158 results on '"Gornall H"'
Search Results
2. CCR7 + selected gene-modified T cells maintain a central memory phenotype and display enhanced persistence in peripheral blood in vivo.
- Author
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Kueberuwa G, Gornall H, Alcantar-Orozco EM, Bouvier D, Kapacee ZA, Hawkins RE, and Gilham DE
- Subjects
- 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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3. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.
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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]
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- 2010
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4. 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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5. Cell-Based Treatment in Acute Myeloid Leukemia Relapsed after Allogeneic Stem Cell Transplantation.
- Author
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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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6. 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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7. 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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8. CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy.
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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]
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- 2024
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9. 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
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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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10. Vasculitis and vasculopathy associated with inborn errors of immunity: an overview.
- Author
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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
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- 2024
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11. 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.
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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]
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- 2024
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12. Chimeric Antigen Receptor T-Cell Therapy in Acute Myeloid Leukemia: State of the Art and Recent Advances.
- Author
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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]
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- 2024
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13. Leveraging iPSC technology to assess neuro-immune interactions in neurological and psychiatric disorders.
- Author
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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]
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- 2023
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14. 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]
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- 2023
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15. RNASEH2C c.194G>A is a Chinese‐specific founder mutation in three unrelated patients with Aicardi‐Goutières syndrome 3.
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Wang, Qingming, Han, Ye, Zhou, Xinlong, Cheng, ShuangXi, Wang, Xin, Chen, Xiaoli, and Yuan, Haiming
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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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16. 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.
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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]
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- 2023
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17. 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
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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
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18. Type I Interferonopathies in Childhood.
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Haşlak, Fatih, Könte, Elif Kılıç, Aslan, Esma, Şahin, Sezgin, and Kasapçopur, Özgür
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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
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19. CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity.
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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.
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- 2023
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20. A re‐examination of the circumscription of Saxifraga mengtzeana (Saxifragaceae).
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Zhang, Xin‐Jian, Gornall, Richard J., Zhang, Zhuo‐Xin, Chen, Jun‐Tong, Sun, Hang, and Deng, Tao
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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
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21. 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
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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
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22. Research advances in cGAS-stimulator of interferon genes pathway and central nervous system diseases: Focus on new therapeutic approaches.
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Jiao Ding, Yijie Dai, Jiahui Zhu, Xuemei Fan, Hao Zhang, and Bo Tang
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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
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23. 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
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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
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24. 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
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25. CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies.
- Author
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Jiawen Huang, Xiaobing Huang, and Juan Huang
- Subjects
HEMATOLOGIC malignancies ,CELLULAR therapy ,CHIMERIC antigen receptors ,CANCER relapse ,B cells - Abstract
In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
26. Differentiating central nervous system demyelinating disorders: The role of clinical, laboratory, imaging characteristics and peripheral blood type I interferon activity.
- Author
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Karathanasis, Dimitris K., Rapti, Anna, Nezos, Adrianos, Skarlis, Charalampos, Kilidireas, Constantinos, Mavragani, Clio P., and Evangelopoulos, Maria Eleftheria
- Subjects
TYPE I interferons ,DEMYELINATION ,BLOOD groups ,CENTRAL nervous system ,IMMUNOGLOBULIN M ,MYELIN proteins ,PHOSPHOLIPID antibodies ,SYMPTOMS - Abstract
Objective: While multiple sclerosis (MS) is considered the cornerstone of autoimmune demyelinating CNS disorders, systemic autoimmune diseases (SADs) are important MS mimickers. We sought to explore whether distinct clinical, laboratory, and imaging characteristics along with quantitation of peripheral blood type I interferon (IFN) activity could aid in differentiating between them. Methods: A total of 193 consecutive patients with imaging features suggesting the presence of CNS demyelinating disease with or without relevant clinical manifestations underwent full clinical, laboratory, and imaging evaluation, including testing for specific antibodies against 15 cellular antigens. Expression analysis of type I IFN-inducible genes (MX-1, IFIT-1, and IFI44) was performed by real-time PCR, and a type I IFN score, reflecting type I IFN peripheral activity, was calculated. After joint neurological/rheumatological evaluation and 1 year of follow-up, patients were classified into MS spectrum and CNS autoimmune disorders. Results: While 66.3% (n = 128) of the patients were diagnosed with MS spectrum disorders (predominantly relapsing-remitting MS), 24.9% (n = 48) were included in the CNS autoimmune group, and out of those, one-fourth met the criteria for SAD (6.7% of the cohort, n = 13); the rest (18.1% of the cohort, n = 35), despite showing evidence of systemic autoimmunity, did not fulfill SAD criteria and comprised the "demyelinating disease with autoimmune features" (DAF) subgroup. Compared to the MS spectrum, CNS autoimmune patients were older, more frequently females, with increased rates of hypertension/hyperlipidemia, family history of autoimmunity, cortical dysfunction, antinuclear antibody titers ≥1/320, anticardiolipin IgM positivity, and atypical for MS magnetic resonance imaging lesions. Conversely, lower rates of infratentorial and callosal MRI lesions, CSF T2 oligoclonal bands, and IgGindex positivity were observed in CNS autoimmune patients. Patients fulfilling SAD criteria, but not the DAF group, had significantly higher peripheral blood type I IFN scores at baseline compared to MS spectrum [median (IQR)]: 50.18 (152.50) vs. -0.64 (6.75), p-value: 0.0001. Conclusion: Our study suggests that underlying systemic autoimmunity is not uncommon in patients evaluated for possible CNS demyelination. Distinct clinical, imaging and laboratory characteristics can aid in early differentiation between MS and CNS-involving systemic autoimmunity allowing for optimal therapeutic strategies. Activated type I IFN pathway could represent a key mediator among MS-like-presenting SADs and therefore a potential therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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27. Mechanistic Interplay between HIV-1 Reverse Transcriptase Enzyme Kinetics and Host SAMHD1 Protein: Viral Myeloid-Cell Tropism and Genomic Mutagenesis.
- Author
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Bowen, Nicole E., Oo, Adrian, and Kim, Baek
- Subjects
REVERSE transcriptase ,VIRAL tropism ,ENZYME kinetics ,VIRAL proteins ,HIV ,MUTAGENESIS ,INTERFERON receptors - Abstract
Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been the primary interest among studies on antiviral discovery, viral replication kinetics, drug resistance, and viral evolution. Following infection and entry into target cells, the HIV-1 core disassembles, and the viral RT concomitantly converts the viral RNA into double-stranded proviral DNA, which is integrated into the host genome. The successful completion of the viral life cycle highly depends on the enzymatic DNA polymerase activity of RT. Furthermore, HIV-1 RT has long been known as an error-prone DNA polymerase due to its lack of proofreading exonuclease properties. Indeed, the low fidelity of HIV-1 RT has been considered as one of the key factors in the uniquely high rate of mutagenesis of HIV-1, which leads to efficient viral escape from immune and therapeutic antiviral selective pressures. Interestingly, a series of studies on the replication kinetics of HIV-1 in non-dividing myeloid cells and myeloid specific host restriction factor, SAM domain, and HD domain-containing protein, SAMHD1, suggest that the myeloid cell tropism and high rate of mutagenesis of HIV-1 are mechanistically connected. Here, we review not only HIV-1 RT as a key antiviral target, but also potential evolutionary and mechanistic crosstalk among the unique enzymatic features of HIV-1 RT, the replication kinetics of HIV-1, cell tropism, viral genetic mutation, and host SAMHD1 protein. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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28. From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer.
- Author
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Sun, Jiangang, Li, Xiaojing, Chen, Peng, and Gao, Yongshun
- Subjects
STOMACH cancer ,EPIDERMAL growth factor ,BISPECIFIC antibodies ,ANTIBODY-drug conjugates ,PROTEIN-tyrosine kinase inhibitors - Abstract
Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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29. Nucleic Acid Sensing by Toll-Like Receptors in the Endosomal Compartment.
- Author
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Miyake, Kensuke, Shibata, Takuma, Fukui, Ryutaro, Sato, Ryota, Saitoh, Shin-Ichiroh, and Murakami, Yusuke
- Subjects
NUCLEIC acids ,TOLL-like receptors ,SINGLE-stranded DNA ,MICROBIAL lipids ,DOUBLE-stranded RNA - Abstract
Toll-like receptors (TLRs) respond to pathogen constituents, such as microbial lipids and nucleic acids (NAs). TLRs recognize NAs in endosomal compartments. Structural and functional studies have shown that recognition of NAs by TLRs depends on NA processing by RNases and DNases. DNase II-dependent DNA degradation is required for TLR9 responses to single-stranded DNAs, whereas RNase T2-dependent RNA degradation enables TLR7 and TLR8 to respond to nucleosides and oligoribonucleotides. In contrast, RNases and DNases negatively regulate TLR responses by degrading their ligands. RNase T2 negatively regulates TLR3 responses to degrading the TLR3 ligand double-stranded RNAs. Therefore, NA metabolism in the endosomal compartments affects the endosomal TLR responses. Dysregulation of NA metabolism in the endosomal compartment drives the TLR-dependent pathologies in human diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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30. Oral Phenotype of Singleton–Merten Syndrome: A Systematic Review Illustrated With a Case Report.
- Author
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Riou, Margot Charlotte, de La Dure-Molla, Muriel, Kerner, Stéphane, Rondeau, Sophie, Legendre, Adrien, Cormier-Daire, Valerie, and Fournier, Benjamin P. J.
- Subjects
ARTERIAL calcification ,PHENOTYPES ,IMPACTION of teeth ,DENTAL caries ,HYPODONTIA ,ALVEOLAR process - Abstract
Background: Singleton–Merten syndrome type 1 (SGMRT1) is a rare autosomal dominant disorder caused by IFIH1 variations with blood vessel calcifications, teeth anomalies, and bone defects. Aim: We aimed to summarize the oral findings in SGMRT1 through a systematic review of the literature and to describe the phenotype of a 10-year-old patient with SGMRT1 diagnosis. Results: A total of 20 patients were described in the literature, in nine articles. Eight IFIH1 mutations were described in 11 families. Delayed eruption, short roots, and premature loss of permanent teeth were the most described features (100%). Impacted teeth (89%) and carious lesions (67%) were also described. Our patient, a 10-year-old male with Singleton–Merten syndrome, presented numerous carious lesions, severe teeth malposition, especially in the anterior arch, and an oral hygiene deficiency with a 100% plaque index. The panoramic X-ray did not show any dental agenesis but revealed very short roots and a decrease in the jaw alveolar bone height. The whole-genome sequencing analysis revealed a heterozygous de novo variant in IFIH1 (NM_022168.4) c.2465G > A (p.Arg822Gln). Conclusion: Confused descriptions of oral features occurred in the literature between congenital findings and "acquired" pathology, especially carious lesions. The dental phenotype of these patients encompasses eruption anomalies (delayed eruption and impacted teeth) and lack of root edification, leading to premature loss of permanent teeth, and it may contribute to the diagnosis. An early diagnosis is essential to prevent teeth loss and to improve the quality of life of these patients. Systematic Review Registration : [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022300025]. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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31. RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration.
- Author
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Castelli, Lydia M., Benson, Bridget C., Huang, Wan-Ping, Lin, Ya-Hui, and Hautbergue, Guillaume M.
- Subjects
MICROSATELLITE repeats ,RNA metabolism ,HELICASES ,RNA ,AMYOTROPHIC lateral sclerosis ,QUADRUPLEX nucleic acids - Abstract
Short repeated sequences of 3−6 nucleotides are causing a growing number of over 50 microsatellite expansion disorders, which mainly present with neurodegenerative features. Although considered rare diseases in relation to the relatively low number of cases, these primarily adult-onset conditions, often debilitating and fatal in absence of a cure, collectively pose a large burden on healthcare systems in an ageing world population. The pathological mechanisms driving disease onset are complex implicating several non-exclusive mechanisms of neuronal injury linked to RNA and protein toxic gain- and loss- of functions. Adding to the complexity of pathogenesis, microsatellite repeat expansions are polymorphic and found in coding as well as in non-coding regions of genes. They form secondary and tertiary structures involving G-quadruplexes and atypical helices in repeated GC-rich sequences. Unwinding of these structures by RNA helicases plays multiple roles in the expression of genes including repeat-associated non-AUG (RAN) translation of polymeric-repeat proteins with aggregating and cytotoxic properties. Here, we will briefly review the pathogenic mechanisms mediated by microsatellite repeat expansions prior to focus on the RNA helicases eIF4A, DDX3X and DHX36 which act as modifiers of RAN translation in C9ORF72-linked amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72-ALS/FTD) and Fragile X-associated tremor/ataxia syndrome (FXTAS). We will further review the RNA helicases DDX5/17, DHX9, Dicer and UPF1 which play additional roles in the dysregulation of RNA metabolism in repeat expansion disorders. In addition, we will contrast these with the roles of other RNA helicases such as DDX19/20, senataxin and others which have been associated with neurodegeneration independently of microsatellite repeat expansions. Finally, we will discuss the challenges and potential opportunities that are associated with the targeting of RNA helicases for the development of future therapeutic approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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32. The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology Points to Consider for Diagnosis and Management of Autoinflammatory Type I Interferonopathies: CANDLE/PRAAS, SAVI, and AGS.
- Author
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Cetin Gedik, Kader, Lamot, Lovro, Romano, Micol, Demirkaya, Erkan, Piskin, David, Torreggiani, Sofia, Adang, Laura A., Armangue, Thais, Barchus, Kathe, Cordova, Devon R., Crow, Yanick J., Dale, Russell C., Durrant, Karen L., Eleftheriou, Despina, Fazzi, Elisa M., Gattorno, Marco, Gavazzi, Francesco, Hanson, Eric P., Lee‐Kirsch, Min Ae, and Montealegre Sanchez, Gina A.
- Subjects
RHEUMATOLOGY ,INTERPROFESSIONAL relations ,QUALITY of life ,AUTOINFLAMMATORY diseases - Abstract
Objective: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome‐associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI), and Aicardi‐Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long‐term monitoring of patients with these rare diseases. Methods: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. Results: The Task Force devised consensus and evidence‐based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long‐term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. Conclusion: These points to consider represent state‐of‐the‐art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
33. CAR-T Cell Performance: How to Improve Their Persistence?
- Author
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López-Cantillo, Gina, Urueña, Claudia, Camacho, Bernardo Armando, and Ramírez-Segura, Cesar
- Subjects
T cells ,CHIMERIC antigen receptors ,IMMUNOLOGIC memory ,CELL metabolism ,CELLULAR therapy - Abstract
Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
34. Aicardi-Goutieres Syndrome-A Case Report.
- Author
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LIZA, NOOR-A-SABAH, ANWAR, S. K. SERJINA, and KUNDU, GOPEN KUMAR
- Subjects
AICARDI syndrome ,CONSANGUINITY ,MOTOR ability ,INTELLECTUAL disabilities ,ACUTE diseases ,NUCLEIC acids - Abstract
Aicardi Goutieres Syndrome is an early-onset leukoencephalopathy with a presumed immune pathogenesis caused by inherited defects in nucleic acid metabolism. It is an inflammatory disorder resulting from mutation of multiple genes. Majority of the affected individuals experience physical as well as intellectual disability. Here we discuss a case of A 2-year old girl of consanguineous marriage diagnosed as Aicardi Goutieres Syndrome who was presented with the sudden loss of motor and cognitive skills after an acute febrile illness. This syndrome was diagnosed by clinical exome sequencing and RNAEH 2A mutant gene identification. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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35. Self or Non-Self? It Is also a Matter of RNA Recognition and Editing by ADAR1.
- Author
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Tassinari, Valentina, Cerboni, Cristina, and Soriani, Alessandra
- Subjects
PATTERN perception receptors ,NUCLEIC acids ,RNA editing ,TYPE I interferons ,CELLULAR recognition ,T cells ,DOUBLE-stranded RNA ,ADENOSINES - Abstract
Simple Summary: A fundamental feature of innate immune cells is to detect the presence of non-self, such as potentially harmful nucleic acids, by germline-encoded specialized receptors called pattern recognition receptors (PRRs). ADAR1 is one key enzyme avoiding aberrant type I interferon (IFN-I) production and immune cell activation by the conversion of adenosine to inosine (A-to-I) in double-stranded RNA (dsRNA) structures that arise in self mRNA containing specific repetitive elements. This review intends to give an up-to-date and detailed overview of the ADAR1-mediated ability to modulate the immune response in autoimmune diseases and cancer progression. A-to-I editing is a post-transcriptional mechanism affecting coding and non-coding dsRNAs, catalyzed by the adenosine deaminases acting on the RNA (ADAR) family of enzymes. A-to-I modifications of endogenous dsRNA (mainly derived from Alu repetitive elements) prevent their recognition by cellular dsRNA sensors, thus avoiding the induction of antiviral signaling and uncontrolled IFN-I production. This process, mediated by ADAR1 activity, ensures the activation of an innate immune response against foreign (non-self) but not self nucleic acids. As a consequence, ADAR1 mutations or its de-regulated activity promote the development of autoimmune diseases and strongly impact cell growth, also leading to cancer. Moreover, the excessive inflammation promoted by Adar1 ablation also impacts T and B cell maturation, as well as the development of dendritic cell subsets, revealing a new role of ADAR1 in the homeostasis of the immune system. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
36. Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts.
- Author
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Oleksy, Barbara, Mierzewska, Hanna, Tryfon, Jolanta, Wypchło, Maria, Wasilewska, Krystyna, Zalewska-Miszkurka, Zofia, Płoski, Rafał, Rydzanicz, Małgorzata, and Szczepanik, Elżbieta
- Published
- 2022
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37. 不同信号肽对嵌合抗原受体T细胞杀伤作用的 影响研究.
- Author
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李 帆, 张琴星, 童祥文, 田高辉, 顾力行, and 徐 瑶
- Subjects
CD19 antigen ,NANOTECHNOLOGY ,PROTEIN precursors ,PEPTIDES ,T cells ,ANTIGENS ,T cell receptors - Abstract
Copyright of China Oncology is the property of Editorial Board of China Oncology 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.)
- Published
- 2022
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38. 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
- 2022
- Full Text
- View/download PDF
39. Anti-TLR7 Antibody Protects Against Lupus Nephritis in NZBWF1 Mice by Targeting B Cells and Patrolling Monocytes.
- Author
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Murakami, Yusuke, Fukui, Ryutaro, Tanaka, Reika, Motoi, Yuji, Kanno, Atsuo, Sato, Ryota, Yamaguchi, Kiyoshi, Amano, Hirofumi, Furukawa, Yoichi, Suzuki, Hitoshi, Suzuki, Yusuke, Tamura, Naoto, Yamashita, Naomi, and Miyake, Kensuke
- Subjects
B cells ,LUPUS nephritis ,MONOCYTES ,DENDRITIC cells ,AUTOANTIBODIES - Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6C
low patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
40. The Role of Ku70 as a Cytosolic DNA Sensor in Innate Immunity and Beyond.
- Author
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Sui, Hongyan, Hao, Ming, Chang, Weizhong, and Imamichi, Tomozumi
- Subjects
NATURAL immunity ,DOUBLE-strand DNA breaks ,DNA ,NUCLEAR proteins ,DNA repair - Abstract
Human Ku70 is a well-known endogenous nuclear protein involved in the non-homologous end joining pathway to repair double-stranded breaks in DNA. However, Ku70 has been studied in multiple contexts and grown into a multifunctional protein. In addition to the extensive functional study of Ku70 in DNA repair process, many studies have emphasized the role of Ku70 in various other cellular processes, including apoptosis, aging, and HIV replication. In this review, we focus on discussing the role of Ku70 in inducing interferons and proinflammatory cytokines as a cytosolic DNA sensor. We explored the unique structure of Ku70 binding with DNA; illustrated, with evidence, how Ku70, as a nuclear protein, responds to extracellular DNA stimulation; and summarized the mechanisms of the Ku70-involved innate immune response pathway. Finally, we discussed several new strategies to modulate Ku70-mediated innate immune response and highlighted some potential physiological insights based on the role of Ku70 in innate immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
41. Immunotherapy in hematological malignancies: recent advances and open questions.
- Author
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Tawfik, Essam A, Aldrak, Norah A, Albrahim, Shahad H, Alzahrani, Dunia A, Alfassam, Haya A, Alkoblan, Samar M, Almalik, Abdulaziz M, Chen, Kok-Siong, Abou-Khalil, Rana, Shah, Khalid, and Zaidan, Nada M
- Published
- 2021
- Full Text
- View/download PDF
42. Evidence in disease and non-disease contexts that nonsense mutations cause altered splicing via motif disruption.
- Author
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Abrahams, Liam, Savisaar, Rosina, Mordstein, Christine, Young, Bethan, Kudla, Grzegorz, and Hurst, Laurence D
- Published
- 2021
- Full Text
- View/download PDF
43. Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation.
- Author
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Ajith, Ashwin, Mulloy, Laura L., Musa, Md. Abu, Bravo-Egana, Valia, Horuzsko, Daniel David, Gani, Imran, and Horuzsko, Anatolij
- Subjects
LABORATORY mice ,TRANSPLANTATION of organs, tissues, etc. ,ALLOIMMUNITY ,GRAFT rejection ,ANIMAL disease models ,EMBRYONIC stem cells - Abstract
The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient's personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient's humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8
+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+ cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
44. Immunotherapy Using Autologous T Cell-Engineered With CD19-specific Chimeric Antigen Receptor for the Treatment of Recurrent /Refractory B Cell Leukemia
- Published
- 2016
45. Advances in Human Immune System Mouse Models for Studying Human Hematopoiesis and Cancer Immunotherapy.
- Author
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Mian, Syed A., Anjos-Afonso, Fernando, and Bonnet, Dominique
- Subjects
CLINICAL drug trials ,IMMUNE system ,HEMATOPOIESIS ,LYMPHOID tissue ,IMMUNOTHERAPY - Abstract
Immunotherapy has established itself as a promising tool for cancer treatment. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
46. Deep White Matter Cysts in a Patient with Aicardi-Goutières Syndrome and SAMHD1 Variants.
- Author
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Poot, Martin
- Published
- 2022
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47. New Tools for Precision and Personalized Treatment in Gastrointestinal Cancers.
- Author
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Ghidini, Michele
- Subjects
GASTROINTESTINAL cancer treatment ,INDIVIDUALIZED medicine ,COLON polyps ,CIGARETTE smokers ,ALCOHOL drinking - Published
- 2021
- Full Text
- View/download PDF
48. Adenosine-to-inosine RNA editing in the immune system: friend or foe?
- Author
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Nakahama, Taisuke and Kawahara, Yukio
- Subjects
RNA editing ,IMMUNE system ,IMMUNOLOGIC diseases ,NUCLEIC acids ,CONGENITAL disorders ,TYPE I interferons - Abstract
Our body expresses sensors to detect pathogens through the recognition of expressed molecules, including nucleic acids, lipids, and proteins, while immune tolerance prevents an overreaction with self and the development of autoimmune disease. Adenosine (A)-to-inosine (I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a post-transcriptional modification that can potentially occur at over 100 million sites in the human genome, mainly in Alu repetitive elements that preferentially form a double-stranded RNA (dsRNA) structure. A-to-I conversion within dsRNA, which may induce a structural change, is required to escape from the host immune system, given that endogenous dsRNAs transcribed from Alu repetitive elements are potentially recognized by melanoma differentiation-associated protein 5 (MDA5) as non-self. Of note, loss-of-function mutations in the ADAR1 gene cause Aicardi–Goutières syndrome, a congenital autoimmune disease characterized by encephalopathy and a type I interferon (IFN) signature. However, the loss of ADAR1 in cancer cells with an IFN signature induces lethality via the activation of protein kinase R in addition to MDA5. This makes cells more sensitive to immunotherapy, highlighting the opposing immune status of autoimmune diseases (overreaction) and cancer (tolerance). In this review, we provide an overview of insights into two opposing aspects of RNA editing that functions as a modulator of the immune system in autoimmune diseases and cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
49. Targeting Cancer Stem Cells by Genetically Engineered Chimeric Antigen Receptor T Cells.
- Author
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Alhabbab, Rowa Y.
- Subjects
CANCER stem cells ,CHIMERIC antigen receptors ,T cells ,CANCER relapse - Abstract
The term cancer stem cell (CSC) starts 25 years ago with the evidence that CSC is a subpopulation of tumor cells that have renewal ability and can differentiate into several distinct linages. Therefore, CSCs play crucial role in the initiation and the maintenance of cancer. Moreover, it has been proposed throughout several studies that CSCs are behind the failure of the conventional chemo-/radiotherapy as well as cancer recurrence due to their ability to resist the therapy and their ability to re-regenerate. Thus, the need for targeted therapy to eliminate CSCs is crucial; for that reason, chimeric antigen receptor (CAR) T cells has currently been in use with high rate of success in leukemia and, to some degree, in patients with solid tumors. This review outlines the most common CSC populations and their common markers, in particular CD133, CD90, EpCAM, CD44, ALDH, and EGFR
VIII , the interaction between CSCs and the immune system, CAR T cell genetic engineering and signaling, CAR T cells in targeting CSCs, and the barriers in using CAR T cells as immunotherapy to treat solid cancers. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
50. Characterisation of ACP5 missense mutations encoding tartrate-resistant acid phosphatase associated with spondyloenchondrodysplasia.
- Author
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Ramesh, Janani, Parthasarathy, Latha K., Janckila, Anthony J., Begum, Farhana, Murugan, Ramya, Murthy, Balakumar P. S. S., El-Mallakh, Rif S., Parthasarathy, Ranga N., and Venugopal, Bhuvarahamurthy
- Subjects
ACID phosphatase ,MISSENSE mutation ,MUTANT proteins ,WESTERN immunoblotting ,MONOCLONAL antibodies - Abstract
Biallelic mutations in ACP5, encoding tartrate-resistant acid phosphatase (TRACP), have recently been identified to cause the inherited immuno-osseous disorder, spondyloenchondrodysplasia (SPENCD). This study was undertaken to characterize the eight reported missense mutations in ACP5 associated with SPENCD on TRACP expression. ACP5 mutant genes were synthesized, transfected into human embryonic kidney (HEK-293) cells and stably expressing cell lines were established. TRACP expression was assessed by cytochemical and immuno-cytochemical staining with a panel of monoclonal antibodies. Analysis of wild (WT) type and eight mutant stable cell lines indicated that all mutants lacked stainable enzyme activity. All ACP5 mutant constructs were translated into intact proteins by HEK-293 cells. The mutant TRACP proteins displayed variable immune reactivity patterns, and all drastically reduced enzymatic activity, revealing that there is no gross inhibition of TRACP biosynthesis by the mutations. But they likely interfere with folding thereby impairing enzyme function. TRACP exists as two isoforms. TRACP 5a is a less active monomeric enzyme (35kD), with the intact loop peptide and TRACP 5b is proteolytically cleaved highly active enzyme encompassing two subunits (23 kD and 16 kD) held together by disulfide bonds. None of the mutant proteins were proteolytically processed into isoform 5b intracellularly, and only three mutants were secreted in significant amounts into the culture medium as intact isoform 5a-like proteins. Analysis of antibody reactivity patterns revealed that T89I and M264K mutant proteins retained some native conformation, whereas all others were in "denatured" or "unfolded" forms. Western blot analysis with intracellular and secreted TRACP proteins also revealed similar observations indicating that mutant T89I is amply secreted as inactive protein. All mutant proteins were attacked by Endo-H sensitive glycans and none could be activated by proteolytic cleavage in vitro. In conclusion, determining the structure-function relationship of the SPENCD mutations in TRACP will expand our understanding of basic mechanisms underlying immune responsiveness and its involvement in dysregulated bone metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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