur sporadically throughout the ranges of both northern and southern taxa. Collections from northwestern Yunnan and Sichuan are best recognized as Saxifraga geifolia Balf.f., whereas those from southeastern Yunnan and neighboring Guangxi are S. mengtzeana. Peltate‐leaved variants of the latter are given no status and are relegated to complete synonymy. Viviparous phenotypes of S. mengtzeana and S. geifolia are recognized at the rank of forma. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
46. A case of Aicardi-Goutières syndrome caused by TREX1 gene mutation.
- Author
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Chenhan, Zheng, Jun, Shao, Yang, Ding, Linliang, Yin, Xiaowen, Gu, Chunya, Ji, and Xuedong, Deng
- Subjects
GENETIC mutation ,FETAL growth retardation ,FETAL brain ,FETAL ultrasonic imaging ,DISABILITIES ,LEUKOENCEPHALOPATHIES ,INTELLECTUAL disabilities - Abstract
Aicardi-Goutières syndrome (AGS) is a rare genetic disorder involving the central nervous system and autoimmune abnormalities, leading to severe intellectual and physical disability with poor prognosis. AGS has a phenotype similar to intrauterine viral infection, which often leads to delays in genetic counseling. In this study, we report a case with a prenatal diagnosis of AGS. The first fetal ultrasound detected bilateral lateral ventricle cystic structures, and fetal MRI was performed to identify other signs. The right parietal lobe signal showed cerebral white matter abnormalities, and fetal brain development level was lower than that of normal fetuses of the same gestational age. Whole-exome sequencing revealed that the fetus carried the TREX1:NM_033629.6:exon2:c.294dup:p. C99Mfs*3 variant, suggesting that the c.294dup mutation of the TREX1 gene was the pathogenic mutation site, and the final comprehensive diagnosis was AGS1. In this article, we also reviewed the previous literature for possible phenotypes in the fetus and found that microcephaly and intrauterine growth retardation may be the first and most important markers of the intrauterine phenotype of AGS. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
47. Research advances in cGAS-stimulator of interferon genes pathway and central nervous system diseases: Focus on new therapeutic approaches.
- Author
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Jiao Ding, Yijie Dai, Jiahui Zhu, Xuemei Fan, Hao Zhang, and Bo Tang
- Subjects
CENTRAL nervous system diseases ,THERAPEUTICS ,TYPE I interferons ,INTERFERONS ,AUTOIMMUNE diseases ,CENTRAL nervous system injuries ,CENTRAL nervous system - Abstract
Cyclic GMP-AMP synthase (cGAS), a crucial innate immune sensor, recognizes cytosolic DNA and induces stimulator of interferon genes (STING) to produce type I interferon and other proinflammatory cytokines, thereby mediating innate immune signaling. The cGAS-STING pathway is involved in the regulation of infectious diseases, anti-tumor immunity, and autoimmune diseases; in addition, it plays a key role in the development of central nervous system (CNS) diseases. Therapeutics targeting the modulation of cGAS-STING have promising clinical applications. Here, we summarize the cGAS-STING signaling mechanism and the recent research on its role in CNS diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
48. Joining Forces for Cancer Treatment: From "TCR versus CAR" to "TCR and CAR".
- Author
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Teppert, Karin, Wang, Xueting, Anders, Kathleen, Evaristo, César, Lock, Dominik, and Künkele, Annette
- Subjects
CANCER treatment ,ANTIGEN receptors ,T cells ,CHIMERIC antigen receptors ,SYNAPSES ,SYNAPTOGENESIS ,TUMOR-infiltrating immune cells - Abstract
T cell-based immunotherapy has demonstrated great therapeutic potential in recent decades, on the one hand, by using tumor-infiltrating lymphocytes (TILs) and, on the other hand, by engineering T cells to obtain anti-tumor specificities through the introduction of either engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs). Given the distinct design of both receptors and the type of antigen that is encountered, the requirements for proper antigen engagement and downstream signal transduction by TCRs and CARs differ. Synapse formation and signal transduction of CAR T cells, despite further refinement of CAR T cell designs, still do not fully recapitulate that of TCR T cells and might limit CAR T cell persistence and functionality. Thus, deep knowledge about the molecular differences in CAR and TCR T cell signaling would greatly advance the further optimization of CAR designs and elucidate under which circumstances a combination of both receptors would improve the functionality of T cells for cancer treatment. Herein, we provide a comprehensive review about similarities and differences by directly comparing the architecture, synapse formation and signaling of TCRs and CARs, highlighting the knowns and unknowns. In the second part of the review, we discuss the current status of combining CAR and TCR technologies, encouraging a change in perspective from "TCR versus CAR" to "TCR and CAR". [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
49. GOBNALL=TEOUGHTON.
- Author
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GORNALL, H.
- Published
- 1901
50. Morphological and molecular identification for Saxifraga yangshuoensis (sect. Irregulares, Saxifragaceae), a new species from Guangxi, China.
- Author
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Hai-Ling CHEN, Wei-Bin XU, Wan-Yi ZHAO, and Yan LIU
- Subjects
SECTS ,SPECIES ,CHLOROPLAST DNA ,GREEN roofs - Abstract
Saxifraga yangshuoensis (Saxifragaceae), a new species from Yangshuo County in northeast Guangxi, China, is described and illustrated. It closely resembles S. damingshanensis and S. shennongii in stolons absent, leaves abaxially usually with spots, smallest petals base with yellow spotted, but differs from its leaves thickly papery, slightly revolute when dried, margin subentire, adaxially densely covered glandular hispid, abaxially densely covered with pale green spots, petiole base margin nearly glabrous and petals apex greenish. Combine morphological comparisons and phylogenetic analysis based on psbA-trnH and matK, confirmed that the new species differed from those similar species of S. sect. Irregulares. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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