Brefeldin A and M-COPA block the export of RTKs from the endoplasmic reticulum via simultaneous inactivation of ARF1, ARF4, and ARF5.

Normal receptor tyrosine kinases (RTKs) need to reach the plasma membrane (PM) for ligand-induced activation, whereas its cancer-causing mutants can be activated before reaching the PM in organelles, such as the Golgi/trans-Golgi network (TGN). Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER. BFA and M-COPA block the function of ADP-ribosylation factors (ARFs) that play a crucial role in ER-Golgi protein trafficking. However, among ARF family proteins, the specific ARFs inhibited by BFA or M-COPA, that is, the ARFs involved in RTKs transport from the ER, remain unclear. In this study, we showed that M-COPA blocked the export of not only KIT but also PDGFRA/EGFR/MET RTKs from the ER. ER-retained RTKs could not fully transduce anti-apoptotic signals, thereby leading to cancer cell apoptosis. Moreover, a single knockdown of ARF1, ARF3, ARF4, ARF5, or ARF6 could not block ER export of RTKs, indicating that BFA/M-COPA treatment cannot be mimicked by the knockdown of only one ARF member. Interestingly, simultaneous transfection of ARF1, ARF4, and ARF5 siRNAs mirrored the effect of BFA/M-COPA treatment. Consistent with these results, in vitro pulldown assays showed that BFA/M-COPA blocked the function of ARF1, ARF4, and ARF5. Taken together, these results suggest that BFA/M-COPA targets at least ARF1, ARF4, and ARF5; in other words, RTKs require the simultaneous activation of ARF1, ARF4, and ARF5 for their ER export.

Comparison of Copper-Tolerance Genes between Different Groups of Acidovorax citrulli.

Acidovorax citrulli populations exhibit genetic and phenotypic variations, particularly in terms of copper tolerance. Group I strains of A. citrulli generally exhibit higher copper tolerance compared to group II strains. This study aims to identify genes involved in copper tolerance to better understand the differences in copper tolerance between group I and group II strains. Representative strains pslb65 (group I) and pslbtw14 (group II) were selected for comparison. Deletion mutants of putative copper-tolerance genes and their corresponding complementary strains were constructed. The copper tolerance of each strain was evaluated using the minimum inhibitory concentration method. The results showed that the copA, copZ, cueR, and cueO genes played major roles in copper tolerance in A. citrulli, while cusC-like, cusA-like, and cusB-like genes had minor effects. The different expression levels of copper-tolerance-related genes in pslb65 and pslbtw14 under copper stress indicated that they had different mechanisms for coping with copper stress. Overall, this study provides insights into the mechanisms of copper tolerance in A. citrulli and highlights the importance of specific genes in copper tolerance.

Autoinflammatory Diseases Due to Defects in Degradation or Transport of Intracellular Proteins.

The number of human inborn errors of immunity has now gone beyond 430. The responsible gene variants themselves are apparently the cause for the disorders, but the underlying molecular or cellular mechanisms for the pathogenesis are often unclear. In order to clarify the pathogenesis, the mutant mice carrying the gene variants are apparently useful and important. Extensive analysis of those mice should contribute to the clarification of novel immunoregulatory mechanisms or development of novel therapeutic maneuvers critical not only for the rare monogenic diseases themselves but also for related common polygenic diseases. We have recently generated novel model mice in which complicated manifestations of human inborn errors of immunity affecting degradation or transport of intracellular proteins were recapitulated. Here, we review outline of these disorders, mainly based on the phenotype of the mutant mice we have generated.

COPA syndrome caused by a novel p.Arg227Cys COPA gene variant.

BACKGROUND: COPA syndrome is a recently described and rare monogenic autosomal dominant disease caused by heterozygous missense mutations in the Coatomer Protein Subunit alpha (COPA) gene that encodes the alpha subunit of coat protein complex I (COPI). Its main clinical manifestations are inflammatory lung disease, arthritis, and renal disease. The development of inflammation in COPA syndrome maybe due to abnormal autophagic response and abnormal activation of type I interferon pathway. To date, 59 cases of COPA have been reported worldwide. METHODS: In this case, Trio-whole exome sequencing was employed in the proband and her parents to identify the underlying genetic cause. COPA variant were detected and the clinical presentation of the patient was described. RESULTS: Herein, we report a case of a 5-year-old girl with COPA syndrome who presented with symptoms of arthritis combined with Anti-neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV), and progressive renal decline with minimal pulmonary involvement. Trio-whole exome sequencing was performed which revealed a novel heterozygous likely pathogenic variation in the COPA gene (c.679C>T,p.Arg227Cys), which was maternally inherited. Her mother was a heterozygote, but she had no phenotypic manifestations. No other mutations associated with the clinical phenotype were identified. CONCLUSION: The present identification and characterization of a novel mutation expands the genotypic spectra of the COPA syndrome and provide reference data to guide future clinical diagnosis and treatment of COPA syndrome.

[Lung involvement in autoinflammatory diseases]. / Atteinte pulmonaire dans les maladies auto-inflammatoires.

Genetic autoinflammatory diseases are now a recognized and rapidly expanding group. The lung involvement historically associated with autoinflammatory diseases is inflammatory seritis, primarily seen in familial Mediterranean fever and other interleukin-1 mediated diseases. Over the last ten years, pulmonary involvement has been the core presentation of two autoinflammatory diseases associated with constitutive type I interferon activation, i.e. SAVI and COPA syndrome. Most patients with these diseases usually develop early progression to pulmonary fibrosis, which is responsible for high rates of morbidity and mortality. Other rare autoinflammatory diseases are associated with alveolar proteinosis, particularly when related to MARS mutations. Additionally, in adults, VEXAS is frequently associated with pulmonary involvement, albeit without prognosis effect. A molecular approach to autoinflammatory diseases enables not only the definition of biomarkers for diagnosis, but also the identification of targeted treatments. Examples include JAK inhibitors in SAVI and COPA syndrome, even though this therapy does not prevent progression to pulmonary fibrosis. Another illustrative example is the efficacy of methionine supplementation in alveolar proteinosis linked to MARS mutations. Overall, in autoinflammatory diseases the lung is now emerging as a possible affected organ. Continuing discovery of new autoinflammatory diseases is likely to uncover further pathologies involving the lung. Such advances are expected to lead to the development of novel therapeutic perspectives.

Chronic limping in childhood, what else other than juvenile idiopathic arthritis: a case series.

BACKGROUND: Limping is a common clinical symptom in childhood; different clinical conditions may lead to limping and the diagnosis of the underlying cause may often be a challenge for the pediatrician. CASE PRESENTATION: We describe the clinical manifestations, radiological pictures and disease course of other causes of limping in childhood, through a case series of seven cases and a brief discussion of each disease. CONCLUSIONS: although trauma is the most common cause of acute limping, when there is no history of traumatic events and the limping has a chronic course, Juvenile Idiopathic Arthritis is usually the most likely clinical diagnosis. However, other some rare conditions should be taken into account if JIA is not confirmed or if it presents with atypical clinical picture.

Insect Peptide CopA3 Mitigates the Effects of Heat Stress on Porcine Muscle Satellite Cells.

Heat stress inhibits cell proliferation as well as animal production. Here, we aimed to demonstrate that 9-mer disulfide dimer peptide (CopA3) supplementation stabilizes porcine muscle satellite cell (PMSC) proliferation and heat shock protein (HSP) expression at different temperatures. Therefore, we investigated the beneficial effects of CopA3 on PMSCs at three different temperatures (37, 39, and 41 °C). Based on temperature and CopA3 treatment, PMSCs were divided into six different groups including treatment and control groups for each temperature. Cell viability was highest with 10 µg/mL CopA3 and decreased as the concentration increased in a dose-dependent manner. CopA3 significantly increased the cell viability at all temperatures at 24 and 48 h. It significantly decreased apoptosis compared to that in the untreated groups. In addition, it decreased the apoptosis-related protein, Bcl-2-associated X (BAX), expression at 41 °C. Notably, temperature and CopA3 had no effects on the apoptosis-related protein, caspase 3. Expression levels of HSP40, HSP70, and HSP90 were significantly upregulated, whereas those of HSP47 and HSP60 were not affected by temperature changes. Except HSP90, CopA3 did not cause temperature-dependent changes in protein expression. Therefore, CopA3 promotes cell proliferation, inhibits apoptosis, and maintains stable HSP expression, thereby enhancing the heat-stress-tolerance capacity of PMSCs.

COPA Syndrome from Diagnosis to Treatment: A Clinician's Guide.

COPA syndrome is a recently described autosomal dominant inborn error of immunity characterized by high titer autoantibodies and interstitial lung disease, with many individuals also having arthritis and nephritis. Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns. This review explores the clinical presentation, genetics, molecular mechanisms, organ manifestations, and treatment approaches for COPA syndrome, and presents a diagnostic framework of suggested indications for patient testing.

JAK Inhibition in Juvenile Idiopathic Arthritis (JIA): Better Understanding of a Promising Therapy for Refractory Cases.

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases with probably differential underlying physiopathology. Despite the revolutionary era of biologics, some patients remain difficult to treat because of disease severity, drug adverse events, drug allergy or association with severe comorbidities, i.e., uveitis, interstitial lung disease and macrophagic activation syndrome. Janus Kinase (JAK) inhibitors are small molecules that target JAK/Signal Transducers and Activators of Transcription (STAT) pathways, which could then prevent the activity of several proinflammatory cytokines. They may provide a useful alternative in these cases of JIA or in patients actually affected by Mendelian disorders mimicking JIA, such as type I interferonopathies with joint involvement, and might be the bridge for haematopoietic stem cell transplantation in these disabling conditions. As these treatments may have side effects that should not be ignored, ongoing and further controlled studies are still needed to provide data underlying long-term safety considerations in children and delineate subsets of JIA patients that will benefit from these promising treatments.

Turismo esportivo e o papel dos eventos universitários: o caso da copa inter atléticas (CIA) / Sports tourism and the role of university events: the case of the inter athletic CUP (CIA)

O presente estudo busca analisar o papel dos eventos esportivos promovidos pelas Associações Atléticas Acadêmicas no impulsionamento do turismo de esportes, especificamente o caso da Copa Inter Atléticas (CIA). A pesquisa foi realizada por meio de levantamento bibliográfico e a aplicação de questionários com amostra não probabilística, visando coletar informações sobre as características, percepções e atitudes de jovens universitários. Identificou-se que às Atléticas se tornaram as principais responsáveis pela disseminação de práticas de sociabilidade e da cultura do lazer universitário no Brasil. Ao analisar a CIA, foi possível verificar que o turismo esportivo possui a capacidade de gerar renovados usos sociais dos espaços urbanos e que o turismo de eventos esportivos pode ser utilizado como um instrumento de apoio ao desenvolvimento de uma região, além de influenciar positivamente a imagem de um destino turístico.

The present study aims to analyze the role of sporting events promoted by Academic Athletic Associations in boosting sports tourism, specifically the case of the Inter Atléticas Cup (CIA). The research was carried out through a bibliographical survey and the application of questionnaires with a non-probabilistic sample, aiming to collect information about the characteristics, perceptions and attitudes of university students. It was identified that Atéticas became the main responsible for the dissemination of sociability practices and university leisure culture in Brazil. By analyzing the CIA, it was possible to verify that sports tourism has the capacity to generate renewed social uses of urban spaces and that sports events tourism can be used as an instrument to support the development of a region, in addition to positively influencing the image of a tourist destination.

Regulation of cGAS and STING signaling during inflammation and infection.

Stimulator of interferon genes (STING) is a sensor of cyclic dinucleotides including cyclic GMP-AMP, which is produced by cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA. The cGAS-STING signaling pathway regulates both innate and adaptive immune responses, as well as fundamental cellular functions such as autophagy, senescence, and apoptosis. Mutations leading to constitutive activation of STING cause devastating human diseases. Thus, the cGAS-STING pathway is of great interest because of its role in diverse cellular processes and because of the potential therapeutic implications of targeting cGAS and STING. Here, we review molecular and cellular mechanisms of STING signaling, and we propose a framework for understanding the immunological and other cellular functions of STING in the context of disease.

Copper Efflux System Required in Murine Lung Infection by Haemophilus influenzae Composed of a Canonical ATPase Gene and Tandem Chaperone Gene Copies.

Copper is an essential micronutrient but is toxic at high concentrations. In Haemophilus influenzae mechanisms of copper resistance and its role in pathogenesis are unknown; however, our previous genetic screen by transposon insertion-site sequencing implicated a putative cation transporting ATPase (copA) in survival in a mouse lung infection model. Here, we demonstrate that H. influenzae copA (HI0290) is responsible for copper homeostasis involving the merR-type regulator, cueR, as well as six tandem copies of the metallochaperone gene, copZ. Deletion of the ATPase and metallochaperone genes resulted in increased sensitivity to copper but not to cobalt, zinc, or manganese. Nontypeable H. influenzae (NTHi) clinical isolate NT127 has the same locus organization but with three copies of copZ. We showed that expression of the NTHi copZA operon is activated by copper under the regulatory control of CueR. NTHi single copA and copZ mutants and, especially, the double deletion copZA mutant exhibited decreased copper tolerance, and the ΔcopZA mutant accumulated 97% more copper than the wild type when grown in the presence of 0.5 mM copper sulfate. Mutants of NT127 deleted of the ATPase (copA) alone and deleted of both the ATPase and chaperones (copZ1-3) were 4-fold and 20-fold underrepresented compared to the parent strain during mixed-infection lung challenge, respectively. Complementation of cop locus deletion mutations restored copper resistance and virulence properties. NTHi likely encounters copper as a host defense mechanism during lung infection, and our results indicate that the cop system encodes an important countermeasure to alleviate copper toxicity.

Predisposición psicológica de heptatletas y decatletas cubanos, evidencias de su asociación con el rendimiento competitivo

La preparación psicológica para las competencias es un proceso que potencia las capacidades y cualidades del deportista durante la preparación para alcanzar el estado óptimo de predisposición psíquica. Son escasas las investigaciones que ofrecen evidencias empíricas de la relación existente entre el estado de predisposición psíquica y el rendimiento competitivo de atletas de pruebas combinadas. El objetivo de este trabajo fue determinar cómo se relacionan el estado de predisposición psicológica y el rendimiento competitivo de los atletas cubanos de pruebas combinadas. La investigación fue no experimental y transversal. La muestra la integraron ocho atletas de pruebas combinadas de la selección nacional cubana de atletismo. Se emplearon el Cuestionario de Predisposición Psicológica para la Competencia y la Escala de rendimiento en la competencia de pruebas combinadas. La claridad de objetivos correlacionó de manera positiva y directa con el rendimiento competitivo en las carreras con vallas (,793 sig. = ,019). La significación de la competencia percibida por los atletas correlacionó de manera positiva y directa con las carreras con vallas y el salto de altura (,826 sig. = ,012 y ,717 sig. = ,045). A medida que aumentó la claridad de objetivos en los atletas estudiados también lo hizo el rendimiento percibido por sus entrenadores en las carreras con vallas que realizaron en la Copa Cuba 2020. A medida que fue mayor la significación de la competencia, también lo fue el rendimiento en carreras con vallas y salto de altura.

SÍNTESE A preparação psicológica para as competições é um processo que aumenta as habilidades e qualidades do atleta durante a preparação para alcançar o estado ideal de predisposição psíquica. Há poucas pesquisas que ofereçam evidências empíricas da relação entre o estado de predisposição psicológica e o desempenho competitivo dos atletas em eventos combinados. O objetivo deste trabalho foi determinar como o estado de predisposição psicológica e o desempenho competitivo dos atletas cubanos em eventos combinados estão relacionados. A pesquisa foi não-experimental e transversal. A amostra consistiu de oito atletas de eventos combinados da equipe nacional de atletismo de Cuba. Foram utilizados o Questionário de Predisposição Psicológica para Competição e a Escala de Desempenho em Competição de Julgamentos Combinados. Clareza de propósito correlacionada positivamente e diretamente com o desempenho competitivo em obstáculos (.793 sig. = .019). A percepção do significado da competência dos atletas se correlacionou positiva e diretamente com obstáculos e saltos em altura (.826 sig. = .012 e .717 sig. = .045). medida que a clareza das metas aumentava nos atletas estudados, também aumentava o desempenho percebido por seus treinadores nas corridas de obstáculos que realizaram na Copa Cuba 2020. medida que a importância da concorrência aumentava, aumentava também o desempenho em obstáculos e saltos altos.

Psychological preparation for competitions is a process that enhances the capacities and qualities of the athlete during the preparation to reach the optimal state of mental predisposition. There are few researches that offer empirical evidence of the relationship between the state of mental predisposition and the competitive performance of athletes in combined events. The objective of this work was to determine how the state of psychological predisposition and the competitive performance of Cuban athletes in combined events are related. The research was non-experimental and cross-sectional. The sample was made up of eight athletes from the combined events of the Cuban national athletics team. The Questionnaire of Psychological Predisposition for Competition and the Performance Scale in the competition of combined tests were used. Goal clarity was positively and directly correlated with competitive performance in hurdles (.793 sig. = .019). The significance of the athletes' perceived competition was positively and directly correlated with hurdles and high jump (.826 sig. = .012 and .717 sig. = .045). As the clarity of objectives increased in the athletes studied, so did the performance perceived by their coaches in the hurdles races they carried out in the 2020 Cuba Cup. As the significance of the competition was greater, so was the performance in hurdle races and high jump.

COPA3 peptide supplementation alleviates the heat stress of chicken fibroblasts.

Heat stress inhibits cellular proliferation and differentiation through the production of reactive oxygen species. Under stress conditions, antioxidant drugs promote stable cellular function by reducing the stress level. We sought to demonstrate 9-mer disulfide dimer peptide (COPA3) supplementation stabilizes fibroblast proliferation and differentiation even under heat stress conditions. In our study, fibroblasts were assigned to two different groups based on the temperature, like 38°C group presented as Control - and 43°C group presented as Heat Stress-. Each group was subdivided into two groups depending upon COPA3 treatment, like 38°C + COPA3 group symbolized Control+ and the 43°C + COPA3 group symbolized as Heat Stress+. Heat stress was observed to decrease the fibroblast viability and function and resulted in alterations in the fibroblast shape and cytoskeleton structure. In contrast, COPA3 stabilized the fibroblast viability, shape, and function. Moreover, heat stress and COPA3 were found to have opposite actions with respect to energy production, which facilitates the stabilization of cellular functions by increasing the heat tolerance capacity. The gene expression levels of antioxidant and heat shock proteins were higher after heat stress. Additionally, heat stress promotes the mitogen-activated protein kinase/ extracellular signal-regulated kinase-nuclear factor erythroid 2-related factor 2 (MAPK/ERK-Nrf2). COPA3 maintained the MAPK/ERK-Nrf2 gene expressions that promote stable fibroblast proliferation, and differentiation as well as suppress apoptosis. These findings suggest that COPA3 supplementation increases the heat tolerance capacity, viability, and functional activity of fibroblasts.

Case report: COPA syndrome with interstitial lung disease, skin involvement, and neuromyelitis spectrum disorder.

This report describes a case of a 22 months Chinese boy with COPA syndrome bearing the c.715G > C (p.A239P) genotype. In addition to interstitial lung diseae, he also suffered from recurrent chilblain-like rashes, which has not been previously reported, and neuromyelitis optica spectrum disorder (NMOSD), which is a very rare phenotype. Clinical manifestations expanded the phenotype of COPA syndrome. Notably, there is no definitive treatment for COPA syndrome. In this report, the patient has achieved short-term clinical improvement with sirolimus.

Imaging findings of COPA Syndrome.

BACKGROUND: Autosomal dominant mutations in the coatomer-associated protein alpha (COPA) gene cause an immune dysregulation disorder associated with pulmonary hemorrhage, lymphoid hyperplasia, arthritis, and glomerulonephritis. OBJECTIVE: To describe the thoracic, musculoskeletal, and renal imaging findings of COPA syndrome with a focus on the evolution of the pulmonary findings. MATERIALS AND METHODS: With approval of the Institutional Review Board, consensus retrospective review of findings on chest radiography and computed tomography (CT), musculoskeletal radiography and magnetic resonance imaging (MRI), and renal ultrasound (US) was performed for pediatric COPA syndrome patients. COPA syndrome patients < 18 years of age presenting between 1992 and 2019 were identified from an institutional rheumatology registry. RESULTS: Twelve pediatric COPA syndrome patients (mean age of 6.5 years at first imaging exam; 6 females) were identified. Imaging exams available for review included 45 chest CT exams on 12 patients, 37 musculoskeletal exams on 4 patients, and 10 renal US exams on 5 patients. All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12). Nine had at least one follow-up chest CT, which showed improvement in nodules (7/9), ground-glass opacities (4/9), and lymphadenopathy (9/9), but worsening of septal thickening (3/9), cyst formation (3/9), and fibrosis (3/9). Four had musculoskeletal imaging revealing synovitis (2/4), bone erosions (1/4), tenosynovitis (1/4), enthesitis (1/4), and subcutaneous nodules (1/4). Five had at least one renal US, revealing renal size abnormalities (4/5) and cortical hyperechogenicity (3/5). CONCLUSION: The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis. Other imaging findings manifesting later in childhood or adolescence relate to arthritis and glomerulonephritis.

Phagotrophic Protists Modulate Copper Resistance of the Bacterial Community in Soil.

Protist predation is a crucial biotic driver modulating bacterial populations and functional traits. Previous studies using pure cultures have demonstrated that bacteria with copper (Cu) resistance exhibited fitness advantages over Cu-sensitive bacteria under the pressure of protist predation. However, the impact of diverse natural communities of protist grazers on bacterial Cu resistance in natural environments remains unknown. Here, we characterized the communities of phagotrophic protists in long-term Cu-contaminated soils and deciphered their potential ecological impacts on bacterial Cu resistance. Long-term field Cu pollution increased the relative abundances of most of the phagotrophic lineages in Cercozoa and Amoebozoa but reduced the relative abundance of Ciliophora. After accounting for soil properties and Cu pollution, phagotrophs were consistently identified as the most important predictor of the Cu-resistant (CuR) bacterial community. Phagotrophs positively contributed to the abundance of a Cu resistance gene (copA) through influencing the cumulative relative abundance of Cu-resistant and -sensitive ecological clusters. Microcosm experiments further confirmed the promotion effect of protist predation on bacterial Cu resistance. Our results indicate that the selection by protist predation can have a strong impact on the CuR bacterial community, which broadens our understanding of the ecological function of soil phagotrophic protists.

The role of CopA in Streptococcus pyogenes copper homeostasis and virulence.

Maintenance of intracellular metal homeostasis during interaction with host niches is critical to the success of bacterial pathogens. To prevent infection, the mammalian innate immune response employs metal-withholding and metal-intoxication mechanisms to limit bacterial propagation. The first-row transition metal ion copper serves critical roles at the host-pathogen interface and has been associated with antimicrobial activity since antiquity. Despite lacking any known copper-utilizing proteins, streptococci have been reported to accumulate significant levels of copper. Here, we report that loss of CopA, a copper-specific exporter, confers increased sensitivity to copper in Streptococcus pyogenes strain HSC5, with prolonged exposure to physiological levels of copper resulting in reduced viability during stationary phase cultivation. This defect in stationary phase survival was rescued by supplementation with exogeneous amino acids, indicating the pathogen had altered nutritional requirements during exposure to copper stress. Furthermore, S. pyogenes HSC5 ΔcopA was substantially attenuated during murine soft-tissue infection, demonstrating the importance of copper efflux at the host-pathogen interface. Collectively, these data indicate that copper can severely reduce the viability of stationary phase S. pyogenes and that active efflux mechanisms are required to survive copper stress in vitro and during infection.

COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer.

RNA editing is among the most common RNA level modifications for generating amino acid changes. We identified a COPA A-to-I RNA editing event in CRC metastasis. Our results showed that the COPA A-to-I RNA editing rate was significantly increased in metastatic CRC tissues and was closely associated with aggressive tumors in the T and N stages. The COPA I164V protein damaged the Golgi-ER reverse transport function, induced ER stress, promoted the translocation of the transcription factors ATF6, XBP1 and ATF4 into the nucleus, and activated the expression of MALAT1, MET, ZEB1, and lead to CRC cell invasion and metastasis. Moreover, the COPA A-to-I RNA editing rate was positively correlated with the immune infiltration score. Collectively, the COPA I164V protein hijacked ER stress to promote the metastasis of CRC, and the COPA A-to-I RNA editing rate may be a potential predictor for patient response to immune checkpoint inhibitor (ICIs) treatment.

Interstitial lung disease in autoinflammatory disease in childhood: A systematic review of the literature.

BACKGROUND/OBJECTIVES: The lung is one of the target organs in the systemic involvement of autoinflammatory disease (AID), and interstitial lung disease (ILD) is the primary phenotype of lung involvement in AID. In this review, we aimed to conduct a systematic review of the available literature to highlight ILD in AID. METHODS: We conducted a systematic literature search in PubMed/MEDLINE and Scopus from the inception of the databases to January 2022. References were first screened by title and then by abstract by two authors. Eighteen original papers were selected for full-text review. RESULTS: During the literature search, we identified 18 relevant articles describing 52 cases of AID and ILD. Of those, 44 patients had stimulator of interferon genes-associated vasculopathy with onset in infancy (SAVI), six had coatomer protein complex (COPA) syndrome, one had haploinsufficiency of A20, and one had mevalonate kinase deficiency. Pulmonary fibrosis, cyst formation, and ground glass areas were the most common findings in chest tomography of patients with COPA syndrome and SAVI. Janus kinase inhibitors were used to treat most of the patients with SAVI, which stabilized ILD. CONCLUSIONS: ILD should be considered carefully in children with AID, especially those with interferonopathy.