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Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
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Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Medicina de Precisão/métodos , Idoso , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Pessoa de Meia-Idade , Mutação , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologiaRESUMO
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown. OBJECTIVE: We aimed to characterize the functional impact and carrier frequency of ADA2 variants. METHODS: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants. RESULTS: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals. CONCLUSIONS: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.
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Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adenosina Desaminase/sangue , Adenosina Desaminase/deficiência , Algoritmos , Predisposição Genética para Doença , Variação Genética , Células HEK293 , Humanos , Doenças do Sistema Imunitário/genética , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/deficiênciaRESUMO
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.
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Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Transtornos da Insuficiência da Medula Óssea/genética , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação/genética , Fenótipo , Aplasia Pura de Série Vermelha/genética , Vasculite/genéticaRESUMO
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly affects medium-sized arteries. With the establishment and refinement of vasculitis nomenclature and diagnostic criteria, clinical findings of PAN and distinguishing features from other vasculitides are now well characterized. Although PAN typically manifests in adulthood, cohort studies in paediatric patients have shaped our understanding of childhood-onset PAN. The paradigm of childhood-onset PAN changed considerably with the landmark discovery of deficiency of ADA2 (DADA2), a monogenic cause of vasculitis that is often indistinguishable from PAN. Testing for DADA2 has provided an explanation to numerous challenging cases of familial PAN and early-onset PAN around the world. The ability to distinguish DADA2 from classic PAN have important therapeutic implications as tumor necrosis factor inhibitors have demonstrated remarkable efficacy in the treatment of DADA2. In this review, we will discuss our current understanding of PAN and DADA2 and highlight similarities and differences between these vasculitides.
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Adenosina Desaminase/deficiência , Poliarterite Nodosa/metabolismo , Humanos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OA is a chronic, progressive and disabling joint disease, leading to a poor quality of life and an enormous social and economic burden. Current therapies for OA patients remain limited, which creates an area of huge unmet medical need. For some time, researchers have been looking for approaches that can inhibit the structural progression of OA. A variety of potential disease-modifying OA drugs have been developed, targeting cartilage, inflammatory pathways or subchondral bone. In addition, non-pharmacological therapies, including joint distraction and weight loss, draw increasing attention, with some showing disease-modifying potential. Thus we performed a comprehensive review to discuss the current status of disease-modifying therapies in OA and appraise the potentials of emerging novel agents.
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Antirreumáticos/uso terapêutico , Gerenciamento Clínico , Osteoartrite/tratamento farmacológico , Qualidade de Vida , Progressão da Doença , Humanos , PrognósticoRESUMO
OBJECTIVE: To investigate the role of albumin-to-globulin ratio (AGR) in systemic lupus erythematosus (SLE) and its relationship with disease activity. METHODS: This retrospective study consecutively selected patients with SLE and healthy controls. Patients were divided into three groups according to the SLE Disease Activity Index 2000 (SLEDAI-2K): group 1 (mild disease activity, SLEDAI-2K ≤ 6), group 2 (moderate disease activity, SLEDAI-2K 7-12) and group 3 (severe disease activity, SLEDAI-2K > 12). Predictors of SLE disease activity were analysed by ordinal logistical regression. RESULTS: A total of 101 Chinese patients with SLE and 75 healthy Chinese controls were included. Patients with SLE had lower AGR values than healthy individuals, and group 3 patients with SLE displayed lower AGR values than those in group 1, but similar values to group 2. AGR was inversely correlated with SLEDAI-2K (r = -0.543). Ordinal logistic regression analysis showed that lower AGR (ß = -1.319) and lower complement C4 (ß = -1.073) were independent risk factors for SLE disease activity. CONCLUSIONS: AGR was decreased in patients with SLE and may be utilized as a useful inflammatory biomarker for monitoring SLE disease activity.
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Lúpus Eritematoso Sistêmico , Albumina Sérica , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C4/metabolismo , Complemento C4/análise , Modelos Logísticos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/análise , Albumina Sérica/metabolismo , Soroglobulinas/análise , Soroglobulinas/metabolismo , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Causative mutations of PBX1 are associated with congenital abnormalities of the kidney and urinary tract (CAKUT), often accompanied by hearing loss, abnormal ear morphology, or developmental delay. The aim of the present investigation was to introduce a novel variant in the PBX1 gene identified in a Chinese family, leading to recurrent neonatal mortality. METHODS: A pregnant woman (gravida 5, para 0), who had experienced recurrent neonatal deaths, sought genetic etiology diagnosis. Whole exome sequencing (WES) was conducted to identify sequence variants and copy number variants in the fetus presenting with posterior nuchal cystic hygroma and fetal hydrops. RESULTS: A novel NM_002585.4:c.694G>C(p.D232H) in PBX1 was identified in the fetus through trio whole exome sequencing (WES), revealing a paternal mosaic PBX1 variant in blood at 11.54% (6/52 variants reads). Subsequent parental Sanger sequencing confirmed the variant detected by WES. Ultimately, the variant was classified as likely pathogenic, leading the family to elect pregnancy termination at 17 weeks gestation. CONCLUSION: The novel variant in the PBX1 gene appears to be a significant factor contributing to recurrent neonatal deaths in the Chinese family. Such findings expand the spectrum of PBX1 gene variants and provide valuable perinatal guidance for diagnosing fetuses with PBX1 mutations.
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Sequenciamento do Exoma , Fator de Transcrição 1 de Leucemia de Células Pré-B , Humanos , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Sequenciamento do Exoma/métodos , Feminino , Gravidez , Recém-Nascido , Morte Perinatal , Masculino , Povo Asiático/genética , Mutação/genética , China , Adulto , Linhagem , População do Leste AsiáticoRESUMO
Post-traumatic stress disorder (PTSD) is a persistent psychiatric condition that arises following exposure to traumatic events such as warfare, natural disasters, or other catastrophic incidents, typically characterized by heightened anxiety, depressive symptoms, and cognitive dysfunction. In this study, animals subjected to single prolonged stress (SPS) were administered evodiamine (EVO) and compared to a positive control group receiving sertraline. The animals were then assessed for alterations in anxiety, depression, and cognitive function. Histological analysis was conducted to examine neuronal changes in the hippocampus. In order to predict the core targets and related mechanisms of evodiamine intervention in PTSD, network pharmacology was used. The metabolic markers pre- and post-drug administration were identified using nontargeted serum metabolomics techniques, and the intersecting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened. Finally, the core targets were validated through molecular docking, enzyme-linked immunosorbent assays, and immunofluorescence staining to confirm the anti-PTSD effects and mechanisms of these targets. As well as improving cognitive impairment, evodiamine reversed anxiety- and depression-like behaviors. It also inhibited the reduction in the number of hippocampal neuronal cells and Nissl bodies in SPS mice inhibited angiotensin converting enzyme (ACE) levels in the hippocampus of SPS mice, and modulated the renin angiotensin pathway and its associated serum metabolites in brain tissue. Evodiamine shows promise as a potential candidate for alleviating the symptoms of post-traumatic stress disorder.
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Modelos Animais de Doenças , Hipocampo , Neurônios , Quinazolinas , Sistema Renina-Angiotensina , Transtornos de Estresse Pós-Traumáticos , Animais , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Quinazolinas/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Masculino , Sistema Renina-Angiotensina/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Depressão/tratamento farmacológico , Simulação de Acoplamento Molecular , Ansiedade/tratamento farmacológico , Camundongos Endogâmicos C57BL , Farmacologia em RedeRESUMO
Sarcopenia has been recognized as an emerging complication of type 2 diabetes mellitus (T2DM). Currently, the pathogenesis of T2DM-related sarcopenia remains unclear. The aim of this study was to investigate the molecular mechanisms and potential therapeutic targets for T2DM-related sarcopenia. In this study, a T2DM-related sarcopenia mouse model was established using db/db mice. Proteins extracted from the gastrocnemius muscles of db/db mice and littermate control db/m mice were analyzed by a 4D label-free quantitative proteomics approach. A total of 131 upregulated and 68 downregulated proteins were identified as differentially expressed proteins (DEPs). Bioinformatics analysis revealed that DEPs were significantly enriched in lipid metabolism. Protein-protein interaction network analysis revealed that six hub proteins, including ACOX1, CPT2, ECI2, ACADVL, ACADL, and ECH1, were involved in the fatty acid oxidation. The hub protein-transcription factor-miRNA network was also constructed using the NetworkAnalyst tool. Finally, the hub proteins were validated by Western blotting and immunohistochemistry and further confirmed to be significantly negatively correlated with muscle mass and grip strength. Our study suggested that lipid metabolism, especially excessive fatty acid oxidation, may be a crucial contributor to the progression of T2DM-related sarcopenia and a common cause of the inter-relationship between T2DM and sarcopenia. Targeting lipid metabolism may be a promising therapeutic strategy for T2DM-related sarcopenia.
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INTRODUCTION: If a large amount of urate crystals is deposited in a joint cavity for an extended period of time, bone erosion will occur and gradually cause skeletal muscle necrosis and joint deformity. The aim of this study was to describe the clinical characteristics and factors associated with bone erosion in gout patients with tophi. METHODS: A total of 210 gout patients with tophi were enrolled and divided into a bone erosion group (n = 135) and a non-bone erosion group (n = 75). Digital radiography (DR) was performed to detect bone erosion in the elbow, wrist, knee, ankle joints, interphalangeal and metatarsophalangeal joints. The clinical characteristics were recorded and compared between the two groups. Multivariate logistic regression analysis was conducted to explore the factors associated with bone erosion. RESULTS: Compared with the non-bone erosion group, the bone erosion group had an older age, longer disease duration of gout and tophi, higher level of serum creatinine (sCr), higher proportion of drinking history and ulceration, and a lower glomerular filtration rate (GFR). Univariate logistic regression analysis results showed that sex, age, body mass index (BMI), gout duration, tophi duration, GFR, white blood cell (WBC) count, sCr level, smoking history, drinking history, and presence of ulceration were associated with bone destruction. Multivariable logistic regression analysis results indicated that tophi duration, drinking history, ulceration and sCr were positively and independently related to bone erosion. CONCLUSIONS: Tophi patients with bone erosion presented different clinical characteristics. Tophi duration, drinking history, ulceration and sCr were associated with bone erosion in gout patients with tophi.
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Gota , Humanos , Gota/complicações , Fatores de Risco , Fumar/efeitos adversos , Índice de Massa Corporal , Taxa de Filtração GlomerularRESUMO
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD.
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Parkinson's disease (PD) is one of the most widespread neurodegenerative diseases. PD is associated with progressive loss of substantia nigra dopaminergic neurons, including various motor symptoms (e.g., bradykinesia, rigidity, and resting tremor), as well as non-motor symptoms (e.g., cognitive impairment, constipation, fatigue, sleep disturbance, and depression). PD involves multiple biological processes, including mitochondrial or lysosomal dysfunction, oxidative stress, insulin resistance, and neuroinflammation. Metabolic syndrome (MetS), a collection of numerous connected cerebral cardiovascular conditions, is a common and growing public health problem associated with many chronic diseases worldwide. MetS components include central/abdominal obesity, systemic hypertension, diabetes, and atherogenic dyslipidemia. MetS and PD share multiple pathophysiological processes, including insulin resistance, oxidative stress, and chronic inflammation. In recent years, MetS has been linked to an increased risk of PD, according to studies; however, the specific mechanism remains unclear. Researchers also found that some related metabolic therapies are potential therapeutic strategies to prevent and improve PD. This article reviews the epidemiological relationship between components of MetS and the risk of PD and discusses the potentially relevant mechanisms and recent progress of MetS as a risk factor for PD. Furthermore, we conclude that MetS-related therapies are beneficial for the prevention and treatment of PD.
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Resistência à Insulina , Síndrome Metabólica , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Doença de Parkinson/tratamento farmacológico , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Doenças Neurodegenerativas/metabolismo , Mitocôndrias/metabolismoRESUMO
Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by damage to nigrostriatal dopaminergic neurons. Key pathogenic mechanisms underlying PD include alpha-synuclein misfolding and aggregation, impaired protein clearance, mitochondrial dysfunction, oxidative stress, and neuroinflammation. However, to date, no study has confirmed the specific pathogenesis of PD. Similarly, current PD treatment methods still have shortcomings. Although some emerging therapies have proved effective for PD, the specific mechanism still needs further clarification. Metabolic reprogramming, a term first proposed by Warburg, is applied to the metabolic energy characteristics of tumor cells. Microglia have similar metabolic characteristics. Pro-inflammatory M1 type and anti-inflammatory M2 type are the two types of activated microglia, which exhibit different metabolic patterns in glucose, lipid, amino acid, and iron metabolism. Additionally, mitochondrial dysfunction may be involved in microglial metabolic reprogramming by activating various signaling mechanisms. Functional changes in microglia resulting from metabolic reprogramming can cause changes in the brain microenvironment, thus playing an important role in neuroinflammation or tissue repair. The involvement of microglial metabolic reprogramming in PD pathogenesis has been confirmed. Neuroinflammation and dopaminergic neuronal death can effectively be reduced by inhibiting certain metabolic pathways in M1 microglia or reverting M1 cells to the M2 phenotype. This review summarizes the relationship between microglial metabolic reprogramming and PD and provides strategies for PD treatment.
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Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Microglia/metabolismo , Doenças Neuroinflamatórias , Doenças Neurodegenerativas/metabolismo , Macrófagos/metabolismo , Neurônios Dopaminérgicos/metabolismoRESUMO
BACKGROUNDMacrophage activation syndrome (MAS) is a life-threatening complication of Still's disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS.METHODWe profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies.RESULTSBulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38+HLA-DR+ cells within CD4+ T cell, CD8+ T cell, and NK cell populations. CD38+HLA-DR+ lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38+HLA-DR+ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38+HLA-DR+ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 - both elevated in MAS patients - synergistically augmented the generation of CD38+HLA-DR+ lymphocytes, while Janus kinase inhibition mitigated this response.CONCLUSIONMAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38+HLA-DR+ cycling lymphocytes that produce IFN-γ.
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Interferon Tipo I , Síndrome de Ativação Macrofágica , Criança , Humanos , Interleucina-15 , Síndrome de Ativação Macrofágica/genética , Antígenos HLA-DR , Linfócitos T CD8-Positivos , Anticorpos , Interferon Tipo I/genéticaRESUMO
Background: Macrophage activation syndrome (MAS) is a severe complication of autoimmune diseases with high mortality. We report the effectiveness of baricitinib as an option for the maintenance therapy in MAS secondary to nodular panniculitis. Case summary: A 24-year-old female came to our hospital with repeated fever and a skin nodule on right tibial tuberosity. Results were notable for raised serum ferritin (SF), triglycerides (TG), elevated liver function enzymes, interleukin-6 (IL-6), interferon-γ (IFN-γ), soluble interleukin-2 receptor (sIL-2R) and decreased activity of NK cells. The pathological biopsy of the subcutaneous nodules indicated nodular panniculitis. Hemophagocytic cells were found in bone marrow aspiration. She was diagnosed as MAS secondary to nodular panniculitis. With the treatment of methylprednisolone (MP) and immunoglobulin, her symptoms and laboratory data gradually improved. Nevertheless, her disease relapsed when the MP dose was tapered. Regarding the usage of JAK inhibitors in MAS, we used baricitinib (JAK1/2 inhibitor) to treat MAS and her symptom and abnormal laboratory findings returned to normal. During follow-up, though the MP dose was tapered, she was stable without a MAS recurrence. Conclusion: The case report suggested baricitinib is an option for MAS in the maintenance therapy phase and is potentially beneficial to prevent recurrence.
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Azetidinas , Síndrome de Ativação Macrofágica , Paniculite , Neoplasias Cutâneas , Adulto , Azetidinas/uso terapêutico , Feminino , Humanos , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/etiologia , Metilprednisolona/uso terapêutico , Purinas/uso terapêutico , Pirazóis , Neoplasias Cutâneas/complicações , Sulfonamidas , Adulto JovemRESUMO
Neutrophils are cells at the frontline of innate immunity that can quickly activate effector functions to eliminate pathogens upon stimulation. However, little is known about the metabolic adaptations that power these functions. Here we show rapid metabolic alterations in neutrophils upon activation, particularly drastic reconfiguration around the pentose phosphate pathway, which is specifically and quantitatively coupled to an oxidative burst. During this oxidative burst, neutrophils switch from glycolysis-dominant metabolism to a unique metabolic mode termed 'pentose cycle', where all glucose-6-phosphate is diverted into oxidative pentose phosphate pathway and net flux through upper glycolysis is reversed to allow substantial recycling of pentose phosphates. This reconfiguration maximizes NADPH yield to fuel superoxide production via NADPH oxidase. Disruptions of pentose cycle greatly suppress oxidative burst, the release of neutrophil extracellular traps and pathogen killing by neutrophils. Together, these results demonstrate the remarkable metabolic flexibility of neutrophils, which is essential for their functions as the first responders in innate immunity.
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Via de Pentose Fosfato , Explosão Respiratória , Glicólise , Neutrófilos/metabolismo , Superóxidos/metabolismoRESUMO
Still's disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still's disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still's disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still's disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still's disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still's disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still's disease and macrophage activation syndrome.
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Artrite Juvenil , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Adulto , Criança , Humanos , Camundongos , Animais , Síndrome de Ativação Macrofágica/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Linfo-Histiocitose Hemofagocítica/genética , Modelos TeóricosRESUMO
OBJECTIVE: The incidence of Hashimoto's thyroiditis (HT) in patients with polycystic ovary syndrome (PCOS) is significantly higher than in normal controls, and there is a risk of more severe metabolic symptoms when the two diseases occur together. This study compares insulin secretion, insulin resistance (IR) and thyroid function in patients with PCOS with and without HT. METHODS: A total of 164 patients (52 patients with HT (HT+) and 112 patients without HT diagnosed PCOS at our hospital were enrolled for testing of oral glucose tolerance, insulin release, thyroid function, the presence of thyroglobulin and thyroid peroxidase antibodies, and blood lipid levels. RESULTS: Patients with PCOS and HT had higher insulin secretion and IR levels than those without HT, while free thyroxine and thyrotropin levels were significantly lower. The ratio of free thyroxine to thyrotropin was higher in patients with HT. CONCLUSION: HT may related with IR and relatively low thyroid function in patients with PCOS. Thus, thyroid function and autoimmune status in patients with PCOS should be evaluated in clinical practice.
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OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. METHODS: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. RESULTS: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. CONCLUSION: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.