Single Nucleotide Polymorphism in Cell Adhesion Molecule L1 Affects Learning and Memory in a Mouse Model of Traumatic Brain Injury.

The L1 cell adhesion molecule (L1) has demonstrated a range of beneficial effects in animal models of spinal cord injury, neurodegenerative disease, and ischemia; however, the role of L1 in TBI has not been fully examined. Mutations in the L1 gene affecting the extracellular domain of this type 1 transmembrane glycoprotein have been identified in patients with L1 syndrome. These patients suffer from hydrocephalus, MASA (mental retardation, adducted thumbs, shuffling gait, aphasia) symptoms, and corpus callosum agenesis. Clinicians have observed that recovery post-traumatic brain injury (TBI) varies among the population. This variability may be explained by the genetic differences present in the general population. In this study, we utilized a novel mouse model of L1 syndrome with a mutation at aspartic acid position 201 in the extracellular domain of L1 (L1-201). We assessed the impact of this specific single nucleotide polymorphism (SNP) localized to the X-chromosome L1 gene on recovery outcomes following TBI by comparing the L1-201 mouse mutants with their wild-type littermates. We demonstrate that male L1-201 mice exhibit significantly worse learning and memory outcomes in the Morris water maze after lateral fluid percussion (LFP) injury compared to male wild-type mice and a trend to worse motor function on the rotarod. However, no significant changes were observed in markers for inflammatory responses or apoptosis after TBI.

Chicoric Acid Ameliorated Beta-Amyloid Pathology and Enhanced Expression of Synaptic-Function-Related Markers via L1CAM in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aß) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aß1-42 and Aß plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aß1-42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aß plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aß levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models.

Integrated Bioinformatics Analysis to Identify a Novel Four-Gene Prognostic Model of Breast Cancer and Reveal Its Association with Immune Infiltration.

Liquid-liquid phase separation (LLPS) impact immune signaling in cancer and related genes have shown prognostic value in breast cancer (BRCA). However, the crosstalk between LLPS and immune infiltration in BRCA remain unclear. Therefore, we aimed to develop a novel prognostic model of BRCA related to LLPS and immune infiltration. BRCA-related, liquid-liquid phase separation (LLPS)-related genes, and differentially expressed genes (DEGs) were identified using public databases. Mutation and drug sensitivity analyses were performed using Gene Set Cancer Analysis database. Univariate cox regression and LASSO Cox regression were used for the construction and verification of prognostic model. Kaplan-Meier analysis was performed to evaluate overall survival (OS). Gene set variation analysis was conducted to analyze key pathways. CIBERSORT was used to assess immune infiltration and its correlation with prognostic genes was determined through Pearson analysis. A total of 6056 BRCA-associated genes, 3775 LLPS-associated genes, and 4049 DEGs, resulting in 314 overlapping genes. Twenty-eight prognostic genes were screened, and some of them were mutational and related to drug sensitivity Subsequently, a prognostic model comprising L1CAM, EVL, FABP7, and CST1 was built. Patients in high-risk group had shorter OS than those in low-risk group. The infiltrating levels of CD8+ T cells, macrophages M0, macrophages M2, dendritic cells activated, and mast cells resting was altered in high-risk group of breast cancer patients compared to low-risk group. L1CAM, EVL, FABP7, and CST1 were related to these infiltrating immune cells. L1CAM, EVL, FABP7, and CST1 were potential diagnostic biomarkers and therapeutic targets for BRCA.

Extracellular vesicles from UTX-knockout endothelial cells boost neural stem cell differentiation in spinal cord injury.

BACKGROUND: Vascular endothelial cells are pivotal in the pathophysiological progression following spinal cord injury (SCI). The UTX (Ubiquitously Transcribed Tetratripeptide Repeat on Chromosome X) serves as a significant regulator of endothelial cell phenotype. The manipulation of endogenous neural stem cells (NSCs) offers a compelling strategy for the amelioration of SCI. METHODS: Two mouse models were used to investigate SCI: NSCs lineage-traced mice and mice with conditional UTX knockout (UTX KO) in endothelial cells. To study the effects of UTX KO on neural differentiation, we harvested extracellular vesicles (EVs) from both UTX KO spinal cord microvascular endothelial cells (SCMECs) and negative control SCMECs. These EVs were then employed to modulate the differentiation trajectory of endogenous NSCs in the SCI model. RESULTS: In our NSCs lineage-traced mice model of SCI, a marked decrease in neurogenesis was observed post-injury. Notably, NSCs in UTX KO SCMECs mice showed enhanced neuronal differentiation compared to controls. RNA sequencing and western blot analyses revealed an upregulation of L1 cell adhesion molecule (L1CAM), a gene associated with neurogenesis, in UTX KO SCMECs and their secreted EVs. This aligns with the observed promotion of neurogenesis in UTX KO conditions. In vivo administration of L1CAM-rich EVs from UTX KO SCMECs (KO EVs) to the mice significantly enhanced neural differentiation. Similarly, in vitro exposure of NSCs to KO EVs resulted in increased activation of the Akt signaling pathway, further promoting neural differentiation. Conversely, inhibiting Akt phosphorylation or knocking down L1CAM negated the beneficial effects of KO EVs on NSC neuronal differentiation. CONCLUSIONS: In conclusion, our findings substantiate that EVs derived from UTX KO SCMECs can act as facilitators of neural differentiation following SCI. This study not only elucidates a novel mechanism but also opens new horizons for therapeutic interventions in the treatment of SCI. Video Abstract.

Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation.

Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveal that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.

Reciprocal regulation of forkhead box C1 and L1 cell adhesion molecule contributes to triple-negative breast cancer progression.

PURPOSE: The potential of targeting forkhead box C1 (FOXC1) as a therapeutic approach for triple-negative breast cancer (TNBC) is promising. However, a comprehensive understanding of FOXC1 regulation, particularly upstream factors, remains elusive. Expression of the L1 cell adhesion molecule (L1CAM), a transmembrane glycoprotein associated with brain metastasis, was observed to be positively associated with FOXC1 transcripts. Thus, this study aims to investigate their relationship in TNBC progression. METHODS: Publicly available FOXC1 and L1CAM transcriptomic data were obtained, and their corresponding proteins were analyzed in four TNBC cell lines. In BT549 cells, FOXC1 and L1CAM were individually silenced, while L1CAM was overexpressed in BT549-shFOXC1, MDA-MB-231, and HCC1937 cells. CCK-8, transwell, and wound healing assays were performed in these cell lines, and immunohistochemical staining was conducted in tumor samples. RESULTS: A positive correlation between L1CAM and FOXC1 transcripts was observed in publicly available datasets. In BT549 cells, knockdown of FOXC1 led to reduced L1CAM expression at both the transcriptional and protein levels, and conversely, silencing of L1CAM decreased FOXC1 protein levels, but interestingly, FOXC1 transcripts remained largely unaffected. Overexpressing L1CAM resulted in increased FOXC1 protein expression without significant changes in FOXC1 mRNA levels. This trend was also observed in BT549-shFOXC1, MDA-MB-231-L1CAM, and HCC1937-L1CAM cells. Notably, alterations in FOXC1 or L1CAM levels corresponded to changes in cell proliferation, migration, and invasion capacities. Furthermore, a positive correlation between L1CAM and FOXC1 protein expression was detected in human TNBC tumors. CONCLUSION: FOXC1 and L1CAM exhibit co-regulation at the protein level, with FOXC1 regulating at the transcriptional level and L1CAM regulating at the post-transcriptional level, and together they positively influence cell proliferation, migration, and invasion in TNBC.

Cyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma.

The matrix metalloprotease A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1) was reported to be involved in tumor progression in several cancer types, but its contributions appear discrepant. At present, the role of ADAMTS1 in oral squamous cell carcinoma (SCC; OSCC) remains unclear. Herein, The Cancer Genome Atlas (TCGA) database showed that ADAMTS1 transcripts were downregulated in head and neck SCC (HNSCC) tissues compared to normal tissues, but ADAMTS1 levels were correlated with poorer prognoses of HNSCC patients. In vitro, we observed that ADAMTS1 expression levels were correlated with the invasive abilities of four OSCC cell lines, HSC-3, SCC9, HSC-3M, and SAS. Knockdown of ADAMTS1 in OSCC cells led to a decrease and its overexpression led to an increase in cell-invasive abilities in vitro as well as tumor growth and lymph node (LN) metastasis in OSCC xenografts. Mechanistic investigations showed that the cyclic increase in ADAMTS1-L1 cell adhesion molecule (L1CAM) axis-mediated epidermal growth factor receptor (EGFR) activation led to exacerbation of the invasive abilities of OSCC cells via inducing epithelial-mesenchymal transition (EMT) progression. Clinical analyses revealed that ADAMTS1, L1CAM, and EGFR levels were all correlated with worse prognoses of HNSCC patients, and patients with ADAMTS1high/L1CAMhigh or EGFRhigh tumors had the shortest overall and disease-specific survival times. As to therapeutic aspects, we discovered that an edible plant-derived flavonoid, apigenin (API), drastically inhibited expression of the ADAMTS1-L1CAM-EGFR axis and reduced the ADAMTS1-triggered invasion and LN metastasis of OSCC cells in vitro and in vivo. Most importantly, API treatment significantly prolonged survival rates of xenograft mice with OSCC. In summary, ADAMTS1 may be a useful biomarker for predicting OSCC progression, and API potentially retarded OSCC progression by targeting the ADAMTS1-L1CAM-EGFR signaling pathway.

Neuropsin promotes hippocampal synaptogenesis by regulating the expression and cleavage of L1CAM.

During early postnatal brain development, the formation of proper synaptic connections between neurons is crucial for the development of functional neural networks. Recent studies have established the involvement of protease-mediated modulations of extracellular components in both synapse formation and elimination. The secretory serine protease neuropsin (also known as kallikrein-8) cleaves a few transmembrane or extracellular matrix proteins in a neural activity-dependent manner and regulates neural plasticity. However, neuropsin-dependent proteolysis of extracellular components and the involvement of these components in mouse brain development are poorly understood. We have observed that during hippocampus development, expression of neuropsin and levels of full-length or cleaved fragments of the neuropsin substrate protein L1 cell adhesion molecule (L1CAM) positively correlate with synaptogenesis. Our subcellular fractionation studies show that the expression of neuropsin and its proteolytic activity on L1CAM are enriched at developing hippocampal synapses. Activation of neuropsin expression upregulates the transcription and cleavage of L1CAM. Furthermore, blocking of neuropsin activity, as well as knockdown of L1CAM expression, significantly downregulates in vitro hippocampal synaptogenesis. Taken together, these findings provide evidence for the involvement of neuropsin activity-dependent regulation of L1CAM expression and cleavage in hippocampal synaptogenesis.

Hybrid Oncocytic Tumors (HOTs) in Birt-Hogg-Dubé Syndrome Patients-A Tale of Two Cities: Sequencing Analysis Reveals Dual Lineage Markers Capturing the 2 Cellular Populations of HOT.

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.

The role of L1CAM as predictor of poor prognosis in stage I endometrial cancer: a systematic review and meta-analysis.

INTRODUCTION: Molecular and genomic profiling in endometrial cancer is increasing popularity. L1 cell adhesion molecule (L1CAM) is frequently mutated in endometrial cancer. In this paper, we aim to evaluate the prognostic role of L1CAM in patients with stage I endometrial cancer. METHODS: We performed a systematic review and meta-analysis searching in PubMed (MEDLINE), EMBASE, and Web of Science database to identify studies reporting the expression of L1CAM in endometrial cancer. The primary endpoint measure was to assess and evaluate the impact of L1CAM on survival outcomes. This study was performed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. RESULTS: Five studies were included. The pooled results suggested that L1CAM expression influences survival outcomes in stage I endometrial cancer. High L1CAM expression correlated with worse disease-free survival (HR 4.11, 95% CI 1.02-16.59, p = 0.047) and overall survival (HR 3.62, 95% CI 1.32-9.31, p = 0.012). High L1CAM level was also associated with a more aggressive FIGO grade and with older age. CONCLUSION: This systematic review supported that L1CAM have a prognostic role in stage I endometrial cancer, thus providing a potential useful tool for tailoring the need of adjuvant therapy.

VAMP7j: A Splice Variant of Human VAMP7 That Modulates Neurite Outgrowth by Regulating L1CAM Transport to the Plasma Membrane.

The vesicle-associated membrane protein 7 (VAMP7) is a SNARE protein of the longin family involved in a wide range of subcellular trafficking events, including neurite sprouting and elongation. The expression of the human gene SYBL1, encoding VAMP7, is finely regulated by alternative splicing. Among the minor isoforms identified so far, VAMP7j is the one most expressed and modulated in the human brain. Therefore, we focused on gaining functional evidence on VAMP7j, which lacks a functional SNARE motif but retains both the longin and transmembrane domains. In human SH-SY5Y cells, we found VAMP7j to modulate neuritogenesis by mediating transport of L1CAM toward the plasma membrane, in a fashion regulated by phosphorylation of the longin domain. VAMP7-mediated regulation of L1CAM trafficking seems at least to differentiate humans from rats, with VAMP7j CNS expression being restricted to primates, including humans. Since L1CAM is a central player in neuritogenesis and axon guidance, these findings suggest the species-specific splicing of SYBL1 is among the fine tuners of human neurodevelopmental complexity.

Flow cytometry-based quantification of genome editing efficiency in human cell lines using the L1CAM gene.

CRISPR/Cas9 is a powerful genome editing system that has remarkably facilitated gene knockout and targeted knock-in. To accelerate the practical use of CRISPR/Cas9, however, it remains crucial to improve the efficiency, precision, and specificity of genome editing, particularly targeted knock-in, achieved with this system. To improve genome editing efficiency, researchers should first have a molecular assay that allows sensitive monitoring of genome editing events with simple procedures. In the current study, we demonstrate that genome editing events occurring in L1CAM, an X-chromosome gene encoding a cell surface protein, can be readily monitored using flow cytometry (FCM) in multiple human cell lines including neuroblastoma cell lines. The abrogation of L1CAM was efficiently achieved using Cas9 nucleases which disrupt exons encoding the L1CAM extracellular domain, and was easily detected by FCM using anti-L1CAM antibodies. Notably, L1CAM-abrogated cells could be quantified by FCM in four days after transfection with a Cas9 nuclease, which is much faster than an established assay based on the PIGA gene. In addition, the L1CAM-based assay allowed us to measure the efficiency of targeted knock-in (correction of L1CAM mutations) accomplished through different strategies, including a Cas9 nuclease-mediated method, tandem paired nicking, and prime editing. Our L1CAM-based assay using FCM enables rapid and sensitive quantification of genome editing efficiencies and will thereby help researchers improve genome editing technologies.

Papillary renal neoplasm with reverse polarity: a clinicopathologic study of 43 cases with a focus on the expression of KRAS signaling pathway downstream effectors.

Papillary renal neoplasm with reverse polarity (PRNRP) is a renal tumor with frequent KRAS mutations. In this study, we aimed to report the clinical, histological, and immunohistochemical characteristics of PRNRP and the protein expression of various KRAS signaling pathway downstream effectors in PRNRP. PRNRP samples from patients who underwent surgical resection at Seoul National University Hospital over an 11-year period (January 2011 to December 2021) were analyzed. We identified 43 PRNRPs, defined as papillary renal tumors with a thin papillary architecture, eosinophilic finely granular cytoplasm, and apical nuclear position. Immunohistochemistry revealed typical characteristics of PRNRP, including exclusively positive GATA3 (43/43); highly positive L1CAM (43/43), PAX8 (43/43), and EMA (43/43); and low positive AMACR (4/43), RCC (1/43), and vimentin (1/43). KRAS signaling pathway effectors, such as p-ERK, RalA, and RalB, were highly expressed in PRNRP compared to papillary renal cell carcinoma (pRCC) with low or high nuclear grade (P < .001, all). Compared to pRCC with high nuclear grade, patients with PRNRP exhibited significantly longer progression-free survival (P < .001). PRNRP showed the best clinical outcome, with no disease progression in any of the cases. Our study analyzed the largest number of PRNRP cases and is the first to analyze the association between PRNRP and the KRAS downstream signaling pathway. PRNRP was found at a high frequency among all papillary renal tumors (43/207) and demonstrated a very good prognosis. PRNRP showed high GATA3, L1CAM, PAX8, and EMA protein expression as well as high p-ERK, RalA, and RalB protein expression.

Circ_0035796 depletion inhibits transforming growth factor-ß1-induced pulmonary fibrosis in a miR-150-5p/L1CAM-dependent manner.

BACKGROUND: The pathogenesis of pulmonary fibrosis is not fully understood. Previous work has demonstrated the important role of circular RNA (circRNA) in pulmonary fibrosis development. This study aims to analyse the role of circ_0035796 in pulmonary fibrosis and the underlying mechanism. METHODS: Human foetal lung fibroblast 1 (HFL1) cells were treated with transforming growth factor-ß1 (TGF-ß1) to mimic a pulmonary fibrosis cell model. The expression of circ_0035796, microRNA-150-5p (miR-150-5p) and L1 cell adhesion molecule (L1CAM) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of L1CAM, collagen I and fibronectin was detected by Western blot. Cell viability was analysed by CCK-8 assay. Cell proliferation, invasion and migration were investigated by 5-Ethynyl-2'-deoxyuridine (EdU) assay, transwell invasion assay and wound-healing assay, respectively. The secretion of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) was analysed by Enzyme-linked immunosorbent assay (ELISA). Oxidative stress was assessed by detecting Superoxide Dismutase (SOD) activity and Malondialdehyde (MDA) level using commercial kits. The association of miR-150-5p with circ_0035796 and L1CAM was identified by dual-luciferase reporter assay, RNA pull-down assay and RNA immunoprecipitation (RIP) assay. RESULTS: Circ_0035796 and L1CAM expression were dramatically upregulated, while miR-150-5p expression was downregulated in TGF-ß1-treated HFL1 cells. TGF-ß1 treatment induced cell proliferation, migration, invasion, IL-6 and TNF-α secretion, and oxidative stress, whereas circ_0035796 depletion relieved these effects. In addition, circ_0035796 acted as a sponge of miR-150-5p and miR-150-5p combined with L1CAM. Moreover, miR-150-5p depletion attenuated circ_0035796 knockdown-mediated effects in TGF-ß1-exposed HFL1 cells. The regulation of miR-150-5p on TGF-ß1-induced fibroblast activation involved the downregulation of L1CAM. Further, circ_0035796 modulated L1CAM expression by interacting with miR-150-5p in TGF-ß1-exposed HFL1 cells. CONCLUSION: Circ_0035796 knockdown ameliorates TGF-ß1-induced pulmonary fibrosis through the miR-150-5p/L1CAM axis in vitro.

Mesonephric-like Adenocarcinoma of the Uterine Corpus: Clinicopathological and Prognostic Significance of L1 Cell Adhesion Molecule (L1CAM) Over-expression.

BACKGROUND/AIM: The expression of L1 cell adhesion molecule (L1CAM) in uterine mesonephric-like adenocarcinoma (MLA) remains understudied. Our aim was to explore the L1CAM expression in uterine MLA, delving into its clinicopathological implications and prognostic significance. PATIENTS AND METHODS: We conducted L1CAM immunostaining in MLA, endometrioid carcinoma (EC), and serous carcinoma (SC), compared L1CAM expression across these histological types, and probed the relationship between L1CAM expression and the clinicopathological features and outcomes of patients with MLA. RESULTS: High L1CAM expression was evident in 15 of 28 MLA cases (53.6%). This rate surpassed that of EC (7.5%) but was less than that of SC (78.9%). A high L1CAM expression correlated with initial distant metastasis, advanced initial stage, lung metastasis, and the recurrence of MLA. L1CAM-high MLA exhibited worse disease-free and overall survival than L1CAM-low MLA. CONCLUSION: L1CAM over-expression was observed in more than half of the MLA cases, and was associated with aggressive clinicopathological traits and adverse outcomes in patients with uterine MLA.

Droj2 Facilitates Somatosensory Neurite Sculpting via GTP-Binding Protein Arf102F in Drosophila.

Developmental remodeling of neurite is crucial for the accurate wiring of neural circuits in the developing nervous system in both vertebrates and invertebrates, and may also contribute to the pathogenesis of neuropsychiatric disorders, for instance, autism, Alzheimer's disease (AD), and schizophrenia. However, the molecular underpinnings underlying developmental remodeling are still not fully understood. Here, we have identified DnaJ-like-2 (Droj2), orthologous to human DNAJA1 and DNAJA4 that is predicted to be involved in protein refolding, as a developmental signal promoting dendrite sculpting of the class IV dendritic arborization (C4da) sensory neuron in Drosophila. We further show that Arf102F, a GTP-binding protein previously implicated in protein trafficking, serves downstream of Droj2 to govern neurite pruning of C4da sensory neurons. Intriguingly, our data consistently demonstrate that both Droj2 and Arf102F promote the downregulation of the conserved L1-type cell-adhesion molecule Neuroglian anterior to dendrite pruning. Mechanistically, Droj2 genetically interacts with Arf102F and promotes Neuroglian downregulation to initiate dendrite severing. Taken together, this systematic study sheds light on an unprecedented function of Droj2 and Arf102F in neuronal development.

L1CAM Is Not a Predictive Factor in Early-stage Squamous-cell Cervical Cancer.

AIM: Our study aimed to assess expression of L1 cell adhesion molecule (L1CAM) in early-stage cervical squamous-cell cancer as a prognostic factor. PATIENTS AND METHODS: This retrospective, single-institution study included 154 patients who underwent radical hysterectomy for early-stage squamous cell cervical cancer between 2007 and 2017. Tumor samples from 154 patients were available for L1CAM analysis by immunohistochemistry. Among all patients, radical abdominal hysterectomy was performed in 144 cases. RESULTS: L1CAM expression was positive in 24 tumors (15.6%) of the whole group. In relation to the grade of differentiation and the presence of lymphovascular invasion, L1CAM expression did not show an association (p=0.154 and p=0.306, respectively). The disease-free interval and overall survival also did not significantly differ between L1CAM-positive and L1CAM-negative cases (p=0.427 and p=0.240, respectively). For histopathological characteristics, L1CAM-positive cases had a significantly higher median tumor size (p=0.015). Even in the selected group of 115 cases without nodal infiltration, L1CAM status had no effect on the relapse rate during follow-up. CONCLUSION: Our study did not confirm the results of previous studies showing L1CAM expression to be a negative prognostic factor in cervical cancer. In our study, increased L1CAM expression in early-stage squamous-cell cervical cancer was not associated with adverse prognosis regarding disease recurrence, disease-free survival, nor overall survival. L1CAM expression was correlated only with the size of the tumor.

Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta-Analysis.

Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development. Proteins and molecular material from any organ, including the central nervous system, can be packed into EVs and transported to the periphery into easily obtainable biological specimens like blood, urine, and saliva. We performed a systematic review and meta-analysis of articles (published before November 15, 2022) reporting biomarker assessment in EVs in PD patients and healthy controls (HCs). Biomarkers were analyzed using random effects meta-analysis and the calculated standardized mean difference (Std.MD). Several proteins and ribonucleic acids have been identified in EVs in PD patients, but only α-synuclein (aSyn) and leucine-rich repeat kinase 2 (LRRK2) were reported in sufficient studies (n = 24 and 6, respectively) to perform a meta-analysis. EV aSyn was significantly increased in neuronal L1 cell adhesion molecule (L1CAM)-positive blood EVs in PD patients compared to HCs (Std.MD = 1.84, 95% confidence interval = 0.76-2.93, P = 0.0009). Further analysis of the biological sample and EV isolation method indicated that L1CAM-IP (immunoprecipitation) directly from plasma was the best isolation method for assessing aSyn in PD patients. Upcoming neuroprotective clinical trials immediately need peripheral biomarkers for identifying individuals at risk of developing PD. Overall, the improved sensitivity of assays means they can identify biomarkers in blood that reflect changes in the brain. CNS-derived EVs in blood will likely play a major role in biomarker development in the coming years. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.