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Abstract Background Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare genetic disorder characterized by progressive cognitive decline and myoclonic epilepsy, caused by pathogenic variants of SERPINI1. We reported a case of genetically confirmed FENIB with de novo H338R mutation in the SERPINI1, in which frontal deficits including inattention and disinhibition, and relevant atrophy in the vmPFC on brain MRI were observed in the early stage of the disease. Case presentation A 23-year-old Japanese man presented with progressive inattention and disinhibition over 4 years followed by myoclonic epilepsy. The whole-genome sequencing and filtering analysis showed de novo heterozygous H338R mutation in the SERPINI1, confirming the diagnosis of FENIB. Single-case voxel-based morphometry using brain magnetic resonance imaging obtained at the initial visit revealed focal gray matter volume loss in the ventromedial prefrontal cortices, which is presumed to be associated with inattention and disinhibition. Conclusion Frontal deficits including inattention and disinhibition can be the presenting symptoms of patients with FENIB. Single-case voxel-based morphometry may be useful for detecting regional atrophy of the frontal lobe in FENIB. Detecting these abnormalities in the early stage of disease may be key findings for differentiating FENIB from other causes of progressive myoclonic epilepsy.

Background: Sevoflurane and propofol are two popular anesthetics used during glioblastoma (GBM) surgery. This investigation compared the molecular subtypes and immune checkpoints of cancer cells following GBM surgery under sevoflurane and propofol anesthesia. Method: The expression profile data and clinical information of glioma samples of different grades were downloaded from The Cancer Genome Atlas database. Weighted gene coexpression network analysis was used to identify hub modules and key genes related to glioma grades (G2 and G3). The GEO database (GSE179004) was used to retrieve glioma surgical specimens with different anesthetic gene expression profiles. The differential expression of immune checkpoint genes under various anesthetic settings was examined using the R‐ggplot2. Results: Compared to sevoflurane, propofol significantly downregulated SERPINI1 and CAMK2A expression. These are also important factors in glioma grading. Simultaneously, SERPINI1 and CAMK2A were also significantly related to the prognosis of GBM and lower‐grade glioma patients and acted as potential tumor suppressors. In addition, propofol increases the expression of the immune checkpoint molecule, PD‐L1. Conclusions: Our study revealed that sevoflurane can more effectively prevent the development of glioma after surgery than propofol, and SERPINI1 can be used as a new independent prognostic factor for glioma. [ABSTRACT FROM AUTHOR]

Abstract Background Sevoflurane and propofol are two popular anesthetics used during glioblastoma (GBM) surgery. This investigation compared the molecular subtypes and immune checkpoints of cancer cells following GBM surgery under sevoflurane and propofol anesthesia. Method The expression profile data and clinical information of glioma samples of different grades were downloaded from The Cancer Genome Atlas database. Weighted gene coexpression network analysis was used to identify hub modules and key genes related to glioma grades (G2 and G3). The GEO database (GSE179004) was used to retrieve glioma surgical specimens with different anesthetic gene expression profiles. The differential expression of immune checkpoint genes under various anesthetic settings was examined using the R‐ggplot2. Results Compared to sevoflurane, propofol significantly downregulated SERPINI1 and CAMK2A expression. These are also important factors in glioma grading. Simultaneously, SERPINI1 and CAMK2A were also significantly related to the prognosis of GBM and lower‐grade glioma patients and acted as potential tumor suppressors. In addition, propofol increases the expression of the immune checkpoint molecule, PD‐L1. Conclusions Our study revealed that sevoflurane can more effectively prevent the development of glioma after surgery than propofol, and SERPINI1 can be used as a new independent prognostic factor for glioma.

Background: Familial encephalopathy with neuroserpin inclusion bodies (FENIB), a rare neurogenetic disease, is characterized by progressive cognitive decline and myoclonus and caused by pathogenic variants of the SERPINI1 gene that lead to the formation of neuroserpin inclusion bodies.Methods: We described the case of an Asian patient with FENIB associated with a pathogenic variant of SERPINI1 and summarized and analyzed the clinical characteristics of the case. In addition, we conducted a literature review of previously reported patients with this disease.Results: The patient, a 16-year-old Chinese girl, presented with progressive cognitive decline and myoclonus that had started at the age of 11 years. The girl was found to carry a de novo heterozygous c.1175G>A (p.G392E) variant of the SERPINI1 gene, which is a pathogenic variant according to the guidelines of the American College of Medical Genetics and Genomics. She had responded poorly to antiseizure medications (ASMs). At the last follow-up, her myoclonus was still out of control, and her self-care ability was poor. Our literature review revealed that 13 similar cases (including 9 cases in male patients) have been reported so far, in which six pathogenetic variations in SERPINI1, including G392E, were responsible for FENIB. All the patients presented with myoclonus, and 12 patients had experienced at least one other type of seizure. Further, as observed in our case, 9 out of 12 patients did not respond to ASMs. Progressive cognitive decline was observed in all the patients, and 10 out of 13 patients had dyskinesia. The median age of disease onset was 21 years, and the median age at the time of death was 33 years. Further, 9 out of 13 patients showed signs of cerebral and/or cerebellar atrophy. Finally, neuroserpin inclusion bodies were identified in six patients who underwent brain biopsy or autopsy.Conclusions: Pathogenic variants of SERPINI1 should be suspected in children with progressive cognitive decline and myoclonus, especially in those with progressive myoclonus epilepsy. Further, gene detection and brain biopsy are important means for the diagnosis of FENIB. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCM) are vascular lesions affecting brain microvessels. While molecular bases of the sporadic condition are not yet well elucidated, familial forms arise following mutations at three different loci KRIT1, CCM2 and PDCD10. However, no germline mutations are detected in a small percentage of families with hereditary history of CCM. In order to detect other possible candidate genes, we performed molecular analysis of SERPINI1 gene in a cohort of patients carrying no mutations in the three CCM loci, aiming to detect mutations likely associated to lesion development. Therefore, we performed molecular analysis of the SERPINI1 gene in a cohort of 18 unrelated patients affected by both familial and sporadic CCM showing no germline causative mutations. Mutational analysis resulted negative and only few single nucleotide polymorphisms were detected. However, the rs11284733 SNP was detected in a high percentage of patients affected by familial form of the disease. This SNP occurs within a noncoding exon retained in an alternative spliced SERPINI1 transcript, suggesting its possible role in gene expression regulation.

Cerebral Cavernous Malformations (CCM) are vascular lesions affecting brain microvessels. While molecular bases of the sporadic condition are not yet well elucidated, familial forms arise following mutations at three different loci KRIT1, CCM2 and PDCD10. However, no germline mutations are detected in a small percentage of families with hereditary history of CCM. In order to detect other possible candidate genes, we performed molecular analysis of SERPINI1 gene in a cohort of patients carrying no mutations in the three CCM loci, aiming to detect mutations likely associated to lesion development. Therefore, we performed molecular analysis of the SERPINI1 gene in a cohort of 18 unrelated patients affected by both familial and sporadic CCM showing no germline causative mutations. Mutational analysis resulted negative and only few single nucleotide polymorphisms were detected. However, the rs11284733 SNP was detected in a high percentage of patients affected by familial form of the disease. This SNP occurs within a noncoding exon retained in an alternative spliced SERPINI1 transcript, suggesting its possible role in gene expression regulation. [ABSTRACT FROM AUTHOR]

Serpini1, which encodes neuroserpin, has been implicated in the development and normal function of the nervous system. Mutations in serpini1 cause familial encephalopathy, a rare neurodegenerative disorder characterized with neuroserpin inclusion bodies. However, function of neuroserpin in the nervous system is not fully understood. In this study, we generated a novel serpini1 mutant zebrafish model to investigate the loss of function of neuroserpin. Serpini1 - deficient mutation was created with the CRISPR/Cas9 technique. No severe morphological characteristics were found in serpini1 - deficient zebrafish. Serpini1 −/− zebrafish larvae did not cause locomotor defects but displayed anxiety-like behavior. Extension of motoneurons axon defect was observed in serpini1 −/− zebrafish. Furthermore, RNA-sequencing analysis revealed that loss of serpini1 resulted in affected expression of neurodegeneration-related genes. • Neuroserpin deficient zebrafish showed increased anxiety. • Neuroserpin deficient zebrafish displayed extension of motoneurons axon defect at 24hpf. • Serpini1 knockout zebrafish resulted in affected expression of neurodegeneration-related genes. [ABSTRACT FROM AUTHOR]

Progressive myoclonic epilepsies are rare neurodegenerative diseases with a wide spectrum of clinical presentations and genetic heterogeneity that render their diagnosis perplexing. Discovering new imputable genes has been an ongoing process in recent years. We present two pediatric cases of progressive myoclonic epilepsy with SERPINI1 pathogenic variants that lead to a severe presentation; we highlight the importance of including this gene, previously known as causing an adult-onset dementia-epilepsy syndrome, in the genetic work-up of childhood-onset progressive myoclonic epilepsies. [ABSTRACT FROM AUTHOR]

An increasingly accepted concept is that the progression of colorectal cancer is accompanied by epithelial-mesenchymal transition ( EMT). In our study, in order to characterize the properties of EMT in 16 colorectal cancer cell lines, the cells were first orthotopically implanted into nude mice, and the tumors in vivo, as well as cells cultured in vitro, were immunostained for EMT markers. The immunostaining revealed that seven of the cells had an epithelial phenotype with a high expression of E-cadherin, whereas other cells showed opposite patterns, such as a high expression of vimentin ( CX-1, COLO205, CloneA, HCT116, and SW48). Among the cells expressing vimentin, some expressed vimentin in the orthotopic tumors but not in the cultured cells ( SW480, SW620, and COLO320). We evaluated these findings in combination with microarray analyses, and selected five genes: CHST11, SERPINI1, AGR2, FBP1, and FOXA1. Next, we downregulated the expression of SERPINI1 with si RNA in the cells, the results of which showed reverse- EMT changes at the protein level and in the cellular morphology. Along with immunohistochemical analyses, we confirmed the effect of the intracellular and secreted SERPINI1 protein of SW620 cells, which supported the importance of SERPINI1 in EMT. The development of therapeutic strategies targeting EMT is ongoing, including methods targeting the transforming growth factor-β signaling pathway as well as the Wnt pathway. SERPINI1 is an important regulator of EMT. Our findings help to elucidate the signaling pathways of EMT, hopefully clarifying therapeutic pathways as well. [ABSTRACT FROM AUTHOR]

Subplate cells are among the first generated neurons in the mammalian cerebral cortex and have been implicated in the establishment of cortical wiring. In rodents some subplate neurons persist into adulthood. Here we would like to highlight several converging findings which suggest a novel secretory function of subplate neurons during cortical development. Throughout the postnatal period in rodents, subplate neurons have highly developed rough endoplasmic reticulum (ER) and are under an ER stress condition. By comparing gene expression between subplate and layer 6, we found that several genes encoding secreted proteins are highly expressed in subplate neurons. One of these secreted proteins, neuroserpin, encoded by the serpini1 gene, is localized to the ER in subplate cells. We propose that subplate might influence cortical circuit formation through a transient secretory function. [ABSTRACT FROM AUTHOR]

Background and aim: Early detection of hepatocellular carcinoma (HCC) enhances effective and curative management. New genetic markers with distinct diagnostic ability are required. Aim: determine the expression of GPC3, PEG10, SERPINI1, MK and QP-C in the peripheral blood of HCC patients. Methods: 74 HCV patients were recruited and divided into three groups; chronic hepatitis (I), liver cirrhosis (II) and HCC (III). Demographics, laboratory and imaging data were collected. Child score and metastatic work up were completed. The expression of the five candidate genes in the peripheral blood was performed by qRT-PCR assay. Results: Groups were gender matched, age in group I was significantly lower than in groups II and III (37.7 vs 50.4 and 55.6, p value <0.005). CHILD score; group II and III A/B/C = (7/5/6) and (20/6/3). AFP was significantly higher in group III than I and II (204 vs 3.9 and 6.9, p < 0.01). In HCC group 69% of the lesions were < 5 cm, and had 1-2 nodules; 14% had metastases. GPC3, PEG10, SERPINI1 and MK mRNA were significantly higher in the HCC group compared to the other groups while QP-C mRNA was higher in chronic hepatitis C group compared to other groups. The gene expression values in HCC patients were independent of the tumor size, AFP levels or extrahepatic metastasis. Combined measurement of the five gene markers showed 100% sensitivity and 33% specificity, 48% PPV and 100% NPV. Conclusion: GPC3, PEG10, SERPINI1 and MK are genetic markers that can represent a useful tool for detection of HCC. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the regulation mechanism of long non-coding RNA (lncRNA) plasmocytoma variant translocation 1 (PVT1) in ovarian cancer (OC)., Methods: The levels of PVT1, microRNA (miR)-543, serpin peptidase inhibitor-clade I (neuroserpin)-member 1 (SERPINI1) in OC tissues and OVCAR-3, A2780, TOV-112D of OC cell lines were detected by quantitative real-time PCR (qRT-PCR) and Western Blot (WB). Cell proliferation, migration, invasion, apoptosis and the regulatory relationship between genes and target genes were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell, flow cytometry and dual luciferase reporter (DLR). The OC patients were followed up for 5 years to analyze the relationship between PVT1 and 5-year overall survival (OS)., Results: In contrast with miR-543, PVT1 and SERPINI1 were highly expressed in OC tissues and cell lines, and high levels of PVT1 were significantly associated with lower 5-year OS of patients. Down-regulating PVT1 not only inhibited the malignant proliferation, migration and invasion of OC cells, but promoted cell apoptosis. PVT1 regulated miR-543 in a targeted manner, and its overexpression could attenuate the anticancer effect of miR-543 on OC cells. In addition, miR-543 also directly targeted SERPINI1, and miR-543 knockdown weakened the inhibitory effect of down-regulated SERPINI1 on OC progression. Furthermore, we found that PVT1 acted as a competitive endogenous RNA to sponge miR-543, thereby regulating the expression of SERPINI1., Conclusion: PVT1 can mediate the molecular mechanism of OC by miR-543/SERPINI1 axis regulatory network, which is a new therapeutic direction for OC., (© 2020 The Author(s).)