Delving into the Role of lncRNAs in Papillary Thyroid Cancer: Upregulation of LINC00887 Promotes Cell Proliferation, Growth and Invasion.

Papillary thyroid carcinoma (PTC) is the most common histological category of thyroid cancer. In recent years, there has been an increasing number of studies on lncRNAs in PTC. Long intergenic non-protein coding RNA 887 (LINC00887) is a critical oncogene in developing other cancers. LINC00887 is upregulated in PTC samples but its role in PTC is currently unclear. This study aimed to investigate the impact the disruption of LINC00887 expression has on PTC progression. We performed a CRISPR/Cas9 strategy for the truncation of LINC00887 in BCPAP and TPC1 cell lines. Functional assays showed that LINC00887 knockdown in both TPC1 and BCPAP cells reduced cell proliferation, colony formation and migration, delayed the cell cycle, and increased apoptosis. These results strengthened the role of LINC00887 in cancer and showed for the first time that this lncRNA could be a potential oncogene in PTC, acting as a tumor promoter. Modulation of the immune system may be one of the etiopathogenic mechanisms of LINC00887 in PTC, as shown by the observed influence of this lncRNA on PD-L1 expression. In addition, the biological pathways of LINC00887 identified to date, such as EMT, the Wnt/ß-catenin signaling pathway or the FRMD6-Hippo signaling pathway may also be relevant regulatory mechanisms operating in PTC.

Long-Term Neurodevelopmental Outcome After Selective Fetoscopic Laser Therapy for Stage I Twin-Twin Transfusion Syndrome.

Twin-twin transfusion syndrome (TTTS) is a serious complication in monochorionic (MC) pregnancies. Fetoscopic laser surgery (FLS) is the primary treatment for advanced TTTS, but managing Quintero stage I TTTS is still controversial. We conducted an observational study evaluating the 2-year neurodevelopment of fetuses, which underwent FLS for stage I TTTS, compared with advanced TTTS and uncomplicated monochorionic diamniotic twins (MCDTs). The study included 156 children: 14 in stage I TTTS group, 28 in advanced TTTS group, and 114 in uncomplicated twin group. In stage I TTTS, 92.9% showed normal neurodevelopment, with no severe neurological impairments observed. These results were comparable with uncomplicated twins (92.1% normal neurodevelopment, P = .921, adjusted odds ratio [aOR] = 1.56, 95% confidence interval [CI] = 0.42-5.79; 1.8% severe impairment, P = .617). Advanced TTTS had a non-significant lower rate of normal neurodevelopment (89.3%, P = .710, aOR = 1.31, 95% CI = 0.12-14.87). In conclusion, FLS for stage I TTTS shows favorable long-term neurodevelopmental outcomes, similar to uncomplicated MC pregnancies.

Assessing the impact of pregnancy planning on obstetric and perinatal outcomes in women with pregestational diabetes mellitus.

AIMS: We investigated the role of pregnancy planning in improving glycemic control and its potential impact on the overall pregnancy outcomes, obstetric outcomes, and perinatal well-being in women with pregestational diabetes mellitus (PGDM). METHODS: A retrospective observational cohort study was conducted, including all pregnant women with PGDM treated in our center 2012 and 2018. RESULTS: Among 425 participants, 26.6 % had planned pregnancies. The lowest rate of pregnancy planning was observed in women with type 2 diabetes mellitus (6.5 %). Women with planned pregnancies had lower BMI. Both pregestational HbA1c levels (6.66 % vs. 7.61 %, p < 0.001) and HbA1c levels at the first prenatal visit (6.39 % vs. 7.24 %, p < 0.001) were significantly lower in the planned pregnancy group. These differences persisted until the end of pregnancy (6.09 % vs. 6.47 %, p = 0.006). Although better glycemic control was associated with a non-significant decrease in fetuses with birth weight over 4000 g (18.1 % vs. 22.1 %) and 4500 g (3.0 % vs. 4.2 %), we did not find significant effects on other morbidity events, maternal outcomes, or the cesarean section rate. CONCLUSIONS: Pregnancy planning in PGDM women improved glycemic control and HbA1c levels. Limited impact on obstetric and perinatal outcomes suggests scope for other focused interventions to optimize maternal and fetal health.

Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease.

Hirschsprung's disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance, with RET as the major disease-causing gene. However, the pathogenesis of HSCR is still not completely understood. Therefore, we applied a computational approach based on multi-omics network characterization and clustering analysis for HSCR-related gene/miRNA identification and biomarker discovery. Protein-protein interaction (PPI) and miRNA-target interaction (MTI) networks were analyzed by DPClusO and BiClusO, respectively, and finally, the biomarker potential of miRNAs was computationally screened by miRNA-BD. In this study, a total of 55 significant gene-disease modules were identified, allowing us to propose 178 new HSCR candidate genes and two biological pathways. Moreover, we identified 12 key miRNAs with biomarker potential among 137 predicted HSCR-associated miRNAs. Functional analysis of new candidates showed that enrichment terms related to gene ontology (GO) and pathways were associated with HSCR. In conclusion, this approach has allowed us to decipher new clues of the etiopathogenesis of HSCR, although molecular experiments are further needed for clinical validations.

Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene.

BACKGROUND: Biallelic variants in EYS are the major cause of autosomal recessive retinitis pigmentosa (arRP) in certain populations, a clinically and genetically heterogeneous disease that may lead to legal blindness. EYS is one of the largest genes (~ 2 Mb) expressed in the retina, in which structural variants (SVs) represent a common cause of disease. However, their identification using short-read sequencing (SRS) is not always feasible. Here, we conducted targeted long-read sequencing (T-LRS) using adaptive sampling of EYS on the MinION sequencing platform (Oxford Nanopore Technologies) to definitively diagnose an arRP family, whose affected individuals (n = 3) carried the heterozygous pathogenic deletion of exons 32-33 in the EYS gene. As this was a recurrent variant identified in three additional families in our cohort, we also aimed to characterize the known deletion at the nucleotide level to assess a possible founder effect. RESULTS: T-LRS in family A unveiled a heterozygous AluYa5 insertion in the coding exon 43 of EYS (chr6(GRCh37):g.64430524_64430525ins352), which segregated with the disease in compound heterozygosity with the previously identified deletion. Visual inspection of previous SRS alignments using IGV revealed several reads containing soft-clipped bases, accompanied by a slight drop in coverage at the Alu insertion site. This prompted us to develop a simplified program using grep command to investigate the recurrence of this variant in our cohort from SRS data. Moreover, LRS also allowed the characterization of the CNV as a ~ 56.4kb deletion spanning exons 32-33 of EYS (chr6(GRCh37):g.64764235_64820592del). The results of further characterization by Sanger sequencing and linkage analysis in the four families were consistent with a founder variant. CONCLUSIONS: To our knowledge, this is the first report of a mobile element insertion into the coding sequence of EYS, as a likely cause of arRP in a family. Our study highlights the value of LRS technology in characterizing and identifying hidden pathogenic SVs, such as retrotransposon insertions, whose contribution to the etiopathogenesis of rare diseases may be underestimated.

Unusual clinical phenotype of Stargardt disease / Fenótipo clínico incomum da doença de Stargardt

ABSTRACT Mutations in the ABCA4 gene are a common cause of Stargardt disease; however, other retinal phenotypes have also been associated with mutations in this gene. We describe an observational case report of an unusual clinical phenotype of Stargardt disease. The ophthalmological examination included best corrected visual acuity, color and autofluorescence photography, fluorescein angiography, optical coherence tomography, and electrophysiology tests. Targeted next-generation sequencing of 99 genes associated with inherited retinal dystrophies was performed in the index patient. A 48-year-old woman presented with a best corrected visual acuity of 20/25 and 20/20. Fundoscopy revealed perifoveal yellow flecked-like lesions. Fluorescein angiography and fundus autofluorescence findings were consistent with pattern dystrophy. Pattern electroretinogram demonstrated bilateral decrease of p50 values. Genetic testing identified two heterozygous missense mutations, c.428C>T, p.(Pro143Leu) and c.3113C>T, p.(Ala.1038Val), in the ABCA4 gene. Based on our results, we believe that these particular mutations in the ABCA4 gene could be associated with a specific disease phenotype characterized by funduscopic appearance similar to pattern dystrophy. A detailed characterization of the retinal phenotype in patients carrying specific mutations in ABCA4 is crucial to understand disease expression and ensure optimal clinical care for patients with inherited retinal dystrophies.

RESUMO Mutações no gene ABCA4 são causa comum da doença de Stargardt, mas outros fenótipos da retina também foram associados a mutações nesse gene. Apresentamos um relato de caso observacional de um fenótipo clínico incomum da doença de Stargardt. O exame oftalmológico incluiu a acuidade visual com melhor correção, fotografia em cores e com autofluorescência, angiofluoresceinografia, tomografia de coerência óptica e testes de eletrofisiologia. Na paciente em questão, realizou-se o sequenciamento de próxima geração de 99 genes associados a distrofias retinais hereditárias. Tratava-se de uma mulher de 48 anos com melhor acuidade visual corrigida de 20/25 e 20/20. A fundoscopia revelou lesões puntiformes amarelas perifoveais. Os resultados da angiofluoresceinografia e da autofluorescência do fundo de olho foram consistentes com distrofia em padrão. A eletrorretinografia por padrões mostrou diminuição bilateral dos valores de p50. Os testes genéticos revelaram duas mutações missense heterozigóticas, c.428C>T, p. (Pro143Leu) e c.3113C>T, p. (Ala.1038Val), no gene ABCA4. Nossos resultados nos fazem pensar que essas mutações específicas em ABCA4 talvez possam estar associadas a um fenótipo específico da doença, caracterizado por uma aparência fundoscópica semelhante à da distrofia em padrão. Uma caracterização detalhada do fenótipo da retina em pacientes portadores de mutações específicas em ABCA4 é crucial para compreender a expressão da doença e para garantir o tratamento clínico ideal para pacientes com distrofias retinais hereditárias.