Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II: Insights into pathophysiology and tissue characterization.

Introduction: Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. Methods: We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. Results: We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. Cholesterol biosynthesis was among the main enriched cellular pathways in both IIa and IIb gray matter. Particularly, the genes HMGCS1, HMGCR, and SQLE were upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Discussion: Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gray or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.

Identification of acetyl-CoA carboxylase alpha as a prognostic and targeted candidate for hepatocellular carcinoma.

PURPOSE: The de novo lipogenesis has been a longstanding observation in hepatocellular carcinoma (HCC). However, the prognostic value and carcinogenic roles of the enzyme Acetyl-CoA carboxylase alpha (ACACA) in HCC remains unknown. METHODS: The proteins with remarkable prognostic significance were screened out from The Cancer Proteome Atlas Portal (TCPA) database. Furthermore, the expression characteristics and prognostic value of ACACA were evaluated in multiple databases and the local HCC cohort. The loss-of-function assays were performed to uncover the potential roles of ACACA in steering malignant behaviors of HCC cells. The underlying mechanisms were conjectured by bioinformatics and validated in HCC cell lines. RESULTS: ACACA was identified as a crucial factor of HCC prognosis. Bioinformatics analyses showed that HCC patients with higher expression of ACACA protein or mRNA levels had poor prognosis. Knockdown of ACACA remarkably crippled the proliferation, colony formation, migration, invasion, epithelial-mesenchymal transition (EMT) process of HCC cells and induced the cell cycle arrest. Mechanistically, ACACA might facilitate the malignant phenotypes of HCC through aberrant activation of Wnt/ß-catenin signaling pathway. In addition, ACACA expression was associated with the dilute infiltration of immune cells including plasmacytoid DC (pDC) and cytotoxic cells by utilization of relevant database analysis. CONCLUSION: ACACA could be a potential biomarker and molecular target for HCC.

Cartilage oligomeric matrix protein acts as a molecular biomarker in multiple cancer types.

PURPOSE: The main function of cartilage oligomeric matrix protein (COMP) is to maintain the synthesis and stability of the extracellular matrix by interacting with collagen. At present, there are relatively few studies on the role of this protein in tumors. This study aimed to explore the relationship between COMP and pan-cancer, and analyzed its diagnostic and prognostic value. METHODS: The Cancer Genome Atlas database, the Genotype-Tissue Expression database and the Cancer Cell Line Encyclopedia database was used for gene expression analysis. The receiver operating characteristic curve was used to assess the diagnostic value of COMP in pan-cancer. Kaplan-Meier plots were used to assess the relationship between COMP expression and prognosis of cancers. R software v4.1.1 was used for statistical analysis, and the ggplot2 package was used for visualization. RESULTS: COMP was significantly overexpressed in 15 human cancers and showed significantly difference in 12 molecular subtypes and 16 immune subtypes. In addition, the expression of COMP is associated with tumor immune evasion. The ROC curve showed that the expression of COMP could predict the occurrence of 16 kinds of tumors with relative accuracy, including adrenocortical carcinoma (ACC) (AUC = 0.737), breast invasive carcinoma (BRCA) (AUC = 0.896), colon adenocarcinoma (COAD) (AUC = 0.760), colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma (COADREAD) (AUC = 0.775), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) (AUC = 0.875), kidney renal papillary cell carcinoma (KIRP) (AUC = 0.773), kidney chromophobe (KICH) (AUC = 0.809), ovarian serous cystadenocarcinoma (OV) (AUC = 0.906), prostate adenocarcinoma (PRAD) (AUC = 0.721), pancreatic adenocarcinoma (PAAD) (AUC = 0.944), rectum adenocarcinoma (READ) (AUC = 0.792), skin cutaneous melanoma (SKCM) (AUC = 0.746), stomach adenocarcinoma (STAD) (AUC = 0.711), testicular germ cell tumors (TGCT) (AUC = 0.823), thymoma (THYM) (AUC = 0.777) and uterine carcinosarcoma (UCS) (AUC = 0.769). Furthermore, COMP expression was correlated with overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in ACC (OS, HR = 4.95, DSS, HR = 5.55, PFI, HR = 2.79), BLCA (OS, HR = 1.59, DSS, HR = 1.72, PFI, HR = 1.36), KIRC (OS, HR = 1.36, DSS, HR = 1.94, PFI, HR = 1.57) and COADREAD (OS, HR = 1.46, DSS, HR = 1.98, PFI, HR = 1.43). We selected previously unreported bladder urothelial carcinoma (BLCA) for further study and found that COMP could be an independent risk factor for OS, DSS and PFI. Moreover, we found differentially expressed genes of COMP in BLCA and obtained top 10 hub genes, including LGR4, LGR5, RSPO2, RSPO1, RSPO3, RNF43, ZNRF3, FYN, LYN and SYK. Finally, we verified the function of COMP at the cellular level by using J82 and T24 cells and found that knockdown of COMP could significantly inhibit migration and invasion. This finding supports that COMP could be a potential biomarker for pan-cancer diagnosis and prognosis encompassing tumor microenvironment, disease stage and prognosis. CONCLUSION: This finding supports that COMP could be a potential biomarker for pan-cancer diagnosis and prognosis encompassing tumor microenvironment, disease stage and prognosis.

Telomerase (hTERT) Overexpression Reveals a Promising Prognostic Biomarker and Therapeutical Target in Different Clinical Subtypes of Pediatric Acute Lymphoblastic Leukaemia.

Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system defined as a clonal expansion of an abnormal lymphoid precursor cell. It mostly affects children under five years of age and is the most common tumor to afflict pediatric patients. The expression of the human telomerase gene (hTERT) in patients with ALL has been studied as a biomarker and could become a new therapeutic target. We evaluate the role of hTERT gene expression in ALL pediatric patients, through quantitative real-time PCR technique, and the possible correlation between hTERT expression and clinical variables: gender, age, white blood cells (WBC), gene fusions, and immunophenotyping. The analysis between healthy controls and ALL patients (N = 244) was statistically significant (p < 0.001), demonstrating hTERT overexpression in these patients. In comparison with the usual set of clinical variables, the data were not statistically significant (p > 0.05), indicating that hTERT is equally overexpressed among patients regardless of gender, age, gene fusions, and immunophenotyping. Moreover, patients who presented a higher hTERT expression level had a significant (p < 0.0001) lower overall survival rate. In summary, hTERT expression emerges as an important molecular pathway in leukemogenesis regardless patient's clinical variables, thus, the data here presented pointed it as a valuable biomarker in pediatric acute lymphoblastic leukemia and a promising target for new therapeutic and prognostic measures.

Hormônio antimülleriano como marcador de fertilidade em fêmeas suínas / Anti-Müllerian hormone as a fertility marker in swine females

O hormônio antimülleriano é conhecido por seu papel na regressão dos ductos de Müller durante a fase de diferenciação sexual dos machos. Ainda assim, esse hormônio atua de forma ainda mais ampla no desenvolvimento de ambos os sexos. O hormônio antimülleriano é diferencialmente expresso em machos e fêmeas durante toda a vida. Nas fêmeas esse hormônio é produzido pelas células da granulosa dos folículos ovarianos e atua modulando os processos de secreção de gonadotrofinas, foliculogênese e esteroidogênese, sendo considerado um biomarcador confiável para fertilidade em diferentes espécies. Apesar de pouquíssimo estudado na espécie suína, alguns trabalhos vêm demonstrando a existência de associações entre os níveis séricos do hormônio antimülleriano e os fenótipos de maior fertilidade. De forma que, o objetivo desta revisão é fazer um levantamento do conhecimento já acumulado acerca da temática, demostrando a importância do desenvolvimento de novos estudos; tendo em vista que o aprofundamento do conhecimento sobre as funções do hormônio antimülleriano nas fêmeas da espécie suína pode contribuir para o melhor entendimento da fisiologia da espécie(AU)

The anti-Müllerian hormone (AMH) is known for its role in the regression of Muller ducts during the phase of sexual differentiation in males. Notwithstanding, this hormone acts more broadly on the development of both sexes. The AMH is differentially expressed both in males and females throughout life. In females, this hormone is produced by granulosa cells of ovarian follicles and modulates the gonadotropin secretion, folliculogenesis, and steroidogenesis, and is considered a reliable fertility biomarker in different species. Despite the lack of studies in the swine species, some reports demonstrated the association between serum levels of AMH and more fertile phenotypes. Therefore, this review aims to survey the current knowledge about this theme, demonstrating the importance of the development of new research, since the strengthening of the knowledge on the functions of the AMH in swine females may contribute to understanding the physiology of the species.(AU)

Hormônio antimülleriano como marcador de fertilidade em fêmeas suínas / Anti-Müllerian hormone as a fertility marker in swine females

O hormônio antimülleriano é conhecido por seu papel na regressão dos ductos de Müller durante a fase de diferenciação sexual dos machos. Ainda assim, esse hormônio atua de forma ainda mais ampla no desenvolvimento de ambos os sexos. O hormônio antimülleriano é diferencialmente expresso em machos e fêmeas durante toda a vida. Nas fêmeas esse hormônio é produzido pelas células da granulosa dos folículos ovarianos e atua modulando os processos de secreção de gonadotrofinas, foliculogênese e esteroidogênese, sendo considerado um biomarcador confiável para fertilidade em diferentes espécies. Apesar de pouquíssimo estudado na espécie suína, alguns trabalhos vêm demonstrando a existência de associações entre os níveis séricos do hormônio antimülleriano e os fenótipos de maior fertilidade. De forma que, o objetivo desta revisão é fazer um levantamento do conhecimento já acumulado acerca da temática, demostrando a importância do desenvolvimento de novos estudos; tendo em vista que o aprofundamento do conhecimento sobre as funções do hormônio antimülleriano nas fêmeas da espécie suína pode contribuir para o melhor entendimento da fisiologia da espécie

The anti-Müllerian hormone (AMH) is known for its role in the regression of Muller ducts during the phase of sexual differentiation in males. Notwithstanding, this hormone acts more broadly on the development of both sexes. The AMH is differentially expressed both in males and females throughout life. In females, this hormone is produced by granulosa cells of ovarian follicles and modulates the gonadotropin secretion, folliculogenesis, and steroidogenesis, and is considered a reliable fertility biomarker in different species. Despite the lack of studies in the swine species, some reports demonstrated the association between serum levels of AMH and more fertile phenotypes. Therefore, this review aims to survey the current knowledge about this theme, demonstrating the importance of the development of new research, since the strengthening of the knowledge on the functions of the AMH in swine females may contribute to understanding the physiology of the species.

New candidate genes associated to endometriosis.

A previous GWAS study performed on Brazilian pooled samples indicated some SNPs (single nucleotide polymorphisms) differentially frequent in infertile patients with endometriosis and controls. Some of them were located in the genes whose biological function suggests that they could be associated with endometriosis pathogenesis; thus, the purpose here was to confirm GWAS findings in a larger group of cases and controls in order to associate the results with the pathogenesis of endometriosis. Then, a genetic association study comprising 394 infertile women with endometriosis and 650 fertile control women was conducted. TaqMan allelic discrimination assays were used to investigate the frequency of three SNPs in the genes KAZN (rs10928050), LAMA5 (rs2427284), and TAC3 (rs733629). The analysis revealed a significant association of KAZN rs10928050 (p = .015) and LAMA5 rs2427284 (p = .0059) SNPs with endometriosis-related infertility, while TAC3 rs733629 showed no difference between cases and controls. As a conclusion, it was possible to observe that individual genotyping of a larger sample of patients and controls confirmed the association among KAZN and LAMA5 with endometriosis-related infertility and revealed new candidate genes contributing to the condition.