Improvement of Na+-K+ ATPase Activity and Gene Expression Associated with Glomerular Ultrastructural Protection in Diabetic Nephropathy by Acacia senegal: Role of Oxidative Stress Disturbances / Mejora de la actividad Na+-K+ ATPasa y la Expresión Génica Asociada con la Protección Ultraestructural Glomerular en la Nefropatía Diabética por Acacia senegal: Papel de las Alteraciones del Estrés Oxidativo

SUMMARY: This study assessed the effects of Acacia Senegal (AS) combined with insulin on Na+/K+-ATPase (NKA) activity and mRNA expression, serum glucose, renal function, and oxidative stress in a rat model of diabetic nephropathy (DN). Sixty rats were equally divided into six groups: normal control, normal+AS, diabetic (DM), DM+insulin, DM+AS, and DM+insulin+AS groups. Diabetes mellitus (type 1) was induced by a single injection of streptozotocin (65 mg/kg), and insulin and AS treatments were carried until rats were culled at the end of week 12. Serum glucose and creatinine levels, hemoglobin A1c (HbA1c) were measured. Renal homogenate levels of NKA activity and gene expression, malondialdehyde, superoxide dismutase (SOD), catalase and reduced glutathione (GSH) were evaluated as well as kidney tissue histology and ultrastructure. Diabetes caused glomerular damage and modulation of blood and tissue levels of creatinine, glucose, HbA1c, malondialdehyde, NKA activity and gene expression, SOD, catalase and GSH, which were significantly (p<0.05) treated with AS, insulin, and insulin plus AS. However, AS+insulin treatments were more effective. In conclusion, combined administration of AS with insulin to rats with DN decreased NKA activity and gene expression as well as oxidative stress, and improved glycemic state and renal structure and function.

Este estudio evaluó los efectos de Acacia senegal (AS) combinada con insulina sobre la actividad Na+/K+- ATPasa (NKA) y la expresión de ARNm, la glucosa sérica, la función renal y el estrés oxidativo en un modelo de nefropatía diabética (ND) en ratas. Sesenta ratas se dividieron equitativamente en seis grupos: control normal, normal+AS, diabética (DM), DM+insulina, DM+AS y DM+insulina+AS. La diabetes mellitus (tipo 1) se indujo mediante una única inyección de estreptozotocina (65 mg/kg), y los tratamientos con insulina y AS se llevaron a cabo hasta que las ratas fueron sacrificadas al final de la semana 12. Se midieron niveles séricos de glucosa y creatinina, hemoglobina A1c (HbA1c). Se evaluaron los niveles de homogeneizado renal de actividad NKA y expresión génica, malondialdehído, superóxido dismutasa (SOD), catalasa y glutatión reducido (GSH), así como la histología y ultraestructura del tejido renal. La diabetes causó daño glomerular y modulación de los niveles sanguíneos y tisulares de creatinina, glucosa, HbA1c, malondialdehído, actividad y expresión génica de NKA, SOD, catalasa y GSH, los cuales fueron tratados significativamente (p<0,05) con AS, insulina e insulina más AS. Sin embargo, los tratamientos con AS+insulina fueron más efectivos. En conclusión, la administración combinada de AS con insulina a ratas con DN disminuyó la actividad de NKA y la expresión genética, así como el estrés oxidativo, y mejoró el estado glucémico y la estructura y función renal.

Estrogen deficiency influences SEC23A gene expression in the odontogenic region of incisors ­ a murine model study / A deficiência de estrógeno influencia a expressão gênica de SEC23A na região odontogênica de incisivos ­ um estudo em modelo murino

Recent scientific evidence suggests a close relationship between estrogen deficiency and vitamin D- related genes. Estrogen and vitamin D were involved with alterations in odontogenesis and tooth eruption process. Objective: The aim of the present study was to evaluate the influence of estrogen deficiency on the expression of genes related to the activation and degradation of vitamin D in the odontogenic region of incisors in a murine model. Material and Methods: This is an experimental clinical study that used female Wistar Hannover rats. The animals were randomly divided into two groups according to the intervention received: Hypoestrogenism Group ­ animals submitted to estrogen deficiency by ovariectomy surgery and Control Group ­ animals submitted to sham surgery. Surgical intervention was performed in the prepubertal period; the animals were followed throughout the pubertal period. After euthanasia, the hemimandibles were removed to evaluate the mRNA expression of the vitamin D-related genes AMDHD1, CYP24A1, NADSYN1 and SEC23A in the odontogenic region of incisors through real time PCR. Student's t test was used to compare means. Kruskal-Wallis test and Dunn's posttest were also used. The level of significance was 5%. Results: SEC23A was overexpressed in the estrogen deficiency condition in the odontogenic region (p=0.021). Conclusion: Estrogen deficiency may influence the expression of the SEC23A gene involved in the activation and degradation of vitamin D in the odontogenic region of incisors in a murine model(AU)

Evidências científicas recentes sugerem uma estreita relação entre a deficiência de estrógeno e os genes relacionados à vitamina D. O estrógeno e a vitamina D estão envolvidos com alterações na odontogênese e no processo de erupção dentária. Objetivo: O objetivo do presente estudo foi avaliar a influência da deficiência de estrógeno na expressão de genes relacionados à ativação e degradação da vitamina D na região odontogênica de incisivos em modelo murino. Material e Métodos: Trata-se de um estudo clínico experimental que utilizou ratas Wistar Hannover fêmeas. Os animais foram divididos aleatoriamente em dois grupos de acordo com a intervenção recebida: Grupo Hipoestrogenismo ­ animais submetidos à deficiência de estrógeno pela cirurgia de ovariectomia e Grupo Controle ­ animais submetidos à cirurgia simulada. A intervenção cirúrgica foi realizada no período pré-púbere; os animais foram acompanhados durante todo o período puberal. Após a eutanásia, as hemimandíbulas foram removidas para avaliar a expressão de mRNA dos genes AMDHD1, CYP24A1, NADSYN1 e SEC23A, relacionados à vitamina D, na região odontogênica de incisivos por meio de PCR em tempo real. O teste t de Student foi utilizado para comparar as médias. Também foram utilizados o teste de Kruskal-Wallis e o pós-teste de Dunn. O nível de significância foi de 5%. Resultados: SEC23A foi superexpresso na condição de deficiência de estrógeno na região odontogênica (p=0,021). Conclusão: A deficiência de estrógeno pode influenciar a expressão do gene SEC23A envolvido na ativação e degradação da vitamina D na região odontogênica de incisivos em modelo murino (AU)

Identification of overlay differentially expressed genes in both rats and goats with blast lung injury through comparative transcriptomics / 中华创伤杂志(英文版)

PURPOSE@#To identify the potential target genes of blast lung injury (BLI) for the diagnosis and treatment.@*METHODS@#This is an experimental study. The BLI models in rats and goats were established by conducting a fuel-air explosive power test in an unobstructed environment, which was subsequently validated through hematoxylin-eosin staining. Transcriptome sequencing was performed on lung tissues from both goats and rats. Differentially expressed genes were identified using the criteria of q ≤ 0.05 and |log2 fold change| ≥ 1. Following that, enrichment analyses were conducted for gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathways. The potential target genes were further confirmed through quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay.@*RESULTS@#Observations through microscopy unveiled the presence of reddish edema fluid, erythrocytes, and instances of focal or patchy bleeding within the alveolar cavity. Transcriptome sequencing analysis identified a total of 83 differentially expressed genes in both rats and goats. Notably, 49 genes exhibited a consistent expression pattern, with 38 genes displaying up-regulation and 11 genes demonstrating down-regulation. Enrichment analysis highlighted the potential involvement of the interleukin-17 signaling pathway and vascular smooth muscle contraction pathway in the underlying mechanism of BLI. Furthermore, the experimental findings in both goats and rats demonstrated a strong association between BLI and several key genes, including anterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4, which exhibited up-regulation.@*CONCLUSIONS@#Anterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4 hold potential as target genes for the prognosis, diagnosis, and treatment of BLI.

High-intensity interval training (treadmill) effects in myokines and endoplasmic reticulum stress of calf muscles in obese mice / Efectos del entrenamiento interválico de alta intensidad (trotadora) en miocinas y estrés del retículo endoplasmático de los músculos surales en ratones obesos

SUMMARY: Obesity is commonly associated with chronic tissue inflammation and skeletal muscle dysfunction. The study aimed to investigate the effects of High-Intensity Interval training (HIIT) on myokines and endoplasmic reticulum (ER) stress of diet- induced obese (DIO) mice. Three-month-old C57BL/6 male mice were fed a control (C) diet (n=20) or a high-fat (HF) diet (n=20) for 16 weeks. Then, half of the groups underwent HIIT (treadmill running) for an additional four weeks. HIIT increased calf muscles' contribution to BW (+24 %) and reduced weight gain in HF/HIIT than in HF (-120 %). Intramuscular fat accumulation was observed in HF and HF/ HIIT. Peak velocity was higher in HF/HIIT compared to HF (+26 %). Plasma insulin did not change, but glycemia was lower in HF/HIIT than in HF (-30 %). Fndc5 (+418 %) and Irisin (+72 %) were higher in HF/HIIT than in HF. Muscle Fgf21 was higher in HF/HIIT compared to HF (+30 %). In addition, NfKb (-53 %) and Tnfa (-63 %) were lower in HF/HIIT than in HF. However, Il1b (-86 %), Il6 (- 48 %), Il7 (-76 %), and Il15 (-21 %) were lower in HF/HIIT than in HF. Finally, HIIT reduced ER stress in HF/HIIT compared to HF: Atf4, -61 %; Chop, -61 %; Gadd45, -95 %. In conclusion, HIIT leads to weight loss and avoids muscle depletion. HIIT improves blood glucose, Irisin-Fndc5, and peak velocity. In addition, HIIT mitigates muscle inflammation and ER stress.

La obesidad es asociada comúnmente con inflamación tisular crónica y disfunción del músculo esquelético. El estudio tuvo como objetivo investigar los efectos del entrenamiento de intervalos de alta intensidad (HIIT) en las mioquinas y el estrés del retículo endoplásmico (ER) de ratones obesos inducidos por dieta (DIO). Se alimentó a ratones macho C57BL/6 de tres meses de edad con una dieta control (C) (n=20) o una dieta rica en grasas (HF) (n=20) durante 16 semanas. Luego, la mitad de los grupos se sometieron a HIIT (carrera en una trotadora) durante cuatro semanas más. HIIT aumentó la contribución de los músculos de la pantorrilla al BW (+24 %) y redujo el aumento de peso en HF/HIIT en HF (-120 %). Se observó acumulación de grasa intramuscular en HF y HF/HIIT. La velocidad máxima fue mayor en HF/HIIT en comparación con HF (+26 %). La insulina plasmática no cambió, pero la glucemia fue menor en HF/HIIT que en HF (-30 %). Fndc5 (+418 %) e Irisin (+72 %) fueron mayores en HF/HIIT que en HF. El Fgf21 muscular fue mayor en HF/ HIIT en comparación con HF (+30 %). Además, NfKb (-53 %) y Tnfa (-63 %) fueron menores en HF/HIIT que en HF. Sin embar- go, Il1b (-86 %), Il6 (-48 %), Il7 (-76 %) e Il15 (-21 %) fueron más bajos en HF/HIIT que en HF. Finalmente, HIIT redujo el estrés de RE en HF/HIIT en comparación con HF: Atf4, -61 %; Picar, - 61 %; Gadd45, -95 %. En conclusión, HIIT conduce a la pérdida de peso y evita el agotamiento muscular. HIIT mejora la glucosa en sangre, Irisin-Fndc5 y la velocidad máxima. Además, HIIT mitiga la inflamación muscular y el estrés ER.

Identification of novel biomarkers with potential for diagnosis and prognosis of gastric cancer: a bioinformatics approach

INTRODUCTION: Gastric cancer (GC) is the fifth most diagnosed neoplasia and the third leading cause of cancer-related deaths. A substantial number of patients exhibit an advanced GC stage once diagnosed. Therefore, the search for biomarkers contributes to the improvement and development of therapies. OBJECTIVE: This study aimed to identify potential GC biomarkers making use of in silico tools. METHODS: Gastric tissue microarray data available in Gene Expression Omnibus and The Cancer Genome Atlas Program was extracted. We applied statistical tests in the search for differentially expressed genes between tumoral and non-tumoral adjacent tissue samples. The selected genes were submitted to an in-house tool for analyses of functional enrichment, survival rate, histological and molecular classifications, and clinical follow-up data. A decision tree analysis was performed to evaluate the predictive power of the potential biomarkers. RESULTS: In total, 39 differentially expressed genes were found, mostly involved in extracellular structure organization, extracellular matrix organization, and angiogenesis. The genes SLC7A8, LY6E, and SIDT2 showed potential as diagnostic biomarkers considering the differential expression results coupled with the high predictive power of the decision tree models. Moreover, GC samples showed lower SLC7A8 and SIDT2 expression, whereas LY6E was higher. SIDT2 demonstrated a potential prognostic role for the diffuse type of GC, given the higher patient survival rate for lower gene expression. CONCLUSION: Our study outlines novel biomarkers for GC that may have a key role in tumor progression. Nevertheless, complementary in vitro analyses are still needed to further support their potential.

O papel dos RNAs longos não codificantes na insuficiência cardíaca: uma revisão de literatura / The role of non-coding long RNAs in heart failure: a literature review / El papel de las RNAs largas no codificantes en la insuficiencia cardiaca: una revisión de la literatura

A Insuficiência Cardíaca (IC) é uma das principais causas de internação hospitalar no mundo e tem um elevado grau de morbidade e mortalidade, sendo um grave problema de saúde pública. Os lncRNAs (RNAs longo não codificantes), têm funções regulatórias transcricionais e/ou pós transcricionais bem complexas e que ainda não são totalmente claras, mas que podem exercer influência sobre as doenças cardiovasculares, dentre elas a IC. Assim o estudo teve como objetivo identificar na literatura o papel dos lncRNAs na patogênese da IC por meio de uma revisão integrativa com busca sistemática. Foram considerados elegíveis para leitura e composição do estudo 33 artigos e os principais papéis dos lncRNA na IC foram relatados como possíveis marcadores biológicos para diagnóstico e prognóstico da doença devido a sua expressividade na corrente sanguínea. Além disso, os lncRNAs podem estar relacionados à capacidade funcional uma vez que o aumento ou diminuição de sua expressão promove redução da apoptose de células endoteliais, melhora a disfunção cardíaca, distúrbios de contratilidade e dos canais de cálcio em pacientes com IC. Portanto, os lncRNAs parecem estar envolvidos na patogênese e/ou fisiopatologia da IC, podendo ser utilizados como biomarcadores genéticos com sensibilidade e especificidade semelhantes ou superiores aos empregados atualmente no diagnóstico e prognóstico da IC.

Heart Failure (HF) is one of the main causes of hospitalization worldwide and has a high degree of morbidity and mortality being considered a public health pro- blem. lncRNAs (non-coding long RNAs) have very complex transcriptional and/or post- transcriptional regulatory functions that are still not entirely clear but may influence car- diovascular diseases, including HF. Thus, the study aimed to identify in the literature the role of lncRNAs in the pathogenesis of HF through an integrative review with a systema- tic search. A total of 33 articles were considered eligible for reading and composition of the study. The roles of lncRNA in HF were reported as possible biological markers for the diagnosis and prognosis of the disease due to its expressiveness in the bloodstream. In addition, lncRNAs may be related to functional capacity since the increase or decrease in their expression promotes a reduction in endothelial cell apoptosis, and improves car- diac dysfunction, contractility, and calcium channel disorders in patients with HF. The- refore, lncRNAs seem to be involved in the pathogenesis and/or pathophysiology of HF and can be used as genetic biomarkers with sensitivity and specificity similar or superior to those currently employed in the diagnosis and prognosis of HF.

La Insuficiencia Cardiaca (IC) es una de las principales causas de hospita- lización en el mundo y tiene un alto grado de morbimortalidad considerándose un pro- blema de salud pública. Los lncRNAs (ARN largos no codificantes) tienen funciones re- guladoras transcripcionales y/o post-transcripcionales muy complejas que aún no están del todo claras pero que pueden influir en las enfermedades cardiovasculares, incluida la IC. Así pues, el estudio se propuso identificar en la literatura el papel de los lncRNAs en la patogénesis de la IC mediante una revisión integradora con una búsqueda sistemática. Un total de 33 artículos fueron considerados elegibles para su lectura y composición del estudio. Las funciones de los lncRNA en la IC se señalaron como posibles marcadores biológicos para el diagnóstico y pronóstico de la enfermedad debido a su expresividad en el torrente sanguíneo. Además, los lncRNAs pueden estar relacionados con la capacidad funcional, ya que el aumento o disminución de su expresión promueve una reducción de la apoptosis de las células endoteliales y mejora la disfunción cardiaca, la contractilidad y los trastornos de los canales de calcio en pacientes con IC. Por tanto, los lncRNAs parecen estar implicados en la patogénesis y/o fisiopatología de la IC y pueden ser utili- zados como biomarcadores genéticos con sensibilidad y spe-cificidad similares o superi- ores a los empleados actualmente en el diagnóstico y pronóstico de la IC.

Estrogen deficiency influences TNF-α and IL-1ß gene expression in the odontogenic region of dental hypofunctional condition / A deficiência de estrógeno influencia a expressão gênica de TNF-α e IL-1ß na região odontogênica de dentes em hipofunção

Objetivo: Evidências científicas sugerem que a deficiência de estrógeno e fatores genéticos influenciam o desenvolvimento do sistema estomatognático. Este estudo teve como objetivo avaliar a influência da deficiência de estrógeno na expressão gênica de TNF-α, IL-1ß, IL-6 e IL-10 durante o desenvolvimento dentário em modelo murino. Material e Métodos: Ratas Wistar Hannover foram divididas em dois grupos de acordo com a intervenção recebida: Grupo Hipoestrogenismo - cirurgia de ovariectomia e Grupo Controle - cirurgia fictícia. Para avaliar o desenvolvimento dentário, o incisivo inferior foi escolhido. O modelo de hipofunção dos incisivos inferiores foi realizado por ajuste incisal. O incisivo homólogo exercia hiperfunção dentária. Os animais foram avaliados durante todo o período puberal. Após a eutanásia, as hemimandíbulas foram removidas para avaliar a expressão gênica do TNF-α, IL-1ß, IL-6 e IL-10 na região odontogênica dos incisivos por meio de PCR em tempo real. Foi realizado o teste de Kruskal-Wallis e o pós-teste de Dunn. O nível de significância foi de 5%. Resultados: Houve diferenças estatisticamente significativas na expressão gênica de TNF-α e IL-1ß entre os grupos hipoestrogenismo e controle sob condição de hipofunção dentária (p=0,0084, p=0,0072, respectivamente). Conclusão: A deficiência de estrógeno influencia a expressão gênica de TNF-α e IL-1ß na região odontogênica de dentes hipofuncionais (AU)

Objective: Scientific evidence suggests that estrogen deficiency and genetic factors have an influence on the development of the stomatognathic system. This study aimed to evaluate the influence of estrogen deficiency on the gene expression of TNF-α, IL-1ß, IL-6 and IL-10 during dental development in a murine model. Material and Methods: Wistar Hannover rats were divided into two groups according to the intervention received: Hypoestrogenism Group - ovariectomy surgery and Control Group - fictitious surgery. To evaluate the dental development, the lower incisor was chosen. The mandibular incisor hypofunction model was performed by incisal adjustment. The homologous incisor exerted a hyperfunction. The animals were evaluated throughout the pubertal period. After euthanasia, the hemimandibles were removed to evaluate the gene expression of the TNF-α, IL-1ß, IL-6 and IL-10 in the odontogenic region of the incisors through real time PCR. Kruskal-Wallis test and Dunn's posttest were performed. The level of significance was 5%. Results: There were statistically significant differences of TNF-α and IL-1ß gene expression between the hypoestrogenism and control groups under hypofunction condition (p=0.0084, p=0.0072, respectively). Conclusion: Estrogen deficiency influences TNF-α and IL-1ß gene expression in the odontogenic region of the hypofunctional teeth. (AU)

Analysis of the difference in metabolites and gene expressions between pre-receptive and receptive endometria / 中华医学遗传学杂志

OBJECTIVE@#To analyze the difference in the gene expression, amino acid and carnitine levels in the cervical secretions between the endometria of pre-receptive and receptive stages, with an aim to provide clues for identifying new molecular markers for endometrial receptivity.@*METHODS@#Fifty nine infertile women treated at the Department of Reproductive Medicine of Linyi People's Hospital from January 6, 2020 to January 31, 2022 were selected as as the study subjects, which were matched with 3 pairs (6 cases) of infertile women preparing for embryo transfer based on factors such as age, body mass index, and length of infertility. Endometrial tissue samples were collected for gene transcription and expression analysis. Twenty five women who had become pregnant through assisted reproductive technology were selected as the control group, and 28 non-pregnant women receiving ovulation monitoring at the Outpatient Department were enrolled as the case group. Status of endometrial receptivity was determined by ultrasonography. In the former group, endometrial tissues were sampled for sequencing, and GO and KEGG database enrichment analysis of differentially expressed genes was carried out. In the latter group, cervical secretions were collected, and amino acid and carnitine levels were measured by mass spectrometry. Statistical analysis was carried out using rank sum test, t test and chi-square test with SPSS v25.0 software.@*RESULTS@#No difference was found in the clinical data of the patients with regard to age, body mass index, infertility years, AMH, FSH, LH, E2, and type of infertility. Compared with the receptive endometrial tissues, there were 100 significantly up-regulated genes and 191 significantly down-regulated genes in the pre-receptive endometrial tissue, with the most significantly altered ones being HLA-DRB5 and MMP10. The biological processes, molecular functions and pathways enriched by more differentially expressed genes in GO and KEGG were mainly immune regulation, cell adhesion and tryptophan metabolism. Analysis of secretion metabolism also revealed a significant difference in the levels of amino acids and carnitine metabolites between the two groups (P < 0.05), in particular those of Alanine, Valine, 3-hydroxybutyrylcarnitine (C4OH) + malonylcarnitine (C3DC)/captoylcarnitine (C10).@*CONCLUSION@#A significant difference has been discovered in the levels of gene transcription and protein expression in the endometrial tissues from the pre-receptive and receptive stages. The levels of amino acids and carnitine, such as Alanine, Valine, 3-hydroxybutyryl carnitine (C4OH)+malonyl carnitine (C3DC)/caproyl carnitine (C10), may be associated with the receptive status of the endometrium, though this need to be verified with larger samples.

Preliminary study on the regulation of acute myeloid leukemia by FLT3 gene expression / 中华医学遗传学杂志

OBJECTIVE@#To assess the influence of FLT3 expression on the prognosis of patients with acute myeloid leukemia (AML) by cell experiment and clinical data analysis.@*METHODS@#Models for FLT3 over-expression and interference-expression in AML cells were constructed. The level of BAK gene expression and its protein product was determined, along with the proliferation and apoptosis of leukemia cells. FLT3 gene expression and FLT3-ITD variant were determined among patients with newly diagnosed AML.@*RESULTS@#Compared with the interference-expression group, the level of BAK gene expression and its protein in FLT3 over-expression AML cells was significantly lower (P < 0.001), which also showed significantly faster proliferation (P < 0.001) and lower rate of apoptosis (P < 0.001). The expression level of FLT3 gene among patients with newly diagnosed AML was also significantly higher compared with the healthy controls (P < 0.001). The FLT3 gene expression of FLT3-ITD positive AML patients was higher than that of FLT3-WT patients (P = 0.002). Survival analysis showed that AML patients with high FLT3 expression in the medium-risk group had a lower complete remission rate and overall survival rate compared with those with a low FLT3 expression (P < 0.001).@*CONCLUSION@#Over-expression of FLT3 may influence the course of AML by promoting the proliferation of leukemia cells and inhibiting their apoptosis, which in turn may affect the prognosis of patients and serve as a negative prognostic factor for AML.

Study on F9 gene expression downregulation and its clinical value in hepatocellular carcinoma / 中华肝脏病杂志

Objective: To analyze the expression levels of the F9 gene and F9 protein in hepatocellular carcinoma by combining multiple gene chip data, real-time fluorescence quantitative PCR (RT qPCR), and immunohistochemistry. Additionally, explore their correlation with the occurrence and development of hepatocellular carcinoma, as well as with various clinical indicators and prognosis. Methods: The mRNA microarray dataset from the GEO database was analyzed to identify the F9 gene with significant expression differences associated with hepatocellular carcinoma. Liver cancer and adjacent tissues were collected from 18 cases of hepatocellular carcinoma. RT-qPCR method was used to detect the F9 gene expression level. Immunohistochemistry was used to detect the F9 protein level. Combined with the TCGA database information, the correlation between F9 gene expression level and prognostic and clinicopathological parameters was analyzed. The biological function of F9 co-expressed genes associated with hepatocellular carcinoma was analyzed by the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Statistical analysis was performed using Graphpad Prism software. Results: Meta-analysis results showed that the expression of the F9 gene was lower in HCC tissues than in non-cancerous tissues. Immunohistochemistry results were basically consistent with those of RT-qPCR. The data obtained from TCGA showed that the F9 gene had lower expression values in stages III-IV, T3-T4, and patients with vascular invasion. A total of 127 genes were selected for bioinformatics analysis as co-expressed genes of F9, which were highly enriched in redox processes and metabolic pathways. Conclusion: This study validates that the F9 gene and F9 protein are lower in HCC. The down-regulation of the F9 gene predicts adverse outcomes, which may provide a new therapeutic target for HCC.

Gene expression and immunolocalization of chitin deacetylase BmCDA2 in silkworm / 生物工程学报

Deacetylation of chitin is closely related to insect development and metamorphosis. Chitin deacetylase (CDA) is a key enzyme in the process. However, to date, the CDAs of Bombyx mori (BmCDAs), which is a model Lepidopteran insect, were not well studied. In order to better understand the role of BmCDAs in the metamorphosis and development of silkworm, the BmCDA2 which is highly expressed in epidermis was selected to study by bioinformatics methods, protein expression purification and immunofluorescence localization. The results showed that the two mRNA splicing forms of BmCDA2, namely BmCDA2a and BmCDA2b, were highly expressed in the larval and pupal epidermis, respectively. Both genes had chitin deacetylase catalytic domain, chitin binding domain and low density lipoprotein receptor domain. Western blot showed that the BmCDA2 protein was mainly expressed in the epidermis. Moreover, fluorescence immunolocalization showed that BmCDA2 protein gradually increased and accumulated with the formation of larval new epidermis, suggesting that BmCDA2 may be involved in the formation or assembly of larval new epidermis. The results increased our understandings to the biological functions of BmCDAs, and may facilitate the CDA study of other insects.

Traditional Chinese Medicine Treatment, Gua Sha, can Induce Subtle Molecular Changes in Gene Expression / 生物医学与环境科学（英文）

OBJECTIVE@#Here, we explored molecular changes that could potentially mediate healing effects of Gua Sha - a method employed by the Chinese traditional medicine with proven track records of safe and efficient applications dating back to ancient times as well as support from randomized controlled trials performed by modern medical studies - yet remaining almost entirely unexplored by the modern-day high-throughput methods of the -omics sciences.@*METHODS@#We investigated transcriptome changes occurring shortly after Gua Sha treatment in the whole blood of healthy volunteers using bulk RNA-seq analysis. We applied various analytical tools to identify genes with consistent expression changes in multiple individuals in response to Gua Sha and their networks.@*RESULTS@#We found that while the changes were very subtle and individual-specific, we could identify consistent upregulation of three histone genes. Further analysis of the potential regulatory networks of these histone genes revealed the enrichment of functions involved in the immune response and inflammation.@*CONCLUSION@#The significance of these results in the context of potential effects of Gua Sha and the next steps in exploring the molecular mechanisms of action of this technique are discussed.

Analysis of Significant Genes and Pathways in Esophageal Cancer Based on Gene Expression Omnibus Database / 中国医学科学杂志(英文版)

Objective To screen antigen targets for immunotherapy by analyzing over-expressed genes, and to identify significant pathways and molecular mechanisms in esophageal cancer by using bioinformatic methods such as enrichment analysis, protein-protein interaction (PPI) network, and survival analysis based on the Gene Expression Omnibus (GEO) database.Methods By screening with highly expressed genes, we mainly analyzed proteins MUC13 and EPCAM with transmembrane domain and antigen epitope from TMHMM and IEDB websites. Significant genes and pathways associated with the pathogenesis of esophageal cancer were identified using enrichment analysis, PPI network, and survival analysis. Several software and platforms including Prism 8, R language, Cytoscape, DAVID, STRING, and GEPIA platform were used in the search and/or figure creation.Results Genes MUC13 and EPCAM were over-expressed with several antigen epitopes in esophageal squamous cell carcinoma (ESCC) tissue. Enrichment analysis revealed that the process of keratinization was focused and a series of genes were related with the development of esophageal cancer. Four genes including ALDH3A1, C2, SLC6A1,and ZBTB7C were screened with significant P value of survival curve.Conclusions Genes MUC13 and EPCAM may be promising antigen targets or biomarkers for esophageal cancer. Keratinization may greatly impact the pathogenesis of esophageal cancer. Genes ALDH3A1, C2, SLC6A1,and ZBTB7C may play important roles in the development of esophageal cancer.

Application of new generation high-throughput RNA sequencing in quality control of live attenuated yellow fever vaccine(chicken embryo cell) virus seed bank / 中国生物制品学杂志

@#Objective To perform quality control in live attenuated yellow fever vaccine(chicken embryo cell)virus seed bank at the genomic level using the new generation Illumina/Solexa sequencing platform.Methods The live attenuated yellow fever vaccine strain YF17D-204 was inoculated into primary chicken embryo cells,and the chicken embryo cell adapted strains of live attenuated yellow fever vaccine were screened to establish YFV17D-CEC tertiary virus seed bank. The genome RNA of virus seeds was extracted,and the RNA library was prepared. The new generation Illumina/Solexa sequencing platform was used for high-throughput RNA sequencing. The whole genome nucleic acid sequence of yellow fever virus was systematically analyzed by using biological softwares such as FastQC,Trimmomatic,SPAdes,GapFiller,PrInSeS-G,Prokka,RepeatMasker,CRT,NCBI Blast~+,KAAS,HMMER3,TMHMM,SignalP,LipoP,ProtCamp and MegAlign.Results The whole genome of YFV17D-CEC tertiary virus seed bank contained 10 862 nucleotides,including an open reading frame(ORF)from 119 to 10 354(10 236 bp),encoding 3 412 amino acids. Sequence alignment analysis showed that the sequence of YF17D-CEC tertiary virus seed bank was 100% identical with YFV17D RKI(JN628279.1),YF/Vaccine/USA/Sanofi-Pasteur-17D-204/UF795AA/YFVax(JX503529.1)and YFV17D-204(KF769015.1),and no mutation occurred in the whole genome of the tertiary virus seed bank. Comparison of the sequences of different live attenuated yellow fever vaccine strains showed that yellow fever virus had multiple polymorphic sites.Conclusion YFV17DCEC has good genetic stability in primary chicken embryo cells. High-throughput RNA sequencing technology can quickly detect the whole genome information of YF17D-CEC virus seed bank,and the sequence analysis data can be used in the gene level quality control of yellow fever vaccine virus seed banks.

Bioinformatics and expression analysis of the Xeroderma Pigmentosum complementation group C (XPC) of Trypanosoma evansi in Trypanosoma cruzi cells / Análises de bioinformática e da expressão do gene Xeroderma Pigmentosum complementation group C (XPC) de Trypanosoma evansi em células de Trypanosoma cruzi

Nucleotide excision repair (NER) acts repairing damages in DNA, such as lesions caused by cisplatin. Xeroderma Pigmentosum complementation group C (XPC) protein is involved in recognition of global genome DNA damages during NER (GG-NER) and it has been studied in different organisms due to its importance in other cellular processes. In this work, we studied NER proteins in Trypanosoma cruzi and Trypanosoma evansi, parasites of humans and animals respectively. We performed three-dimensional models of XPC proteins from T. cruzi and T. evansi and observed few structural differences between these proteins. In our tests, insertion of XPC gene from T. evansi (TevXPC) in T. cruzi resulted in slower cell growth under normal conditions. After cisplatin treatment, T. cruzi overexpressing its own XPC gene (TcXPC) was able to recover cell division rates faster than T. cruzi expressing TevXPC gene. Based on these tests, it is suggested that TevXPC (being an exogenous protein in T. cruzi) interferes negatively in cellular processes where TcXPC (the endogenous protein) is involved. This probably occurred due interaction of TevXPC with some endogenous molecules or proteins from T. cruzi but incapacity of interaction with others. This reinforces the importance of correctly XPC functioning within the cell.

O reparo por excisão de nucleotídeos (NER) atua reparando danos no DNA, como lesões causadas por cisplatina. A proteína Xeroderma Pigmentosum complementation group C (XPC) está envolvida no reconhecimento de danos pela via de reparação global do genoma pelo NER (GG-NER) e tem sido estudada em diferentes organismos devido à sua importância em outros processos celulares. Neste trabalho, estudamos proteínas do NER em Trypanosoma cruzi e Trypanosoma evansi, parasitos de humanos e animais, respectivamente. Modelos tridimensionais das proteínas XPC de T. cruzi e T. evansi foram feitos e observou-se poucas diferenças estruturais entre estas proteínas. Durante testes, a inserção do gene XPC de T. evansi (TevXPC) em T. cruzi resultou em crescimento celular mais lento em condições normais. Após o tratamento com cisplatina, T. cruzi superexpressando seu próprio gene XPC (TcXPC) foi capaz de recuperar as taxas de divisão celular mais rapidamente do que T. cruzi expressando o gene TevXPC. Com base nesses testes, sugere-se que TevXPC (sendo uma proteína exógena em T. cruzi) interfere negativamente nos processos celulares em que TcXPC (a proteína endógena) está envolvida. Isso provavelmente ocorreu pois TevXPC é capaz de interagir com algumas moléculas ou proteínas endógenas de T. cruzi, mas é incapaz de interagir com outras. Isso reforça a importância do correto funcionamento de XPC dentro da célula.

Obesidade genética não sindrômica: histórico, fisiopatologia e principais genes / Non-syndromic genetic obesity: history, pathophysiology and key genes

A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.

Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.

Expression Levels of the CA9, WT1, and PRAME genes and genotyping-associated antigens for the diagnosis and prognosis of colorectal cancer

Background: Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide, and is one of the major health problems in Asia, Africa, Europe, and America. The tumor antigens recently are of interesting indicators as diagnostic and prognostic tools, The aim of the present study is to detect the expression levels of carbonic anhydrase IX (CA9), the Wilms tumor gene (WT1), and the preferentially expressed antigen in melanoma (PRAME) in the peripheral blood of CRC patients in comparison with healthy controls. Methods: A prospective case-control study of CRC patients was conducted. We included 25 newly-diagnosed CRC eligible patients and obtained peripheral blood samples of them as well as 10 blood samples from the control group. All samples were then submitted to deoxyribonucleic acid (DNA) extraction and a molecular study through real-time polymerase chain reaction (PCR). Results: The CRC group consisted of 15 (60%) female and 10 (40%) male patients with a mean age of 50.52 ± 9.8 years, while the control group included 4 (40%) female and 6 (60%) male patients with a mean age of 47.7 ± 7.9 years. The CRC group, 24 (96%) of patient samples were CA9-positive with strong statistically significant differences (p < 0.00001; sensitivity: 96%; specificity: 90%). Regarding the WT1 gene, there were 11 (44%) positive samples in the CRC group, with no statistically significant differences (p = 0.055; sensitivity: 44%; specificity: 90%). The PRAME gene was positive in 9 (36%) samples in the CRC group, with no statistically significant differences (p = 0.357; sensitivity: 36%; specificity: 80%. Among CA9 (24 patients; 96%) of patients with CRC expressed positive results, in WT1 11(91.6%) CRC patients expressed gene, and in PRAME gene, 9 patients with CRC (81.8%) expressed positive results. Conclusion: Overexpression of the CA9 gene in CRC of high sensitivity and specificity to be used as a tool to discriminate CRC from benign associate with high accuracy compare to WT1 and PRAME genes. (AU)

Chronic Lymphocytic Leukemia (CLL): evaluation of AKT protein kinase and microRNA gene expression related to disease pathogenesis

Abstract The present study evaluated 56 patients diagnosed with Chronic Lymphocytic Leukemia (CLL) and a control group of 44 clinically healthy subjects with no previous history of leukemia. Genetic expressions of AKT and microRNAs were evaluated by quantitative PCR (qPCR). A significant increase in AKT gene expression in patients when compared to controls was observed (p = 0.017). When the patients were stratified according to Binet subgroups, a significant difference was observed between the subgroups, with this protein kinase appearing more expressed in the B+C subgroup (p = 0.013). Regarding miRNA expression, miR-let-7b and miR-26a were reduced in CLL patients, when compared to controls. However, no significant differences were observed in these microRNA expressions between the Binet subgroups (A versus B+C). By contrast, miR-21 to miR-27a oncogenes showed no expression difference between CLL patients and controls. AKT protein kinase is involved in the signaling cascade that occurs with BCR receptor activation, leading to increased lymphocyte survival and protection against the induction of cell death in CLL. Thus, increased AKT protein kinase expression and the reduction of miR-let-7b and miR-26a, both tumor suppressors, may explain increased lymphocyte survival in CLL patients and may be promising markers for the prognostic evaluation of this disease.

Estudo imuno-histoquímico e classificação molecular dos adenocarcinomas de endométrio com expressão heterogênea dos genes de reparo do DNA / Immunohistochemical study and molecular classification of endometrial adenocarcinomas with heterogeneous expression of DNA repair genes

Introdução: O carcinoma endometrial (CE) foi classificado pelo sistema de Bokhman em tipos I e II com base em observações clínicas e epidemiológicas. O tipo I corresponde aos tumores de baixo grau e o tipo II aos tumores de alto grau. Adicionalmente, estudos recentes propuseram que a classificação também fosse baseada em aspectos histológicos e moleculares com base nos dados do TCGA (The Cancer Genome Atlas). Foram identificados quatro grupos moleculares distintos de CE: (1) com mutações no POLE (fenótipo "ultramutado"), (2) "alto número de cópias" (mutações em TP53), (3) !baixo número de cópias" (em que os tumores não apresentam nenhuma das alterações descritas nos outros tipos) e (4) tumores com predomínio de instabilidade de microssatélites. A imunohistoquímica (IHC) para proteínas do gene de reparo é usada para identificar a deficiência de genes de reparo do DNA (Mismatch Repair ­ MMR) associada à instabilidade de microssatélites(MSI). A coloração nuclear positiva representa a expressão retida de proteínas MMR, enquanto a perda completa representa deficiência de MMR. O padrão de expressão heterogênea (HEP), ou seja, concomitância em um mesmo espécime de áreas positivas e totalmente negativas tem sido observada em CE. No presente momento, as principais diretrizes determinam que a presença de HEP seja interpretada como expressão retida de proteínas MMR. Não há, porém, consenso quanto à classificação e interpretação de HEP, nem conhecimento do impacto da classificação de HEP como subtipo molecular diferente em relação às características clínicas e prognósticas. Objetivos: realizar a classificação molecular dos casos de CE com HEP das proteínas relacionadas aos genes de reparo do DNA e comparação do perfil molecular entre áreas positivas e negativas no estudo imunohistoquímico. Materiais e Métodos: De janeiro/2007 a dezembro/2017 foram identificados 356 casos de CE, 16 deles com HEP. A classificação molecular foi feita com base no protocolo PROMISE para CE. Cada área (expressão retida ou perdida) foi macrodissecada e o status molecular foi avaliado separadamente quanto ao status MSI (Idylla), metilação do promotor MLH1 (NGS - ponto de corte para positividade ≥ 15%), status POLE (NGS) e status p53 (IHC). Variáveis clínicas e patológicas também foram avaliadas e correlacionadas com cada caso. Resultados: A histologia endometrioide foi predominante (15 casos), bem como ausência de invasão linfovascular (11 casos), ausência de padrão MELF (10 casos), graus FIGO 1 e 2 (13 casos), invasão miometrial < 50% (13 casos) e estadiamento T1 (13 casos). Todos os pacientes estavam vivos e sem evidência de doença no último acompanhamento, exceto por um caso, cujo status de sobrevida era desconhecido. Dois casos que seriam descritos como apresentando expressão retida de proteínas relacionadas a genes de reparo do DNA por IHC apresentaram-se na análise molecular com instabilidade de microssatélites(MSI-H). Nos casos de HEP, a proteína MSH6 foi a maisfrequentemente envolvida (9 casos, 7 isolados). A proteína MLH1 apresentou-se alterada em 6 casos, sendo a única proteína associada a co-alterações (com MSH6 e PMS2). Seis casos apresentaram-se metilados por MLH1, padrão encontrado tanto em áreas com perda quanto em áreas com retenção das proteínas relacionadas a MMR por IHC e dois casos apresentaram metilação em apenas uma das áreas. Em relação ao status de POLE, 6 casos apresentaram mutação, 2 com mutações tanto em áreas com perda quanto em áreas com retenção de expressão, 3 apenas na área com perda e 1 apenas na área com retenção. Dois casos apresentam padrão aberrante de p53 (MSH6 alterados) em ambas as áreas. Conclusão: em pacientes portadoras CE e com tumores apresentando HEP a correlação entre a IHC e os achados moleculares é heterogênea e o diagnóstico entre casos com retenção ou das proteínas relacionadas a MMR não é factível apenas com realização de IHC. A análise molecular deve ser realizada em todos os casos de CE com HEP para determinar adequadamente as característicasintrínsecas de cada tumor. Devido à raridade desse achado, esta proposta é financeiramente viável e tem o potencial de mudar a prática clínica em um subconjunto de pacientes, permitindo tratamentos inovadores. HEP deve ser relatado como um padrão distinto e não considerado como uma expressão sinônimo de expressão retida de proteínas MMR em CE.

Introduction: Endometrial adenocarcinoma is classified by the Bokhman system in type I and II based on clinical and epidemiological observations, whereas the type I represents low grade tumors and type II high grade tumors. Additionally, a classification based on histological aspects and molecular profile has been proposed. The TCGA (The Cancer Genome Atlas) identified four molecular groups of endometrial adenocarcinomas: (1) mutations in POLE ("ultramutated" phenotype), (2) "high copy number" (mutations in TP53), (3) "low number of copies " (in which the tumors do not exhibit any of the changes described in the other types) and (4) tumors with predominance of microsatellite instability. In a small number of patients, heterogeneous staining is observed in the evaluation protein expression for mismatch repair genes. Objectives: to evaluate and perform the molecular classifications of cases of endometrial carcinoma with heterogeneous staining by IHC of proteins related to mismatch repair genes and comparison of the molecular profile of positive and negative areas in the IHC study. Cases and Methods: From January/2007 to December/2017 354 cases with EC were identified, 16 of those with HEP. Molecular classification was made based on the PROMISE protocol for EC. Each area (retained and lost expression) was macrodissected and molecular status was evaluated separately regarding MSI status (Idylla), MLH1 promoter methylation (NGS - cutoff for positivity ≥ 15%), POLE status (NGS) and p53 status (IHC). Clinical and pathologic variables were also evaluated and correlated with each case. Results: Endometrioid histology was predominant (15 cases), as absent lymphovascular invasion (11 cases), absence of MELF pattern (10 cases), FIGO Grade 1 and 2 (13 cases), and T1 stage (13 cases). All patients were alive and disease-free at the last follow-up. Two cases that would be described as retained by IHC presented in the molecular analysis as MSI-H. In HEP cases MSH6 was more frequent (9 cases, 7 isolated). MLH1 was altered in 6 cases, and wasthe only protein associated with co-alterations (with MSH6 and PMS2). Six cases were MLH1 methylated, found both in lost and retained areas. As POLE status, there were 6 mutated cases, 2 of those with mutations both in lost and retained areas, and 3 the lost area. Two cases had p53 aberrant pattern (MSH6 altered), that was seen both in the retained and in the lost areas. Conclusion: Correlation between IHC and molecular findings is heterogeneous, and determination between retained or lost expression of MMR proteins by IHC when HEP occurs, however feasible, does not represent the actual molecular alterations. Thus, molecular analysis should be performed every case to adequately determine the intrinsic features of each tumor. Due to the rarity of this finding, this is financially viable and has the potential to change clinical practice in a subset of patients. HEP should be reported as a distinct pattern, and not considered as a synonym expression of retained expression of MMR proteins in EC.

Studying Juvenile Idiopathic Arthritis through a Network Medicine Approach / Estudando a Artrite Idiopática Juvenil mediante uma abordagem de medicina de redes

Juvenile Idiopathic Arthritis (JIA) is a group of inflammatory conditions of unknown etiology whose underlying molecular pathophysiology is still not well characterized. Several studies have attempted to fill this gap by characterizing the gene expression profiles of JIA patients. However, there is a lack of systematic assessment of the reliability of these transcriptome results on the disease classification, prescription, and monitoring. In addition, despite this disease is more common in females, none of these studies have tried to assess the impact of sex on disease pathophysiology. In this project, we performed a comprehensive systematic review and a gene expression meta-analysis to reveal the core molecular JIA pathophysiology taking into consideration the patient sex. We gathered and cataloged more than 60,000 entries of genomic features reported as JIA-related in the functional genomics literature, and found a dramatic disparity among the JIA transcriptome studies. Near 15,000 genes have been reported as perturbed in JIA leukocytes. Less than one percent of these genes were reported in at least a quarter of the reviewed studies. We then removed the study-specific analytical bias by re-analyzing more than 700 unique pediatric transcriptome profiles from nine JIA studies using a common analytical framework. The differential expression results from different studies were combined using a random effect model meta-analysis approach. We implemented this differential gene expression meta-analysis methodology in the MetaVolcanoR R package that we made available in Bioconductor. Using this package, we confirmed several gene expression signatures previously associated with JIA and uncover new genes whose expression was perturbed in JIA patients. The effect sizes of the topmost reported perturbed genes coincide with our meta-analysis results. Through a meta-coexpression approach, we characterized the cell type signatures of circulating leukocytes in the JIA affected children. Additionally, we characterized the JIA sexual dimorphism. We found that systemic JIA female patients over-activate a gene expression signature which comprises early myelocytes and band neutrophil expression markers. This signature is correlated with the disease status and response to IL-1 receptor blockade. This suggests that sJIA pathophysiology is characterized by a sexually dimorphic neutrophilia that impacts disease progression and the response to anti-IL-1 treatments. We further assessed this immature neutrophil and female-biased signature in other contexts. We found that this signature presents a sex-dependent expression over human lifetime, in other inflammatory diseases, and its expression increases during pregnancy

A Artrite Idiopática Juvenil (AIJ) é um grupo de condições inflamatórias de etiologia desconhecida, cuja patofisiologia molecular subjacente ainda não está bem caracterizada. Vários estudos tentaram preencher essa lacuna, caracterizando os perfis de expressão gênica de pacientes com AIJ. No entanto, há uma falta de avaliação sistemática desses resultados transcriptômicos na classificação, prescrição e monitoramento da doença. Além disso, apesar de esta doença ser mais comum em mulheres, nenhum desses estudos tentou avaliar o impacto do sexo na fisiopatologia da doença. Neste projeto, realizamos uma revisão sistemática abrangente e uma metanálise de expressão gênica para revelar a fisiopatologia molecular da AIJ levando em consideração o sexo do paciente. Reunimos e catalogamos mais de 60.000 entradas de características genômicas reportadas como relacionadas à AIJ na literatura. Entre os estudos de transcriptoma, encontramos uma disparidade dramática. Cerca de 15.000 genes foram reportados como perturbados nos leucócitos da AIJ, sendo que menos de um por cento desses genes foram relatados em pelo menos um quarto dos estudos revisados. Em seguida, re-analisamos mais de 700 transcriptomas pediátricos de nove estudos usando uma abordagem analítica comum. Os resultados de expressão diferencial foram combinados usando meta-análise de modelo de efeitos aleatórios. Implementamos esta abordagem de meta-análise de expressão gênica diferencial no pacote MetaVolcanoR R que disponibilizamos no Bioconductor. Usando este pacote, confirmamos várias assinaturas de expressão gênica previamente associadas à AIJ e descobrimos novos genes cuja expressão está perturbada em pacientes com AIJ. Os tamanhos dos efeitos dos genes mais reportados como perturbados coincidem com os resultados da nossa meta-análise. Por meio de uma análise de meta-co-expressão, caracterizamos as assinaturas dos tipos de leucócitos circulantes. Além disso, caracterizamos o dimorfismo sexual da AIJ. Descobrimos que pacientes do sexo feminino com AIJ sistêmica super-ativam genes característicos de mielócitos precoces e neutrófilos bastonetes. Esta assinatura está correlacionada com o estado clínico da doença e à resposta ao tratamento por bloqueio do receptor de IL-1. Isto sugere que a fisiopatologia da AIJs é caracterizada por uma neutrofilia sexualmente dimórfica que afeta a progressão da doença e a resposta aos tratamentos anti-IL-1. Avaliamos ainda esta assinatura neutrofílica em outros contextos. Descobrimos que essa assinatura apresenta uma expressão dependente do sexo ao longo da vida humana, em outras doenças inflamatórias, e sua expressão aumenta durante a gravidez