Using a Geosocial Networking App to Investigate New HIV Infections and Related Risk Factors Among Student and Nonstudent Men Who Have Sex With Men in Chengdu, China: Open Cohort Study.

BACKGROUND: In China, condomless sex among men who have sex with men (MSM) is the primary route of HIV infection in young people. Chengdu is a hotspot for reported HIV cases among young people nationwide. Extensive use of geosocial networking (GSN) smartphone apps has dramatically changed the pattern of sexual behavior among young MSM (YMSM). However, data on HIV incidence and the risk behavior of YMSM using the GSN app are still obscure. OBJECTIVE: This study aims to analyze and understand the HIV incidence and its risk factors among YMSM using GSN apps in Chengdu, China. METHODS: An open cohort study was conducted among YMSM aged 18-24 years through a gay GSN smartphone app in Chengdu, China, from July 2018 to December 2020. Every participant completed a web-based questionnaire on sociodemographic characteristics, sexual behaviors, and other related statuses; made a reservation for a web-based HIV testing; and then voluntarily got tested at the designated testing site. At least one additional HIV test was taken via the app during the study period, and participants were evaluated at the end of the study or at the time of HIV seroconversion. By dividing the sum of the observed HIV seroconversions by the observed person-years, HIV incidence was calculated and compared between the student and nonstudent MSM. Univariate and multivariate (Cox proportional hazards regression) analyses were used to discuss the risk factors for new HIV infections. RESULTS: In the study cohort, 24 seroconversions occurred among 625 YMSM who took at least two HIV tests through the app during the study period, contributing to 505 observed person-years. The HIV incidence rate per 100 person-years was 4.75 (95% CI 2.89-6.61) among all MSM, 3.60 (95% CI 1.27-5.93) among student MSM, and 5.88 (95% CI 2.97-8.79) among nonstudent MSM. In addition, the HIV incidence per 100 person-years was 11.11 (95% CI 4.49-17.73) among those who had resided in the area for 6 months or less and 7.14 (95% CI 1.52-12.77) among those with senior high school or less education. Two or more sexual partners (adjusted hazards ratio [HR] 3.63, 95% CI 1.08-12.23) in the preceding 6 months was a risk factor for new HIV infections. Consistent condom use for anal sex (adjusted HR 0.38, 95% CI 0.16-0.88) and insertive anal sex only (adjusted HR 0.10, 95% CI 0.01-0.75) in the preceding 6 months were protective factors for new HIV infections. CONCLUSIONS: The rate of new HIV infections among YMSM who actively used GSN smartphone apps was high, especially among migrant nonstudent MSM. Targeted interventions on GSN smartphone apps should be implemented to provide demand-adapted prevention and services to reduce the threat of HIV.

Deletions in GSN gene associated with growth traits of four Chinese cattle breeds.

The aim of this study was to assess the potential of 21 bp mutation in the second intron of the GSN gene as a molecular marker-assisted by exploring the effect of 21 bp mutation on growth traits in four beef cattle breeds. Gelsolin (GSN), a member of the superfamily of gel proteins, is involved in the regulation of a variety of cellular activities in the organism and plays an important function in cell motility, apoptosis, signal transduction and inflammatory responses. Gelatin can not only negatively regulate the pro-apoptotic effect of P53 protein, but also promote apoptosis by blocking the interaction between actin and deoxyribonuclease, so, the GSN gene was selected as a candidate gene in this study. In this study, a 21 bp mutation on the second intron to the GSN gene was verified in 573 individuals of Yunling (YL, n = 220), Jiaxian (JX, n = 140), Xianan (XN, n = 114) and Qinchuan (QC, n = 97) cattle breeds using Once PCR and agarose gel electrophoresis. The association analysis of polymorphisms in the GSN gene with growth traits in four breeds was revealed: in YL cattle, the heart girth and forehead size of heterozygous ID genotype were significantly higher than II genotype (P < 0.05). In JX cattle, the withers height, body length and heart girth of II and ID genotype were significantly highest than DD genotype (P < 0.01); the height at hip cross and height at sacrum of II genotype was significantly highest than DD genotype (P < 0.01), but ID genotype was significantly higher than DD genotype. In XN cattle, the abdominal girth and circumference of the cannon bone of II genotype were significantly higher than ID genotype (P < 0.05). In QC cattle, the hucklebone width of ID genotype was significantly the highest than II genotype (P < 0.01). The results suggest that GSN may be an important candidate gene and that a 21 bp mutation on the second intron to the GSN gene can be used for molecular marker-assisted selection of four beef cattle breeds.

The p53 and Calcium Regulated Actin Rearrangement in Model Cells.

Long-term cellular stress maintains high intracellular Ca2+ concentrations which ultimately initiates apoptosis. Our interest is focused on how the gelsolin (GSN) and junctional mediating and regulating Y protein (JMY) play important roles in stress response. Both of these proteins can bind p53 and actin. We investigated using in vitro fluorescence spectroscopy and found that the p53 competes with actin in GSN to inhibit p53-JMY complex formation. A high Ca2+ level initializes p53 dimerization; the dimer competes with actin on JMY, which can lead to p53-JMY cotransport into the nucleus. Here we investigated how the motility and division rate of HeLa cells changes due to low-voltage electroporation of GSN or JMY in scratching assays. We revealed that JMY inhibits their motion, but that it can accelerate the cell division. GSN treatment slows down cell division but does not affect cell motility. HeLa cells fully recovered the gap 20 h after the electroporation with JMY and then started to release from the glass slides. Taken together, our in vitro results indicate that GSN and JMY may play an important role in the cellular stress response.

Plasma Gelsolin Reinforces the Diagnostic Value of FGF-21 and GDF-15 for Mitochondrial Disorders.

Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is highly relevant. Previous studies identified Gelsolin as a regulator of cell survival adaptations triggered by mitochondrial defects. Gelsolin presents a circulating plasma isoform (pGSN), whose altered levels could be a hallmark of mitochondrial dysfunction. Therefore, we investigated the diagnostic performance of pGSN for MD relative to FGF-21 and GDF-15. Using ELISA assays, we quantified plasma levels of pGSN, FGF-21, and GDF-15 in three age- and gender-matched adult cohorts: 60 genetically diagnosed MD patients, 56 healthy donors, and 41 patients with unrelated neuromuscular pathologies (non-MD). Clinical variables and biomarkers' plasma levels were compared between groups. Discrimination ability was calculated using the area under the ROC curve (AUC). Optimal cut-offs and the following diagnostic parameters were determined: sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and efficiency. Comprehensive statistical analyses revealed significant discrimination ability for the three biomarkers to classify between MD and healthy individuals, with the best diagnostic performance for the GDF-15/pGSN combination. pGSN and GDF-15 preferentially discriminated between MD and non-MD patients under 50 years, whereas FGF-21 best classified older subjects. Conclusion: pGSN improves the diagnosis accuracy for MD provided by FGF-21 and GDF-15.

Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a Novel GSN Variant p.Glu580Lys.

Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic GSN variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel GSN variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous GSN variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

Research on the Correlation of Serum PCT and Plasma GSN Levels with the Prognosis of Urosepsis Patients.

OBJECTIVE: To explore the correlation of procalcitonin (PCT) and gelsolin (GSN) with the prognosis of urosepsis patients. METHOD: The data of 71 urosepsis patients from March 2015 to April 2019 who were admitted to and treated in Affiliated Hospital of Hebei University were analyzed and compared with those of 92 healthy persons. Serum PCT and plasma GSN levels at different times after treatment were detected. According to prognosis, patients were classified into the good prognosis group or the poor prognosis group. The serum PCT and plasma GSN levels of both groups were compared. RESULT: The serum PCT level of the urosepsis group on the 1st, 3rd, 5th and 7th days was obviously higher than that of the control group (P<0.05). The plasma GSN levels of the urosepsis group on the 1st, 3rd, 5th and 7th days were obviously lower than those of the control group (P<0.05). The serum PCT level of the poor prognosis group on the 1st, 3rd, 5th and 7th days was obviously higher than that of the good prognosis group (P<0.05). The plasma GSN level of the poor prognosis group on the 1st, 3rd, 5th and 7th days was obviously lower than that of the good prognosis group (P<0.05). PCT was an independent risk factor influencing the prognosis of urosepsis patients and that GSN was a protective factor (P<0.05). CONCLUSION: The serum PCT and plasma GSN levels can accurately predict the severity and prognosis of urosepsis patients and reflect the disease state of early urosepsis patients. High PCT levels and low GSN levels indicate poor prognosis, and clinicians should consider these values.

Regulation and related mechanism of GSN mRNA level by hnRNPK in lung adenocarcinoma cells.

Gelsolin (GSN) is an actin filament-capping protein that plays a key role in cell migration. Here we show that heterogeneous nuclear ribonucleoprotein K (hnRNPK) regulates GSN expression level by binding to the 3'-untranslated region (3'UTR) of GSN mRNA in non-small cell lung cancers (NSCLC) H1299 cells which are highly metastatic and express high level of GSN. We found that hnRNPK overexpression increased the mRNA and protein level of GSN, whereas hnRNPK knockdown by siRNA decreased the mRNA and protein level of GSN in both H1299 and A549 cells, indicating a positive role of hnRNPK in the regulation of GSN expression. Furthermore, hnRNPK knockdown affected the migration ability of H1299 and A549 cells which could be rescued by ectopic expression of GSN in those cells. Conversely, GSN knockdown in hnRNPK-overexpressing cells could abort the stimulatory effect of hnRNPK on the cell migration. These results suggest that hnRNPK function in the regulation of cell migration is GSN-dependent. Taken together, these data unveiled a new mechanism of regulation of the GSN expression by hnRNPK and provides new clues for the discovery of new anti-metastatic therapy.

[Value of RNA oxidation product 8-oxo-Gsn in evaluating renal function in patients with chronic kidney disease].

Objective: To investigate the relationship of DNA oxidative product 8-oxo-dGsn and RNA oxidative product 8-oxo-Gsn with chronic kidney disease (CKD). Methods: Between January 2015 and December 2016, 146 cases of CKD (30, 30, 31, 30 and 25 cases of CKD stage 1-5, respectively) were collected in the Department of Nephrology in Beijing Hospital. Among them, 70 cases were male, accounting for 47.95%. The age distribution ranged from 21 to 88 years, with an average age of (56.43±16.79) years. Their fasting blood and morning urine were collected. The levels of 8-oxo-dGsn and 8-oxo-Gsn in plasma and urine were quantified by isotope-diluted liquid chromatography mass spectrometry (MS)/MS (ID-LC-MS/MS). Results: The urine 8-oxo-Gsn/Cr in patients with CKD stage 1-5 was (3.07±1.07) µmol/mol, (3.42±1.34) µmol/mol, (3.72±1.47) µmol/mol, (3.90±1.93) µmol/mol and (3.75±2.26) µmol/mol, respectively. The urinary 8-oxo-Gsn content in CKD stage 4 patients was significantly higher than those of other 4 stages (P<0.05). The serum/urine ratio of 8-oxo-Gsn was 0.02±0.02, 0.03±0.02, 0.06±0.04, 0.10±0.05 and 0.34±0.03, respectively, and in CKD stage 4 and 5 patients, it increased significantly, especially in CKD stage 5 cases (P<0.05). Expression of 8-oxo-Gsn had a good correlation with renal function[the Spearman 's correlation coefficient: serum 8-oxo-Gsn and serum creatinine was 0.629 (P<0.001); urine/serum 8-oxo-Gsn and eGFR was 0.799 (P<0.001); serum/urine 8-oxo-Gsn and serum/urine creatinine was 0.888 (P<0.001)]. With age increasing, CKD patients showed increased RNA oxidation, and 8-oxo-Gsn increased significantly in patients over 60 years (P<0.05). After multiple linear regression analysis, 8-oxo-Gsn was only associated with serum creatinine (ß=0.656, t=8.275, P<0.001). Conclusions: Our finding indicates that the RNA oxidation occurs in patients with renal disease, and its oxidation increased as the disease progressing. The significant increase in the ratio of plasma and urinary 8-oxo-Gsn is of great importance on evaluating renal function.

Expression, purification, and characterization of recombinant 8 kDa gelsolin fragment.

A mutation (D187N/Y) in human plasma gelsolin (GSN) leads to the generation of an 8 kDa GSN fragment (8 kDa-GSN), and consequently causes the familial amyloidosis of Finnish type. Because of its faster kinetics of amyloid formation under physiologically relevant conditions, 8 kDa-GSN is used to explore gelsolin amyloidosis and screen small molecules that can disaggregate amyloids. However, the synthetic 8 kDa-GSN is expensive, and substantial quantities of 8 kDa-GSN are needed for the screen. Here we report a study to obtain recombinant 8 kDa-GSN with high yield from Escherichia coli. Firstly, 8 kDa-GSN in fusion with Mxe GyrA intein was purified by Ni-affinity chromatography. Then 8 kDa-GSN was released by intein-mediated protein cleavage, and separated from intein by ion-exchange chromatography. The yield of 8 kDa-GSN was only 1.5 mg/L from bacterial culture in the previous report, while it was improved to 4.25 mg/L in our study. Finally, the amyloidogenic property of 8 kDa-GSN was validated by circular dichroism spectrometry and dynamic light scattering.

Gelsolin promotes cell growth and invasion through the upregulation of p-AKT and p-P38 pathway in osteosarcoma.

The gelsolin (GSN) has been involved in the regulation of tumor formation and development, but the biological role of GSN in the pathogenesis of osteosarcoma (OS) has not been well characterized. In this study, we show that high expression of GSN was observed in OS tissues and correlated with tumor size, advanced Enneking stage, and poor patient prognosis. Knockdown of GSN significantly inhibited cell proliferation and invasiveness in the OS cell lines. Furthermore, stable overexpression of GSN in OS cells resulted in a significant increase in cell growth and motility with the downregulation of p-AKT and p-P38 pathway. Finally, overexpression of GSN promoted growth of OS tumors in SCID mice. Taken together, these results provided the first evidence that GSN might contribute to OS cancer development and could be an attractive therapeutic target for patients with OS.

Gelsolin rs1078305 and rs10818524 polymorphisms were associated with risk of oral squamous cell carcinoma in a Chinese Han population.

BACKGROUND: Gelsolin (GSN) is one of the most abundant actin-binding proteins, and is involved in cancer development and progression. PATIENTS AND METHODS: A hospital-based case-control study including 201 patients with OSCC and 199 healthy controls was conducted. Seventeen single-nucleotide polymorphisms (SNPs) of GSN were investigated by Sequenom Mass ARRAY and iPLEX-MALDI-TOF technology. RESULTS: Through comparison of the 17 SNPs on GSN gene between the two groups, SNP rs1078305 and rs10818524 were verified to be significantly associated with an increased risk of OSCC. For GSN rs1078305, the TT genotype was associated with increased risk for OSCC (OR = 1.92, 95% CI = 1.11-3.32, p = 0.028). CT/TT variants were also associated with increased risk for OSCC compared to the CC genotype (OR = 1.83, 95% CI = 1.25-3.84, p = 0.032). CONCLUSION: The rs1078305 and rs10818524 SNPs of GSN were associated with increased risk for OSCC development in a Chinese Han population.

GSN synergies with actin-related transfer molecular chain to promote invasion and metastasis of HCC.

BACKGROUND: Previous studies have shown that the ability of tumor cells to move and migrate is related to the molecular chain pathway mediated by actin. This study focused on the molecular mechanism of gelsolin (GSN) as an important actin-binding protein in promoting HCC invasion and metastasis. METHODS: The relationship between GSN expression and clinical characteristics was observed by immunohistochemistry (IHC). In vitro and in vivo experiments confirmed the role of GSN in HCC metastasis. Dual-immunoprecipitation (IP), immunofluorescence (IF), western blotting, and the gelatinase activity assay were used to investigate the mechanism of GSN-promoting metastasis. PEX fusion proteins were used to intervene in the transfer molecular chain. RESULTS: Our study found that GSN promoted HCC invasion and metastasis through its synergistic effect with actin-related transfer molecular chain (actin-CD44-MMPs). Concretely, as an important binding molecule of actin, GSN activated MMP2 by interacting with MMP14. Furthermore, CD44 might be a key node in the above-mentioned mechanism. The use of MMP14 domain (PEX fusion protein) to competitively bind to CD44 helped to inhibit the activation of downstream MMP2. CONCLUSIONS: GSN played crucial roles in HCC metastatic process. An improved understanding of the multiple effects of GSN in HCC might facilitate a deeper appreciation of GSN as an important HCC regulator. The study identified GSN and its regulated transfer molecular chain as potential therapeutic targets for HCC.

Geosocial networking mobile applications use and HIV and other sexually transmitted infections among men who have sex with men in Southern China: A cross-sectional study.

Introduction: Men who have sex with men (MSM) are increasingly using geosocial networking (GSN) mobile applications (apps) to socialize in the community. Our study aimed to compare sexual behaviors between app-using MSM (app users) and non-app-using MSM (non-app users), and evaluate the association between app use and sexually transmitted infections (STIs). Methods: Eligible MSM were recruited from January to August 2017 in three metropolitan cities: Guangzhou, Shenzhen and Wuxi. A self-completed tablet-based questionnaire was collected about socio-demographic characteristics, sexual behaviors and app use. Blood samples were collected to test for HIV and syphilis. Rectal swabs taken by nurses and urine samples taken by participants themselves were collected to test for gonorrhea and chlamydia. Anogenital warts were checked by a clinician. Chi square tests and logistic regression were used to compare the prevalence of STIs and the characteristics between app users and non-app users. Results: A total of 572 MSM were included in our analysis, 59.9, 25.7, and 23.4% MSM were recruited from Guangzhou, Shenzhen, and Wuxi, respectively. The majority of participants were 20-29 years old (61.7%). 89.0% of MSM had ever used at least one GSN app, and 63.8% MSM had anal intercourse (AI) partners found via apps. Among app users, 62.7% spent <30 min on apps per day on average in the past 6 months. Compared with non-app users, app users were more likely to have an education level of college and above [adjusted OR (AOR) 3.36, 95% confidence interval (CI) 1.65-7.03], have regular sex partners (2.40, 1.16-5.19), have two or more casual sex partners (2-5: 2.90, 1.21-6.90; ≥6: 13.91, 3.13-82.90), have condomless anal intercourse (CAI) with casual sex partners in the past 6 months (2.50, 1.28-5.04), do not know their last sex partners' HIV status (2.16, 1.13-4.21), have tested for HIV in the past year (2.09, 1.07-4.09) and be circumcised (4.07, 1.29-18.42). Prevalence of HIV (8.3 vs. 7.9%, P = 0.93), syphilis (6.9 vs. 11.1%, P = 0.34), gonorrhea (5.1 vs. 6.3%, P = 0.90), chlamydia (18.5 vs. 12.7%, P = 0.36), and anogenital warts (4.9 vs. 4.8%, P = 1.00) were similar between app users and non-app users. Conclusions: GSN app users were more likely to have high-risk sexual behaviors, but the prevalence of HIV and other STIs were similar to non-app users. Longitudinal studies comparing the incidence of HIV/STIs between long-term app users and non-app users may be necessary to clarify the impact of app use on HIV/STIs risk.

Gelsolin: A comprehensive pan-cancer analysis of potential prognosis, diagnostic, and immune biomarkers.

Introduction: Gelsolin (GSN), a calcium-regulated actin-binding protein, is out of balance in various cancers. It can mediate cytoskeletal remodeling and regulate epithelial-mesenchymal conversion (EMT), but the studies on GSN function in pan-cancer are limited. Methods: We studied the transcription level, prognostic impact, diagnostic value, genetic, epigenetic modification, methylation level and immune significance of GSN in pan-cancer to fully comprehend the function of GSN in various malignancies based on multiple databases like The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Results: Pan-cancer research showed that GSN was downregulated in most tumors and expressed differently in immunological and molecular subtypes of many cancers. GSN had varying impacts on the prognosis of various tumor types. However, all had moderate to high diagnostic efficiency, and serum GSN had good diagnostic value in breast cancer patients (AUC = 0.947). Moreover, GSN was a distinguishing prognosis factor for some specific cancer types. The GSN protein was hypophosphorylated, and its promoter was hypermethylated in most cancers. GSN was linked to the infiltration level of several immunity cells and was essential in anti-tumor immune cell infiltration. KEGG and GSEA analyses showed that GSN was vital in the functions and proteoglycans processes in cancer, chemokine signaling pathway and other immune-related pathways, DNA methylation and cell cycle. Discussion: In conclusion, GSN possesses the ability to be a predictive, diagnostic, and immune indicator in pan-cancer.

Fusion of the High-mobility Group AT-Hook 2 (HMGA2) and the Gelsolin (GSN) Genes in Lipomas With t(9;12)(q33;q14) Chromosomal Translocation.

BACKGROUND/AIM: Lipomas are benign tumors composed of mature fat cells. They are common soft tissue tumors that often carry chromosome aberrations involving 12q14 resulting in rearrangements, deregulation, and generation of chimeras of the high-mobility group AT-hook 2 gene (HMGA2) which maps in 12q14.3. In the present study, we report the finding of t(9;12)(q33;q14) translocation in lipomas and describe its molecular consequences. MATERIALS AND METHODS: Four lipomas from two male and two female adult patients were selected because their neoplastic cells carried a t(9;12)(q33;q14) as the sole karyotypic aberration. The tumors were investigated using RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing techniques. RESULTS: RNA sequencing of a t(9;12)(q33;q14)-lipoma detected an in-frame fusion of HMGA2 with the gelsolin gene (GSN) from 9q33. RT-PCR together with Sanger sequencing confirmed the presence of an HMGA2::GSN chimera in the tumor as well as in two other tumors from which RNA was available. The chimera was predicted to code for an HMGA2::GSN protein which would contain the three AT-hook domains of HMGA2 and the entire functional part of GSN. CONCLUSION: t(9;12)(q33;q14) is a recurrent cytogenetic aberration in lipomas and generates an HMGA2::GSN chimera. Similar to what is seen in other rearrangements of HMGA2 in mesenchymal tumors, the translocation physically separates the part of HMGA2 encoding AT-hook domains from the gene's 3'-terminal part which contains elements that normally regulate HMGA2 expression.

2D-DIGE-MS Proteomics Approaches for Identification of Gelsolin and Peroxiredoxin 4 with Lymph Node Metastasis in Colorectal Cancer.

BACKGROUND/AIMS: A combination of fluorescence two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry approach was used to search for potential markers for prognosis and intervention of colorectal cancer (CRC) at different stages of lymph node metastasis (LMN). This quantitative proteomic survey aimed to investigate the LNM-associated proteins and evaluate the clinicopathological characteristics of these target proteins in CRC from stage I to stage IV. METHODS: Sixteen CRC cases were categorized into paired non-LNM and LNM groups, and two-dimensional difference gel electrophoresis and MS proteome analysis were performed. Differential protein expression between non-LNM and LNM CRC was further validated in a tissue microarray, including 40 paraffin-embedded samples by immunohistochemistry staining. Moreover, a Boyden chamber assay, flow cytometry, and shRNA were used to examine the epithelial-mesenchymal transition and mechanism invasiveness of the differentially expressed proteins in DLD-1 cells and in vivo xenograft mouse model. RESULTS: Eighteen differentially expressed proteins were found between non-LNM and LNM CRC tissues. Among them, protein levels of Gelsolin (GSN) and peroxiredoxin 4 (PRDX4) were abundant in node-positive CRC. Downregulation of GSN and PRDX4 markedly suppressed migration and invasiveness and also induced cell cycle G1/S arrest in DLD-1. Mechanistically, the EGFR/RhoA/PKCα/ERK pathways are critical for transcriptional activation of histone modification of H3 lysine 4 trimethylation (H3K4me3) of GSN and PRDX4 promoters, resulting in upregulation of GSN, PRDX4, Twist-1/2, cyclinD1, proliferating cell-nuclear antigen, ß-catenin, N-cadherin, and matrix metalloprotein-9. CONCLUSIONS: GSN and PRDX4 are novel regulators in CRC lymph node metastasis to potentially provide new insights into the mechanism of CRC progression and serve as a biomarker for CRC diagnosis at the metastatic stage.

Clinical Features and Brain MRI Findings in Korean Patients with AGel Amyloidosis.

PURPOSE: AGel amyloidosis is systemic amyloidosis caused by pathogenic variants in the GSN gene. In this study, we sought to characterize the clinical and brain magnetic resonance image (MRI) features of Korean patients with AGel amyloidosis. MATERIALS AND METHODS: We examined 13 patients with AGel amyloidosis from three unrelated families. Brain MRIs were performed in eight patients and eight age- and sex-matched healthy controls. Therein, we analyzed gray and white matter content using voxel-based morphometry (VBM), tract-based spatial statistics (TBSS), and FreeSurfer. RESULTS: The median age at examination was 73 (interquartile range: 64-76) years. The median age at onset of cutis laxa was 20 (interquartile range: 15-30) years. All patients over that age of 60 years had dysarthria, cutis laxa, dysphagia, and facial palsy. Two patients in their 30s had only mild cutis laxa. The median age at dysarthria onset was 66 (interquartile range: 63.5-70) years. Ophthalmoparesis was observed in three patients. No patient presented with muscle weakness of the limbs. Axial fluid-attenuated inversion recovery images of the brain showed no significant differences between the patient and control groups. Also, analysis of VBM, TBSS, and FreeSurfer revealed no significant differences in cortical thickness between patients and healthy controls at the corrected significance level. CONCLUSION: Our study outlines the clinical manifestations of prominent bulbar palsy and early-onset cutis laxa in 13 Korean patients with AGel amyloidosis and confirms that AGel amyloidosis mainly affects the peripheral nervous system rather than the central nervous system.

A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation.

Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutants present in the G2 domain have been thoroughly characterized, leading to clarification of the functional mechanism. The molecular events underlying the pathological aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the interface between G4 and G5, are here explored for the first time. Structural studies point to destabilization of the interface between G4 and G5 due to three structural determinants: ß-strand breaking, steric hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.

3'untranslated regions (3'UTR) of Gelsolin mRNA displays anticancer effects in non-small cell lung cancer (NSCLC) cells.

RNA-based therapeutics has attracted substantial interest from both academics and pharmaceutical companies. In this study, we investigated the function and the underlying mechanism of Gelsolin (GSN) 3'UTR in NSCLC H1299 and A549 cells. We found that transfected Flag-GSN plasmids significantly increased the proliferation, migration and invasion of NSCLC cells, whereas GSN 3'UTR could suppress the promotional effect of GSN protein on the development of NSCLC in vitro. Interestingly, we observed that these in vitro anticancer effects of GSN 3'UTR was independent of the co-expression with GSN coding sequence. Moreover, transfected GSN 3'UTR affected the actin-cytoskeleton remodeling and epithelial-mesenchymal transition (EMT) processes in H1299 and A549 cells, and targeted the co-expressed proteins to the plasma membrane. Subsequently, RNA pull-down assays have been performed to identify Tra2ß protein as a GSN 3'UTR binder. We then showed that Tra2ß was important for the localized protein expression mediated by GSN 3'UTR. Taken together, our results suggested that GSN 3'UTR may exert anticancer functions in NSCLC cells through regulating the subcellular localized expression of GSN protein mediated by the interaction between GSN 3'UTR-Tra2ß.

Gelsolin Contributes to the Motility of A375 Melanoma Cells and This Activity Is Mediated by the Fibrous Extracellular Matrix Protein Profile.

Skin melanocytes reside on the basement membrane (BM), which is mainly composed of laminin, collagen type IV, and proteoglycans. For melanoma cells, in order to invade into the skin, melanocytes must cross the BM. It has been reported that changes in the composition of the BM accompany melanocytes tumorigenesis. Previously, we reported high gelsolin (GSN)-an actin-binding protein-levels in melanoma cell lines and GSN's importance for migration of A375 cells. Here we investigate whether melanoma cells migrate differently depending on the type of fibrous extracellular matrix protein. We obtained A375 melanoma cells deprived of GSN synthesis and tested their migratory properties on laminin, collagens type I and IV, fibronectin, and Matrigel, which resembles the skin's BM. We applied confocal and structured illuminated microscopy (SIM), gelatin degradation, and diverse motility assays to assess GSN's influence on parameters associated with cells' ability to protrude. We show that GSN is important for melanoma cell migration, predominantly on laminin, which is one of the main components of the skin's BM.