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Pulmonary arterial hypertension (PAH) is a debilitating vascular disorder characterized by abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and collagen synthesis, contributing to vascular remodeling and elevated pulmonary vascular resistance. This study investigated the critical role of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) in cell proliferation and collagen synthesis in PASMCs in PAH. Here we show that ATIC levels are significantly increased in the lungs of MCT-induced PAH rat model and hypoxia-induced PAH mouse model and PDGF-stimulated PASMCs. Inhibition of ATIC attenuated platelet-derived growth factor (PDGF)-induced cell proliferation and collagen I synthesis in PASMCs. Conversely, overexpression or knockdown of ATIC causes a significant promotion or inhibition of Ras and ERK activation, cell proliferation and collagen synthesis in PASMCs. Moreover, ATIC deficiency attenuated Ras activation in the lungs of hypoxia-induced PAH mice. Further, Ras inhibition attenuates ATIC overexpression- and PDGF-induced collagen synthesis and PASMC proliferation. Notably, we identified that transcription factor MYC, EGR1, and SP1 directly binds to promoters of Atic gene and regulate ATIC expression. These results provide the first evidence that ATIC promotes PASMC proliferation in pulmonary vascular remodeling through the Ras signaling pathway.
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AIMS: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of pulmonary hypertension (PH). Proliferative cells utilize purine bases from the de novo purine synthesis (DNPS) pathways for nucleotide synthesis; however, it is unclear whether DNPS plays a critical role in VSMC proliferation during development of PH. The last two steps of DNPS are catalysed by the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC). This study investigated whether ATIC-driven DNPS affects the proliferation of pulmonary artery smooth muscle cells (PASMCs) and the development of PH. METHODS AND RESULTS: Metabolites of DNPS in proliferative PASMCs were measured by liquid chromatography-tandem mass spectrometry. ATIC expression was assessed in platelet-derived growth factor-treated PASMCs and in the lungs of PH rodents and patients with pulmonary arterial hypertension. Mice with global and VSMC-specific knockout of Atic were utilized to investigate the role of ATIC in both hypoxia- and lung interleukin-6/hypoxia-induced murine PH. ATIC-mediated DNPS at the mRNA, protein, and enzymatic activity levels were increased in platelet-derived growth factor-treated PASMCs or PASMCs from PH rodents and patients with pulmonary arterial hypertension. In cultured PASMCs, ATIC knockdown decreased DNPS and nucleic acid DNA/RNA synthesis, and reduced cell proliferation. Global or VSMC-specific knockout of Atic attenuated vascular remodelling and inhibited the development and progression of both hypoxia- and lung IL-6/hypoxia-induced PH in mice. CONCLUSION: Targeting ATIC-mediated DNPS compromises the availability of purine nucleotides for incorporation into DNA/RNA, reducing PASMC proliferation and pulmonary vascular remodelling and ameliorating the development and progression of PH.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Camundongos , Animais , Roedores/metabolismo , Remodelação Vascular/fisiologia , Artéria Pulmonar , Purinas/metabolismo , Células Cultivadas , Hipóxia/metabolismo , RNA Mensageiro/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proliferação de Células , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of arterial diseases, especially in arterial restenosis after angioplasty or stent placement. VSMCs reprogram their metabolism to meet the increased requirements of lipids, proteins, and nucleotides for their proliferation. De novo purine synthesis is one of critical pathways for nucleotide synthesis. However, its role in proliferation of VSMCs in these arterial diseases has not been defined. METHODS: De novo purine synthesis in proliferative VSMCs was evaluated by liquid chromatography-tandem mass spectrometry. The expression of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last 2 steps of the de novo purine synthesis pathway, was assessed in VSMCs of proliferative arterial neointima. Global and VSMC-specific knockout of Atic mice were generated and used for examining the role of ATIC-associated purine metabolism in the formation of arterial neointima and atherosclerotic lesions. RESULTS: In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes, including ATIC, were observed in the neointima of the injured vessels and atherosclerotic lesions both in mice and humans. Global or specific knockout of Atic in VSMCs inhibited cell proliferation, attenuating the arterial neointima in models of mouse atherosclerosis and arterial restenosis. CONCLUSIONS: These results reveal that de novo purine synthesis plays an important role in VSMC proliferation in arterial disease. These findings suggest that targeting ATIC is a promising therapeutic approach to combat arterial diseases.
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Aterosclerose , Hidroximetil e Formil Transferases , Humanos , Camundongos , Animais , Neointima , Purinas , Proliferação de Células , Miócitos de Músculo Liso , Aterosclerose/genéticaRESUMO
Upper tract urothelial carcinoma (UTUC), including renal, pelvic, and ureteral carcinoma, has a high incidence rate in Taiwan, which is different from that in Western countries. Therefore, it is imperative to elucidate the mechanisms underlying UTUC growth and metastasis. To explore the function of miR-145-5p in UTUC, we transfected the BFTC909 cell line with miR-145-5p mimics and analyzed the differences in protein levels by performing two-dimensional polyacrylamide gel electrophoresis. Real-time polymerase chain reaction and Western blot analysis were used to analyze 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inositol monophosphate cyclohydrolase (ATIC) messenger RNA and protein levels. A dual-luciferase assay was performed to identify the target of miR-145-5p in ATIC. The effects of miR-145-5p and ATIC expression by cell transfection on cell proliferation, migration, and invasion were also assessed. miR-145-5p downregulated ATIC protein expression. High ATIC expression is associated with tumor stage, metastasis, recurrence, and a poor prognosis in patients with UTUC. Cell function assays revealed that ATIC knockdown inhibited the proliferation, migration, and invasive abilities of UTUC cells. In contrast, miR-145-5p affected the proliferation, migration, and invasive abilities of UTUC cells by directly targeting the 3'-untranslated regions of ATIC. Furthermore, we used RNA sequencing and Ingenuity Pathway Analysis to identify possible downstream genes regulated by ATIC and found that miR-145-5p regulated the protein levels of fibronectin 1, Slug, cyclin A2, cyclin B1, P57, and interferon-induced transmembrane 1 via ATIC. ATIC may be a valuable predictor of prognosis and a potential therapeutic target for UTUC.
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Carcinoma de Células de Transição , Hidroximetil e Formil Transferases , MicroRNAs , Neoplasias da Bexiga Urinária , Humanos , MicroRNAs/genética , Carcinoma de Células de Transição/genética , Linhagem Celular Tumoral , Neoplasias da Bexiga Urinária/genética , Hidroximetil e Formil Transferases/genética , Proliferação de Células/genética , Ribonucleotídeos , Movimento Celular/genética , Regulação Neoplásica da Expressão GênicaRESUMO
5-Amino-4-imidazolecarboxamide-ribosiduria (AICA-ribosiduria) is an extremely rare inborn error of purine biosynthesis metabolism caused by pathogenic variants in ATIC gene that encodes a protein catalyzing the last steps of the de novo purine biosynthesis. To date, only six cases have been reported presenting a severe phenotype characterized by coarse facies and variable dysmorphic features, intrauterine and postnatal growth retardation, severe and early neurodevelopment delay, profound congenital visual deficit, scoliosis and, less frequently, epilepsy, aortic coarctation, chronic hepatic cytolysis, nephrocalcinosis and mild genitalia malformation. In this article, we report two new cases of AICA-ribosiduria carrying new pathogenic variants in ATIC (c.421C>T;p.Arg141Ter and c.1753A>G p.Thr585Ala) associated to a milder phenotype compared to previously reported patients. Particularly, the children showed few dysmorphic features (bulging forehead, depressed nasal bridge, and flat nasal tip), postnatal growth impairment, psychomotor delay since the second year of life, reduction of visual acuity (from mild impairment to low vision from the age of 5 years and to partial blindness from the age of 7 years) and mild hepatic dysfunctions. Scoliosis as well as epilepsy, renal involvement, or genitalia malformation were not detected. According to literature data, we found an abnormal accumulation of intermediates of de novo purine biosynthesis in the urine of both siblings. This report expands the spectrum of phenotypic severity associated to ATIC biallelic pathogenic variants and prompts the need to investigate ultra-rare causes of metabolic disorders such as AICA-ribosiduria in subjects with early neurological and sensory involvement of uncertain etiology.
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Deficiência Intelectual , Escoliose , Humanos , Irmãos , Transtornos da Visão , Fenótipo , Purinas/metabolismoRESUMO
Oesophageal squamous-cell carcinoma (ESCC) is a malignant tumor of the digestive system with a poor prognosis. Recent studies have shown the promoting effect of hsa_circ_0058063 (circ_0058063) on ESCC, but the potential regulatory mechanisms of circ_0058063 in ESCC remain largely unclear. The levels of circ_0058063, microRNA-4319 (miR-4319) and mRNA of thrombospondin-1 (THBS1) were indicated by quantitative real-time polymerase chain reaction in ESCC tissues and cells. Meanwhile, the level of THBS1 was quantified by western blot analysis. In addition, the cell functions were examined by CCK8 assay, Edu assay, flow cytometry assay and transwell assay. Furthermore, the interplay between miR-4319 and circ_0058063 or THBS1 was detected by dual-luciferase reporter assay. Finally, an in vivo experiment was implemented to confirm the effect of circ_0058063. The level of circ_0058063 and THBS1 were increased, and the miR-4319 level was decreased in ESCC tissues in contrast to that in normal tissues and cells. For functional analysis, circ_0058063 deficiency inhibited cell vitality, cell proliferation, migration and invasion in ESCC cells, whereas promoted cell apoptosis. Moreover, miR-4319 was confirmed to repress the progression of ESCC cells by suppressing THBS1. In mechanism, circ_0058063 acted as a miR-4319 sponge to regulate the level of THBS1. Besides, circ_0058063 knockdown also attenuated tumour growth in vivo. Circ_0058063 facilitates the development of ESCC through increasing THBS1 expression by regulating miR-4319, which also offered an underlying targeted therapy for ESCC treatment.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Apoptose , Proliferação de Células , Neoplasias Esofágicas/genética , MicroRNAs/genética , Linhagem Celular TumoralRESUMO
Purines are essential molecules that are components of vital biomolecules, such as nucleic acids, coenzymes, signaling molecules, as well as energy transfer molecules. The de novo biosynthesis pathway starts from phosphoribosylpyrophosphate (PRPP) and eventually leads to the synthesis of inosine monophosphate (IMP) by means of 10 sequential steps catalyzed by six different enzymes, three of which are bi-or tri-functional in nature. IMP is then converted into guanosine monophosphate (GMP) or adenosine monophosphate (AMP), which are further phosphorylated into nucleoside di- or tri-phosphates, such as GDP, GTP, ADP and ATP. This review provides an overview of inborn errors of metabolism pertaining to purine synthesis in humans, including either phosphoribosylpyrophosphate synthetase (PRS) overactivity or deficiency, as well as adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), and adenylosuccinate synthetase (ADSS) deficiencies. ITPase deficiency is being described as well. The clinical spectrum of these disorders is broad, including neurological impairment, such as psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscle presentations or consequences of hyperuricemia, such as gouty arthritis or kidney stones. Clinical signs are often nonspecific and, thus, overlooked. It is to be hoped that this is likely to be gradually overcome by using sensitive biochemical investigations and next-generation sequencing technologies.
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Adenilossuccinato Liase , Erros Inatos do Metabolismo da Purina-Pirimidina , Adenilossuccinato Liase/deficiência , Adenilossuccinato Liase/genética , Adenilossuccinato Liase/metabolismo , Transtorno Autístico , Humanos , Inosina Monofosfato , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , PurinasRESUMO
In the previous studies, circular RNA (circRNA) has been shown to be closely related to the occurrence and development of various cancers. However, the role and mechanism of circ-ATIC in the progression of esophageal squamous cell carcinoma (ESCC) is not yet clear. Quantitative real-time PCR was used to detect the expression levels of circ-ATIC, microRNA (miR)-326 and inhibitor of DNA binding 1 (ID1) in tissues (n = 50) and cells. Cell counting kit 8 assay, colony formation assay, flow cytometry, wound-healing assay and transwell assay were performed to measure the proliferation, apoptosis, migration, and invasion of cells. In addition, the oxidative stress of cells was evaluated by detecting the productions of superoxide dismutase and malondialdehyde. Animal studies were implied to explore the role of circ-ATIC in ESCC tumor growth. The relationship between circ-ATIC and miR-326 or ID1 was determined by dual-luciferase reporter assay and RNA immunoprecipitation assay. Additionally, the protein expression of ID1 was examined by western blot assay. Circ-ATIC was found to be upregulated in ESCC tissues and cells. Silenced circ-ATIC suppressed the proliferation, migration, invasion, promoted the apoptosis and oxidative stress of ESCC cells. The tumor growth of ESCC also was inhibited by circ-ATIC knockdown. Furthermore, we found that circ-ATIC could sponge miR-326, and miR-326 could target ID1. The rescue experiments revealed that miR-326 inhibitor could reverse the negative regulation of circ-ATIC silencing on ESCC progression, and ID1 overexpression also inverted the inhibitory effect of miR-326 on ESCC progression. In addition, we confirmed that the expression of ID1 was positively regulated by circ-ATIC. Our study showed that circ-ATIC facilitated the progression of ESCC by regulating the miR-326/ID1 axis, indicating that circ-ATIC might be a target for ESCC treatment.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
The purinosome is a dynamic metabolic complex composed of enzymes responsible for de novo purine biosynthesis, whose formation has been associated with elevated purine demand. However, the physiological conditions that govern purinosome formation in cells remain unknown. Here, we report that purinosome formation is up-regulated in cells in response to a low-oxygen microenvironment (hypoxia). We demonstrate that increased purinosome assembly in hypoxic human cells requires the activation of hypoxia inducible factor 1 (HIF-1) and not HIF-2. Hypoxia-driven purinosome assembly was inhibited in cells lacking 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a single enzyme in de novo purine biosynthesis, and in cells treated with a small molecule inhibitor of ATIC homodimerization. However, despite the increase in purinosome assembly in hypoxia, we observed no associated increase in de novo purine biosynthesis in cells. Our results indicate that this was likely due to a reduction in mitochondrial one-carbon metabolism, resulting in reduced mitochondrion-derived one-carbon units needed for de novo purine biosynthesis. The findings of our study further clarify and deepen our understanding of purinosome formation by revealing that this process does not solely depend on cellular purine demand.
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Hidroximetil e Formil Transferases/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Complexos Multienzimáticos/metabolismo , Nucleotídeo Desaminases/metabolismo , Purinas/biossíntese , Hipóxia Celular , Células HeLa , Humanos , Hidroximetil e Formil Transferases/genética , Fator 1 Induzível por Hipóxia/genética , Complexos Multienzimáticos/genética , Nucleotídeo Desaminases/genéticaRESUMO
5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH (ATIC), which catalyzes the last two steps of de novo purine synthesis. It is characterized biochemically by the accumulation of AICA-riboside in urine. AICA-ribosiduria had been reported in only one individual, 15 years ago. In this article, we report three novel cases of AICA-ribosiduria from two independent families, with two novel pathogenic variants in ATIC. We also provide a clinical update on the first patient. Based on the phenotypic features shared by these four patients, we define AICA-ribosiduria as the syndromic association of severe-to-profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante-postnatal growth impairment, and severe scoliosis. Dysmorphic features were observed in all four cases, especially neonatal/infancy coarse facies with upturned nose. Early-onset epilepsy is frequent and can be pharmacoresistant. Less frequently observed features are aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis. Alteration of the transformylase activity of ATIC might result in a more severe impairment than the alteration of the cyclohydrolase activity. Data from literature points toward a cytotoxic mechanism of the accumulated AICA-riboside.
Assuntos
Anormalidades Congênitas/genética , Epilepsia/genética , Hidroximetil e Formil Transferases/deficiência , Deficiência Intelectual/genética , Complexos Multienzimáticos/genética , Nucleotídeo Desaminases/deficiência , Aminoimidazol Carboxamida/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Hidroximetil e Formil Transferases/genética , Hidroximetil e Formil Transferases/metabolismo , Lactente , Recém-Nascido , Masculino , Complexos Multienzimáticos/metabolismo , Mutação , Nucleotídeo Desaminases/genética , Nucleotídeo Desaminases/metabolismo , Fenótipo , Ribonucleosídeos/metabolismoRESUMO
Tumor-associated (TA) autoantibodies have been identified at the early tumor stage before developing clinical symptoms, which holds hope for early cancer diagnosis. We identified a TA autoantibody from HBx-transgenic (HBx-tg) hepatocellular carcinoma (HCC) model mouse, characterized its target antigen, and examined its relationship to human HCC. The mimotopes corresponding to the antigenic epitope of TA autoantibody were screened from a random cyclic peptide library and used for the detection of serum TA autoantibody. The target antigen of the TA autoantibody was identified as an oncogenic bi-functional purine biosynthesis protein, ATIC. It was upregulated in liver cancer tissues of HBx-tg mouse as well as human HCC tissues. Over-expressed ATIC was also secreted extracellularly via the cancer-derived exosomes, which might cause auto-immune responses. The cyclic peptide mimotope with a high affinity to anti-ATIC autoantibody, CLPSWFHRC, distinguishes between serum samples from HCC patients and healthy subjects with 70.83% sensitivity, 90.68% specificity (AUC = 0.87). However, the recombinant human ATIC protein showed a low affinity to anti-ATIC autoantibody, which may be incompatible as a capture antigen for serum TA autoantibody. This study indicates that anti-ATIC autoantibody can be a potential HCC-associated serum biomarker and suggests that autoantibody biomarker's efficiency can be improved by using antigenic mimicry to native antigens present in vivo.
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Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Epitopos/imunologia , Hidroximetil e Formil Transferases/imunologia , Neoplasias Hepáticas/diagnóstico , Complexos Multienzimáticos/imunologia , Nucleotídeo Desaminases/imunologia , Peptídeos Cíclicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autoanticorpos/imunologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/imunologia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Biblioteca de Peptídeos , Prognóstico , Adulto JovemRESUMO
The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de novo synthesis. It metabolizes 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is an AMP analogue, leading to activation of AMP-activated kinase (AMPK). We investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG)-mediated DNA damage response and AICAR-mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damage and shortening of the lifespan. HG up-regulated the expression and activity of the Caenorhabditis elegans homologue of ATIC, C55F2.1 (atic-1), and increased the levels of reactive oxygen species and methylglyoxal-derived advanced glycation end products. Overexpression of atic-1 decreased the lifespan and head motility and increased neuronal damage under both standard and HG conditions. Inhibition of atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, reactive oxygen species, and methylglyoxal-derived advanced glycation end product accumulation. This effect was independent of an effect on DNA damage or antioxidant defense pathways, such as superoxide dismutase (sod-3) or glyoxalase-1 (glod-4), but was dependent on AMPK and accumulation of AICAR. Through AMPK, AICAR treatment also reduced the negative effects of HG. The mitochondrial inhibitor rotenone abolished the AICAR/AMPK-induced amelioration of HG effects, pointing to mitochondria as a prime target of the glucotoxic effects in C. elegans We conclude that atic-1 is involved in glucotoxic effects under HG conditions, either by blocked atic-1 expression or via AICAR and AMPK induction.
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Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Glucose/metabolismo , Hidroximetil e Formil Transferases/metabolismo , Complexos Multienzimáticos/metabolismo , Nucleotídeo Desaminases/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Hidroximetil e Formil Transferases/genética , Complexos Multienzimáticos/genética , Neurônios/metabolismo , Nucleotídeo Desaminases/genética , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: To identify and classify the barriers and facilitators of the individualisation process of the standardised care plan in hospitalisation wards. BACKGROUND: The administration of individualised care is one of the features of the nursing process. Care plans are the structured record of the diagnosis, planning and evaluation stages of the nursing process. Although the creation of standardised care plan has made recording easier, it is still necessary to record the individualisation of the care. It is important to study the elements that influence the individualisation process from the nurses' perspective. DESIGN: Qualitative study with the grounded theory approach developed by Strauss and Corbin. METHODS: Thirty-nine nurses from three hospitals participated by way of theoretical sampling. In-depth interviews were conducted, as well as participant observation, document analysis and focus group discussion. The analysis consisted of open, axial and selective coding until data saturation was reached. EQUATOR guidelines for qualitative research (COREQ) were applied. RESULTS: For both barriers and facilitators, three thematic categories emerged related to organisational, professional and individual aspects. The identified barriers included routines acquired in the wards, the tradition of narrative records, lack of knowledge and limited interest in individualisation. The identified facilitators included holding clinical care sessions, use of standardised care plan and an interface terminology, the nurse's expertise and willingness to individualise. CONCLUSION: The individualisation process of the standardised care plan involves multiple barriers and facilitators, which influence its degree of accuracy. RELEVANCE TO CLINICAL PRACTICE: Implementing strategies at an organisational level, professional level and individual level to improve the way the process is carried out would encourage individualising the standardised care plan in a manner that is consistent with the needs of the patient and family; it would improve the quality of care and patient satisfaction.
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Enfermagem de Cuidados Críticos/organização & administração , Planejamento de Assistência ao Paciente/organização & administração , Adulto , Feminino , Grupos Focais , Teoria Fundamentada , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Adulto JovemRESUMO
Mitochondrial myopathy (MM) is characterised by muscle weakness, exercise intolerance and various histopathological changes. Recently, a subset of MM has also been associated with aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) in skeletal muscle. This aberrant mTORC1 activation promotes increased de novo nucleotide synthesis, which contributes to abnormal expansion and imbalance of skeletal muscle deoxyribonucleoside triphosphates (dNTP) pools. However, the exact mechanism via which mTORC1-stimulated de novo nucleotide biosynthesis ultimately disturbs muscle dNTP pools remains unclear. In this article, it is proposed that mTORC1-stimulated de novo nucleotide synthesis in skeletal muscle cells with respiratory chain dysfunction promotes an asymmetric increase of purine nucleotides, probably due to NAD+ deficiency. This in turn could disrupt purine nucleotide-dependent allosteric feedback regulatory mechanisms, ultimately leading to dNTP pools aberration. Pharmacological down-modulation of aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) activity is also proposed as a potential therapeutic strategy in MM exhibiting mTORC1-driven abnormal metabolic reprogramming, including aberrant dNTPs pools.
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Miopatias Mitocondriais/metabolismo , Nucleotídeos de Purina/metabolismo , Animais , Humanos , Hidroximetil e Formil Transferases/antagonistas & inibidores , Hidroximetil e Formil Transferases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miopatias Mitocondriais/tratamento farmacológico , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/metabolismo , Nucleotídeo Desaminases/antagonistas & inibidores , Nucleotídeo Desaminases/metabolismoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear. METHODS: ATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays. RESULTS: Here, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells. CONCLUSION: Taken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling.
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Adenilato Quinase/metabolismo , Carcinoma Hepatocelular/patologia , Hidroximetil e Formil Transferases/metabolismo , Neoplasias Hepáticas/patologia , Complexos Multienzimáticos/metabolismo , Nucleotídeo Desaminases/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Intervalo Livre de Doença , Ativação Enzimática , Técnicas de Silenciamento de Genes , Humanos , Hidroximetil e Formil Transferases/deficiência , Hidroximetil e Formil Transferases/genética , Terapia de Alvo Molecular , Complexos Multienzimáticos/deficiência , Complexos Multienzimáticos/genética , Nucleotídeo Desaminases/deficiência , Nucleotídeo Desaminases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
This study investigated whether the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene (ATIC) 347 C/G polymorphism can predict the response to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). We conducted a meta-analysis of studies on the association between ATIC 347 C/G polymorphism and non-responsiveness to or toxicity of MTX in RA patients, using PUBMED, EMBASE, and COCHRANE. Nine comparative studies from 6 articles including 1056 RA patients met our inclusion criteria. This final group of studies comprised 5 studies on response to MTX and 4 on toxicity of MTX in RA patients in relation to the ATIC 347 C/G polymorphism status. Meta-analysis showed association between the ATIC 347 GG + GC genotype and non-response to MTX therapy (OR = 1.572, 95 % CI 1.146-2.156, p = 0.005). Stratification by ethnicity indicated significant association between the ATIC 347 GG + GC genotype and non-response to MTX in Caucasians (OR = 1.884, 95 % CI 1.236-2.873, p = 0.003), but not in Asian patients. Similarly, associations were noted for the ATIC 347 C/G polymorphism through analysis using recessive and overdominant models. Meta-analysis revealed association between the ATIC 347 GG + GC genotype and MTX toxicity (OR = 1.454 95 % CI 1.034-2.044, p = 0.032). Stratification by ethnicity indicated significant association between the ATIC 347 GG + GC genotype and MTX toxicity in Caucasians (OR = 1.741, 95 % CI 1.080-2.806, p = 0.023), but not in Asian patients. The ATIC 347 C/G polymorphism may be associated with non-responsiveness to and or toxicity of MTX in Caucasian RA patients.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Hidroximetil e Formil Transferases/genética , Metotrexato/uso terapêutico , Complexos Multienzimáticos/genética , Nucleotídeo Desaminases/genética , Polimorfismo Genético , Antirreumáticos/efeitos adversos , Artrite Reumatoide/genética , Estudos de Associação Genética , Humanos , Metotrexato/efeitos adversos , Farmacogenética , Resultado do TratamentoRESUMO
PURPOSE: This study aimed to evaluate the frequency of psychosocial aspects of basic nursing care, as e-charted by nurses, when using an interface terminology. METHODS: An observational, multicentre study was conducted in acute wards. The main outcome measure was the frequency of use of the psychosocial interventions in the electronic nursing care plans, analysed over a 12 month retrospective review. FINDINGS: Overall, 150,494 electronic care plans were studied. Most of the intervention concepts from the interface terminology were used by registered nurses to illustrate the psychosocial aspects of fundamentals of care in the electronic care plans. CONCLUSIONS AND IMPLICATIONS: The results presented help to demonstrate that the interventions of this interface terminology may be useful to inform psychosocial aspects of basic and advanced nursing care. CLINICAL RELEVANCE: The identification of psychosocial elements of basic nursing care in the nursing documentation may lead to obtain a deeper understanding of those caring interventions nurses consider essential to represent nurse-patient interactions. The frequency of psychosocial interventions may contribute to delineate basic and advanced nursing care.
Assuntos
Comunicação , Enfermagem de Cuidados Críticos , Registros de Enfermagem/estatística & dados numéricos , Psicoterapia/estatística & dados numéricos , Registros Eletrônicos de Saúde , Humanos , Pesquisa em Avaliação de Enfermagem , Planejamento de Assistência ao Paciente , Estudos RetrospectivosRESUMO
A 56-year-old woman debuted with a palpable painless mass in the anterior thorax wall at the level of the second and third right parasternal intercostal space, which progressively increased in size over 5 months accompanied by localized skin rash, mild dyspnea and chest pain when changing position. Imaging studies showed a soft tissue mass measuring 75 × 62 mm and a density of 34 Hounsfield Units that had caused the lysis of the costal arches and grew expansively towards the anterior mediastinum, without identifying mediastinal adenopathies only by this imaging method. Core biopsy was performed, which was initially diagnosed as histiocytic sarcoma (HS); however, when the diagnostic panel was expanded to include molecular and NGS studies, the final diagnosis was anaplastic large cell lymphoma with ALK::ATIC fusion. Here, we report a very rare neoplasm with unusual clinical presentation, histopathology and molecular features.
Assuntos
Sarcoma Histiocítico , Linfoma Anaplásico de Células Grandes , Humanos , Feminino , Pessoa de Meia-Idade , Sarcoma Histiocítico/patologia , Sarcoma Histiocítico/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Anaplásico de Células Grandes/diagnóstico , Quinase do Linfoma Anaplásico/genética , Diagnóstico Diferencial , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/genéticaRESUMO
In a recent study, Liu and colleagues demonstrated a role for the purine biosynthesis enzyme ATIC and its substrate in regulating the protein levels of the Parkinson's disease kinase LRRK2, which rescues neurodegeneration and neuroinflammation in distinct animal models. This work highlights a novel avenue to target LRRK2 protein levels as a strategy to prevent neurodegeneration in Parkinson's disease.
Assuntos
Doença de Parkinson , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Modelos Animais , MutaçãoRESUMO
BACKGROUND: There are currently no validated criteria that entirely explain or predict response to methotrexate (MTX) treatment in rheumatoid arthritis (RA). We tried to identify the connection between three variants (RFC1 G80A (rs1051266), TYMS 2R/3R (rs34743033), and ATIC C347G (rs2372536)) in the folate pathway of MTX metabolism and the response to MTX monotherapy in a cohort of RA cases. METHODS: A prospective study on 100 RA patients on MTX monotherapy was performed. Disease activity was measured at the start of treatment and 6 months after treatment with MTX. The patients were then split into two groups: those who responded to the treatment and those who did not. The molecular genetic study for the RFC1 (G80A) variant was employed via the PCR-restriction fragment length polymorphism (PCR-RFLP) technique, the ATIC (C347G) variant was performed using TaqMan allelic discrimination real-time PCR, and the tandem repeat sequences of TYMS (2R/3R) were amplified by conventional PCR and detected by agarose gel electrophoresis. RESULTS: The genotype distribution of RFC-1 (G80A) showed significant variations among non-responders and responders in the recessive genetic model. A significant difference was found in TYMS (2R/3R) in the dominant and heterozygous genetic models. However, ATIC (C347G) genotype frequency did not exhibit substantial link with drug response in all genetic models. Furthermore, the genotype and allele rates of the analyzed variants did not show any significant association with adverse events in all genetic models. CONCLUSION: The 80AA genotype of RFC-1 G80A and the 2R/3R or 3R/3R genotypes of TYMS 2R/3R are more vulnerable to the good consequences of MTX therapy. Key Points ⢠Current recommendations support the gold standard role of MTX as a first-line monotherapy for RA patients. However, up to 40% of RA patients do not respond or exhibit partial response to MTX. ⢠Persistent disease activity due to treatment unresponsiveness will affect the long-term outcomes in RA patients. ⢠We aimed, through molecular genetic study, to identify the connection between three variants in the folate pathway of MTX metabolism and the response to methotrexate monotherapy in a cohort of RA patients.