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PLoS One Biochemistry

Current research reports and chronological list of recent articles..




PLoS One is an international, peer-reviewed, open-access, online publication.

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Additional research articles see Current Chemistry Research Articles. Magazines with similar content (biochemistry):

 - Annual Reviews of Biochemistry,

 - Biochemical Journal,

 - Biochemistry,

 - Biochimie,

 - ChemBioChem,

 - FEBS Journal,

 - Journal of Biochemistry,

 - Trends in Biochemical Sciences.



PLoS One Biochemistry - Abstracts



Effects of arsenic on the topology and solubility of promyelocytic leukemia (PML)-nuclear bodies

by Seishiro Hirano, Osamu Udagawa

Promyelocytic leukemia (PML) proteins are involved in the pathogenesis of acute promyelocytic leukemia (APL). Trivalent arsenic (As3+) is known to cure APL by binding to cysteine residues of PML and enhance the degradation of PML-retinoic acid receptor α (RARα), a t(15;17) gene translocation product in APL cells, and restore PML-nuclear bodies (NBs). The size, number, and shape of PML-NBs vary among cell types and during cell division. However, topological changes of PML-NBs in As3+-exposed cells have not been well-documented. We report that As3+-induced solubility shift underlies rapid SUMOylation of PML and late agglomeration of PML-NBs. Most PML-NBs were toroidal and granular dot-like in GFPPML-transduced CHO-K1 and HEK293 cells, respectively. Exposure to As3+ and antimony (Sb3+) greatly reduced the solubility of PML and enhanced SUMOylation within 2 h in the absence of changes in the number and size of PML-NBs. However, the prolonged exposure to As3+ and Sb3+ resulted in agglomeration of PML-NBs. Exposure to bismuth (Bi3+), another Group 15 element, did not induce any of these changes. ML792, a SUMO activation inhibitor, reduced the number of PML-NBs and increased the size of the NBs, but had little effect on the As3+-induced solubility change of PML. These results warrant the importance of As3+- or Sb3+-induced solubility shift of PML for the regulation intranuclear dynamics of PML-NBs.
Datum: 20.05.2022


Protective effect conferred by prior infection and vaccination on COVID-19 in a healthcare worker cohort in South India

by Malathi Murugesan, Prasad Mathews, Hema Paul, Rajiv Karthik, Joy John Mammen, Priscilla Rupali

Background

The emergence of newer variants with the immune escape potential raises concerns about breakthroughs and re-infections resulting in future waves of infection. We examined the protective effect of prior COVID-19 disease and vaccination on infection rates among a cohort of healthcare workers (HCW) in South India during the second wave driven mainly by the delta variant.

Methods and findings

Symptomatic HCWs were routinely tested by RT-PCR as per institutional policy. Vaccination was offered to all HCWs in late January, and the details were documented. We set up a non-concurrent cohort to document infection rates and estimated protective efficacy of prior infection and vaccination between 16th Apr to 31st May 2021, using a Cox proportional hazards model with time-varying covariates adjusting for daily incidence. Between June 2020 and May 2021, 2735 (23.9%) of 11,405 HCWs were infected, with 1412, including 32 re-infections, reported during the second wave. 6863 HCWs received two doses of vaccine and 1905 one dose. The protective efficacy of prior infection against symptomatic infection was 86.0% (95% CI 76.7%–91.6%). Vaccination combined with prior infection provided 91.1% (95% CI 84.1%–94.9%) efficacy. In the absence of prior infection, vaccine efficacy against symptomatic infection during the second wave was 31.8% (95% CI 23.5%– 39.1%).

Conclusions

Prior infection provided substantial protection against symptomatic re-infection and severe disease during a delta variant driven second wave in a cohort of health care workers.


Datum: 20.05.2022


Expression profiles of miR3181 and miR199a in plasma and placenta of virally suppressed HIV-1 infected Cameroonian pregnant women at delivery

by Livo F. Esemu, Honore Awanakam, Dieudonne Nanfa, Michael Besong, Idriss Tsayem, Celine Nguefeu Nkenfou, Jude Bigoga, Rose Leke, Sobngwi Eugene, Lishomwa C. Ndhlovu, Gabriel Ekali Loni

Human immunodeficiency virus (HIV)-1 infection during pregnancy reduces the transplacental transfer of protective maternal antibodies needed to confer immunity during early postnatal life. However, the mediation of MicroRNA in this dysregulation is not well understood MicroRNAs 3181 and 199a have been shown to mediate neonatal Fc receptor (FcRn)-like transmembrane antibody transfer and endocytosis respectively but their expression levels in the placenta and plasma in women living with HIV have not been extensively investigated. The objective of this study was to determine how the expression levels of miR-3181 and miR-199a in the placenta and plasma are affected in women chronically infected with HIV who are on antiretroviral therapy (ART) and are virally suppressed at delivery. In this pilot case-control study, plasma and placenta biopsies were obtained from 36 (18 HIV+ and 18 HIV-) Cameroonian women at delivery. MicroRNAs 3181 and 199a expression levels were measured using RT-qPCR, data was analyzed using SPSS22.0 and R 3.60, and p values below 0.05 were considered statistically significant. All the HIV-infected women were on known ART regimens and were virally suppressed. There was no significant difference in the levels of miR-3181 (p>0.05) in the placenta and plasma amongst HIV-infected and HIV uninfected women. The expression levels of miR-199a were significantly greater in the plasma compared to the placenta of HIV+ (p = 0.00005) and HIV- (p = 0.027) women. Moreover, there was a significantly higher (p = 0.02) level of miR-199a in the plasma of women with HIV and their uninfected counterparts. Linear regression models adjusted for systolic pressure showed no significant difference (p>0.05) in the levels of miR-199a and miR-3181 in both the placenta and plasma due to HIV infection. Our findings suggest that even though ART uptake and viral suppression might help in maintaining miR3181 and miR199a levels in the placenta of women with HIV at comparative levels to those of their HIV negative counterparts, the significantly higher levels of miR-199a in the plasma of women with HIV compared to the placenta might highlight lurking systemic dangers and requires further investigation.
Datum: 20.05.2022


Mendelian randomization analysis of plasma levels of CD209 and MICB proteins and the risk of varicose veins of lower extremities

by Alexandra S. Shadrina, Elizaveta E. Elgaeva, Ian B. Stanaway, Gail P. Jarvik, Bahram Namjou, Wei-Qi Wei, Joe Glessner, Hakon Hakonarson, Pradeep Suri, Yakov A. Tsepilov

Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study. We conducted MR analysis using a fixed effects inverse-variance weighted meta-analysis of Wald ratios method. For MICB and CD209, we used data from a large-scale genome-wide association study (GWAS) for plasma protein levels (N = 3,301). For VVs, we used GWAS data obtained in the FinnGen project (N = 128,698), the eMERGE network (phase 3, N = 48,429), and the UK Biobank data available in the Gene ATLAS (N = 452,264). The data used in the study were obtained in individuals of European descent. The results for MICB did not pass criteria for statistical significance and replication. The results for CD209 passed all statistical significance thresholds, indicating that the genetically predicted increase in CD209 level is associated with increased risk of VVs (βMR (SE) = 0.07 (0.01), OR (95% CI) = 1.08 (1.05–1.10), P-value = 5.9 ×10−11 in the meta-analysis of three cohorts). Our findings provide further support that CD209 can potentially be involved in VVs. In future studies, independent validation of our results using data from more powerful GWASs for CD209 measured by different methods would be beneficial.
Datum: 20.05.2022


Impact of the twin pandemics: COVID-19 and oil crash on Saudi exchange index

by Dania AL-Najjar

This study aims to explore the effects of COVID-19 indicators and the oil price crash on the Saudi Exchange (Tadawul) Trading Volume and Tadawul Index (TASI) for the period from January 1, 2020, to December 2, 2020. The independent variable is oil price, and the COVID-19 indicators are lockdown, first and second decreases of Repo and Reverse Repo rates, Saudi government response, and cumulative deceased cases. The study adopts two phases. In the first phase, linear regression is used to identify the most influential variables affecting Trading volume and TASI. According to the results, the trading volume model is significant with an adjusted R2 of 65.5% and a standard error of 81. The findings of this model indicate a positive effect of cumulative deceased cases and first decrease of Repo and Reverse Repo rates and a negative effect of oil prices on Trading Volume. The TASI model is significant with an adjusted R2 of 86% and a standard error of 270. The results of this model indicate that lockdown and first decrease of Repo and Reverse Repo rates have a significant negative effect on TASI while the cumulative decrease in cases and oil prices have a positive effect on TASI. In the second phase, linear regression, and neural network predictors (with and without validation) are applied to predict the future TASI values. The neural network model indicates that the neural networks can achieve the best results if all independent variables are used together. By combining the collected results, the study finds that oil price has the most substantial effect on the changes in TASI as compared to the COVID-19 indicators. The results indicate that TASI rapidly follows the changes in oil prices.
Datum: 20.05.2022


Effect of airway clearance therapies on mucociliary clearance in adults with cystic fibrosis: A randomized controlled trial

by Aaron Trimble, Kirby Zeman, Jihong Wu, Agathe Ceppe, William Bennett, Scott Donaldson

Background

Cystic fibrosis (CF) is an inherited disorder causing impaired mucociliary clearance within the respiratory tract, and is associated with bronchiectasis, chronic respiratory infections, and early death. Airway clearance therapies have long been a cornerstone of management of individuals with CF, although evidence supporting their use is lacking. We designed a randomized controlled trial to quantitatively compare the effects of different forms of airway clearance on mucociliary clearance.

Methods

Three different physiotherapy methods to augment cough-clearance were studied in addition to cough-clearance alone: high-frequency chest-wall oscillating vest, oscillatory positive expiratory pressure, and whole-body vibration. We used gamma scintigraphy after inhalation of radiolabeled particles to quantify mucus clearance before, during, and after physiotherapy. As secondary endpoints, we measured concentrations of small molecules in exhaled breath that may impact mucus clearance.

Results

Ten subjects were enrolled and completed study procedures. No differences were identified between any method of airway clearance, including cough clearance alone. We did identify changes in certain small molecule concentrations in exhaled breath following airway clearance.

Conclusions

Due to the limitations of this study, we do not believe the negative results suggest a change in clinical practice with regard to airway clearance. Findings pertaining to small molecules in exhaled breath may serve as future opportunities for study.


Datum: 20.05.2022


The General Growth Tendency: A tool to improve publication trend reporting by removing record inflation bias and enabling quantitative trend analysis

by Joost L. D. Nelis, Gonçalo Rosas da Silva, Jordi Ortuño, Aristeidis S. Tsagkaris, Benny Borremans, Jana Haslova, Michelle L. Colgrave, Christopher T. Elliott

The trend of the number of publications on a research field is often used to quantify research interest and effort, but this measure is biased by general publication record inflation. This study introduces a novel metric as an unbiased and quantitative tool for trend analysis and bibliometrics. The metric was used to reanalyze reported publication trends and perform in-depth trend analyses on patent groups and a broad range of field in the life-sciences. The analyses confirmed that inflation bias frequently results in the incorrect identification of field-specific increased growth. It was shown that the metric enables a more detailed, quantitative and robust trend analysis of peer reviewed publications and patents. Some examples of the metric’s uses are quantifying inflation-corrected growth in research regarding microplastics (51% ± 10%) between 2012 and 2018 and detecting inflation-corrected growth increase for transcriptomics and metabolomics compared to genomics and proteomics (Tukey post hoc p
Datum: 20.05.2022


Differential gene expression profile of multinodular goiter

by Wenberger Lanza Daniel de Figueiredo, Eraldo Ferreira Lopes, Deborah Laredo Jezini, Lorena Naciff Marçal, Enedina Nogueira de Assunção, Paulo Rodrigo Ribeiro Rodrigues, Adolfo José da Mota, Diego Monteiro de Carvalho, Spartaco Astolfi Filho, João Bosco Lopes Botelho

Introduction

The goiter, a neglected heterogeneous molecular disease, remains a major indication for thyroidectomies in its endemic regions.

Objectives

This study analyzed differential gene expression in surgical specimens diagnosed with multi nodular and compared the data to that of thyroid tissue without multinodular goiter from patients undergoing thyroidectomy in Manaus-AM, Brazil using RNA-seq technology.

Methodology

The transcriptome information of the surgical specimen fragments with and without multinodular goiter was accessed by Illumina HiSeq 2000 New Generation Sequencing (NGS) using the RNA-seq NEBNext® Ultra RNA Library Prep Kit for Illumina®—#E7530L protocol and differential gene expression analysis.

Results

Differences were found between the gene expression profiles of the diseased tissues and those of the healthy control tissues; at least 70 genes were differentially expressed. The HOTS gene was expressed only in multinodular goiter tissues (p Conclusion

These results demonstrate that the gene expression profile of multinodular goiter is pro-tumoral and that HOTS can play a central role in multinodular goiter development.


Datum: 20.05.2022


Predicting speed of progression of lens opacification after pars plana vitrectomy with silicone oil

by Philipp Schindler, Luca Mautone, Vasyl Druchkiv, Toam Katz, Martin Stephan Spitzer, Christos Skevas

Purpose

An increasing number of posterior segment disorders is routinely managed with pars plana vitrectomy (PPV). In older, phakic patients cataract formation is expected within the first two years after surgery. For younger patients its progression is individually fluctuating. This study uses an objective quantitative measurement for lens-status-monitoring after PPV with silicone oil to derive predictions for progression and severity of post-operative lens opacification evaluated in patients with rhegmatogenous retinal detachment (RRD).

Methods

Data acquisition was performed prospectively between March 2018 and March 2021. PentacamHR® Nucleus Staging mode (PNS) was used to objectively gather data about nuclear cataracts after PPV at different time points. Data was grouped into training and test sets for a mathematical prediction model. Via backward variable selection method a mathematical formula was set up by means of which predictions about lens densitometry (LD) can be calculated.

Results

20 males [58.8%] and 14 females [41.2%] matched the inclusion criteria (mean age 50.6 years [23–75; ±12.3]). Average follow-up was 8.1 months (3,4–17.4; ±3.4). Mean baseline LD of the treated and fellow eye before surgery was 11.1% (7.7%-17.6%; ±2.0) and 11.2% (7.7%-14.8%; ±1.5), respectively. Predicted LD values by the model for five pre-selected patients closely match the observed data with an average deviation of 1.06%.

Conclusions

Using an objective parameter like LD delivered by the PentacamHR® PNS mode additionally to the patient’s age allows us to make an individual prediction for any time after PPV with silicone oil due to RRD for all ages. The accuracy of the model was stronger influenced by baseline LD as cofactor in the equation than patient’s age. The application for the prediction lens opacification [which can be accessed for free under the following link (https://statisticarium.com/apps/sample-apps/LensDensityOil/)] can help vitreoretinal surgeons for patient consultation on the possibility to combine PPV with cataract surgery.


Datum: 20.05.2022


Functional role of formate dehydrogenase 1 (FDH1) for host and nonhost disease resistance against bacterial pathogens

by Seonghee Lee, Ramu S. Vemanna, Sunhee Oh, Clemencia M. Rojas, Youngjae Oh, Amita Kaundal, Taegun Kwon, Hee-Kyung Lee, Muthappa Senthil-Kumar, Kirankumar S. Mysore

Nonhost disease resistance is the most common type of plant defense mechanism against potential pathogens. In the present study, the metabolic enzyme formate dehydrogenase 1 (FDH1) was identified to associate with nonhost disease resistance in Nicotiana benthamiana and Arabidopsis thaliana. In Arabidopsis, AtFDH1 was highly upregulated in response to both host and nonhost bacterial pathogens. The Atfdh1 mutants were compromised in nonhost resistance, basal resistance, and gene-for-gene resistance. The expression patterns of salicylic acid (SA) and jasmonic acid (JA) marker genes after pathogen infections in Atfdh1 mutant indicated that both SA and JA are involved in the FDH1-mediated plant defense response to both host and nonhost bacterial pathogens. Previous studies reported that FDH1 localizes to mitochondria, or both mitochondria and chloroplasts. Our results showed that the AtFDH1 mainly localized to mitochondria, and the expression level of FDH1 was drastically increased upon infection with host or nonhost pathogens. Furthermore, we identified the potential co-localization of mitochondria expressing FDH1 with chloroplasts after the infection with nonhost pathogens in Arabidopsis. This finding suggests the possible role of FDH1 in mitochondria and chloroplasts during defense responses against bacterial pathogens in plants.
Datum: 20.05.2022


Assessing climate change impacts on Pacific salmon and trout using bioenergetics and spatiotemporal explicit river temperature predictions under varying riparian conditions

by Andrew R. Spanjer, Andrew S. Gendaszek, Elyse J. Wulfkuhle, Robert W. Black, Kristin L. Jaeger

Pacific salmon and trout populations are affected by timber harvest, the removal and alteration of riparian vegetation, and the resulting physical changes to water quality, temperature, and associated delivery of high-quality terrestrial prey. Juvenile salmon and trout growth, a key predictor of survival, is poorly understood in the context of current and future (climate-change mediated) conditions, with resource managers needing information on how land use will impact future river conditions for these commercially and culturally important species. We used the Heat Source water temperature modeling framework to develop a spatiotemporal model to assess how riparian canopy and vegetation preservation and addition could influence river temperatures under future climate predictions in a coastal river fed by a moraine-dammed lake: the Quinault River in Washington State. The model predicted higher water temperatures under future carbon emission projections, representative concentration pathway (RCP) 4.5 and 8.5, with varying magnitude based on different riparian vegetation scenarios. We used the daily average temperature output from these scenarios to predict potential juvenile fish growth using the Wisconsin bioenergetics model. A combination of riparian vegetation removal and continued high carbon emissions resulted in a predicted seven-day average daily maximum temperature (7DADM) increase of 1.7°C in the lower river by 2080; increases in riparian shading mitigate this 7DADM increase to only 0.9°C. Under the current thermal regime, bioenergetics modeling predicts juvenile fish lose weight in the lower river; this loss of potential growth worsens by an average of 20–83% in the lower river by 2080, increasing with the loss of riparian shading. This study assess the impact of riparian vegetation management on future thermal habitat for Pacific salmon and trout under warming climates and provide a useful spatially explicit modeling framework that managers can use to make decisions regarding riparian vegetation management and its mechanistic impact to water temperature and rearing juvenile fish.
Datum: 20.05.2022


Based on network pharmacology and molecular docking to predict the mechanism of Huangqi in the treatment of castration-resistant prostate cancer

by Zesen Lin, Zechao Zhang, Xuejin Ye, Min Zhu, Zhihong Li, Yu Chen, Shuping Huang

Background

As a kind of traditional Chinese medicine, HQ is widely mentioned in the treatment of cancerous diseases in China, which has been proven to have a therapeutic effect on cancerous diseases, such as prostate cancer. To predict the specific mechanism of HQ in the treatment of CRPC, we will conduct preliminary verification and discussion based on a comprehensive consideration of network pharmacology and molecular docking.

Methods

TCMSP was used to obtain the compounds and reach the effective targets of HQ. The targets of CRPC were reached based on GeneCards database and CTD database. GO and KEGG were utilized for the analysis of overlapping targets. The software of Openbabel was used to convert the formats of ligands and reporters. In addition, molecular docking studies were performed by using the software of Autodock Vina.

Result

It can be seen from the database results that there were 87 active compounds (20 key active compounds) in HQ, and 33 targets were screened out for CRPC treatment. GO and KEGG pathway enrichment analyses identified 81 significant GO terms and 24 significant KEGG pathways. There is a difference in terms of the expression of core protein between cancer patients and healthy people. The expression of core protein in patients also has an impact on the life cycle. The results of molecular docking showed that the docking activity of drug molecules and core proteins was better.

Conclusions

It is concluded from the results of this network pharmacology and molecular docking that HQ makes a multi-target and multi-biological process, and results in the multi-channel synergistic effect on the treatment of CRPC by regulating cell apoptosis, proliferation and metastasis, which still needs further verification by experimental research.


Datum: 20.05.2022


Tetanus seroprotection among children in the Democratic Republic of the Congo, 2013–2014

by Alvan Cheng, Angie Ghanem-Uzqueda, Nicole A. Hoff, Hayley Ashbaugh, Reena H. Doshi, Patrick Mukadi, Roger Budd, Stephen G. Higgins, Christina Randall, Sue Gerber, Michel Kabamba, Guilluame Ngoie Mwamba, Emile Okitolonda-Wemakoy, Jean Jacques Muyembe-Tanfum, Anne W. Rimoin

Background

Tetanus is a potentially fatal disease that is preventable through vaccination. While the Democratic Republic of the Congo (DRC) has continued to improve implementing routine vaccination activities throughout the country, they have struggled to maintain high childhood vaccine coverage. This study aims to examine the seroprevalence of tetanus in children 6 to 59 months to identify areas for intervention and improvement of vaccination coverage.

Methods

In collaboration with the 2013–2014 Demographic and Health Survey, we assessed the seroprevalence of tetanus antibodies among children in the DRC. Dried blood spot samples collected from children 6–59 months of age were processed using a prototype DYNEX Multiplier® chemiluminescent automated immunoassay instrument with a multiplex measles, mumps, rubella, varicella and tetanus assay. Multivariable logistic regression was used to determine factors associated with tetanus vaccination and seroprotection.

Results

Overall, 36.1% of children 6–59 months of age reported receiving at least 1 dose of tetanus vaccine while 28.7% reported receiving 3 doses; tetanus seroprotection was 40%. Increasing age in children was associated with decreased tetanus seroprotection, but increased number tetanus vaccinations received. Factors related to increased tetanus seroprotection included number of children in the household, wealth index of the family, urban residence compared to rural, level of maternal education, and province and geography.

Conclusions

Our findings in this nationally representative sample indicate that serology biomarkers may help identify children who are not fully immunized to tetanus more accurately than reported vaccination. While children may be captured for routine immunization activities, as children age, decreasing seroprevalence may indicate additional need to bolster routine vaccination activities and documentation of vaccination in school aged children. Additionally, the study highlights gaps in rural residential areas and vaccination coverage based on maternal education, indicating that policies targeting maternal education and awareness could improve the coverage and seroprevalence of tetanus antibodies in the DRC.


Datum: 19.05.2022


Complete chloroplast genome of <i>Ilex dabieshanensis</i>: Genome structure, comparative analyses with three traditional <i>Ilex</i> tea species, and its phylogenetic relationships within the family Aquifoliaceae

by Ting Zhou, Kun Ning, Zhenghai Mo, Fan Zhang, Yanwei Zhou, Xinran Chong, Donglin Zhang, Yousry A. El-Kassaby, Jian Bian, Hong Chen

Ilex dabieshanensis K. Yao & M. B. Deng is not only a highly valued tree species for landscaping, it is also a good material for making kuding tea due to its anti-inflammatory and lipid-lowering medicinal properties. Utilizing next-generation and long-read sequencing technologies, we assembled the whole chloroplast genome of I. dabieshanensis. The genome was 157,218 bp in length, exhibiting a typical quadripartite structure with a large single copy (LSC: 86,607 bp), a small single copy (SSC: 18,427 bp) and a pair of inverted repeat regions (IRA and IRB: each of 26,092 bp). A total of 121 predicted genes were encoded, including 113 distinctive (79 protein-coding genes, 30 tRNAs, and 4 rRNAs) and 8 duplicated (8 protein-coding genes) located in the IR regions. Overall, 132 SSRs and 43 long repeats were detected and could be used as potential molecular markers. Comparative analyses of four traditional Ilex tea species (I. dabieshanensis, I. paraguariensis, I. latifolia and I. cornuta) revealed seven divergent regions: matK-rps16, trnS-psbZ, trnT-trnL, atpB-rbcL, petB-petD, rpl14-rpl16, and rpl32-trnL. These variations might be applicable for distinguishing different species within the genus Ilex. Phylogenetic reconstruction strongly suggested that I. dabieshanensis formed a sister clade to I. cornuta and also showed a close relationship to I. latifolia. The generated chloroplast genome information in our study is significant for Ilex tea germplasm identification, phylogeny and genetic improvement.
Datum: 19.05.2022


Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia

by Dominique F. Leitner, Evgeny Kanshin, Manor Askenazi, Yik Siu, Daniel Friedman, Sasha Devore, Drew Jones, Beatrix Ueberheide, Thomas Wisniewski, Orrin Devinsky

Background

Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways.

Methods and findings

We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4–26; n = 10, Control, mean age 13.1, range 3–45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at -9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences.

Conclusions

Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects.

Clinical trials registration

ClinicalTrials.gov NCT02451696.


Datum: 19.05.2022


 


Category: Current Chemistry Research

Last update: 28.03.2018.






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