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Anticancer therapeutic strategies for targeting mutant p53-Y220C

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Journal of Biomedical Research 2024年第3期38卷 222-232页

作者： Vitaly Chasov Damir Davletshin Elvina Gilyazova regina Mirgayazova Anna Kudriaeva Raniya Khadiullina Youyong Yuan Emil Bulatov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazan 420008Russia Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of SciencesMoscow 117997Russia Institute of Life Sciences School of MedicineSouth China University of TechnologyGuangzhouGuangdong 510006China

The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.

关键词： p53 Y220C mutation small molecule DNA-binding domain immunotherapy T cell receptor mimic antibody

Ca^(2+) binding to the C_(2)E domain of otoferlin is required for hair cell exocytosis and hearing

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Protein & Cell 2024年第4期15卷 305-312页

作者： Han Chen Mehar Monga Qinghua Fang Loujin Slitin Jakob Neef Shashank S.Chepurwar regina Célia Mingroni Netto Karina Lezirovitz Alfredo Tabith,Jr. Fritz Benseler Nils Brose Kathrin Kusch Carolin Wichmann Nicola Strenzke Barbara Vona Julia Preobraschenski Tobias Moser Institute for Auditory Neuroscience and InnerEarLab University Medical Center Göttingen37075 GöttingenGermany Collaborative Research Center 889 University of Göttingen37075 GöttingenGermany Auditory Neuroscience and Synaptic Nanophysiology Group Max Planck Institute for Multidisciplinary Sciences37075 GöttingenGermany Göttingen Graduate Center for Neurosciences Biophysics and Molecular BiosciencesUniversity of Göttingen37075 GöttingenGermany Biochemistry of Membrane Dynamics Group Institute for Auditory NeuroscienceUniversity Medical Center Göttingen37075 GöttingenGermany Molecular Architecture of Synapses Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Center for Biostructural Imaging of Neurodegeneration University Medical Center Göttingen37075 GöttingenGermany Auditory Systems Physiology Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Departamento de Genética e Biologia Evolutiva Centro de Pesquisas sobre o Genoma Humano e Células-TroncoInstituto de BiociênciasUniversidade de São PauloSão Paulo 05508-220Brazil Laboratório de Otorrinolaringologia/LIM32 Faculdade de MedicinaHospital das ClínicasUniversidade de São PauloSão PauloSP 05508-220Brazil DERDIC Pontifícia Universidade Católica de São PauloSão Paulo 05508-220Brazil Department of Molecular Neurobiology Max Planck Institute for Multidisciplinary Sciences37075 GöttingenGermany Multiscale Bioimaging Cluster of Excellence(MBExC) University of Göttingen37075 GöttingenGermany Functional Auditory Genomics Group Auditory Neuroscience and Optogenetics LaboratoryGerman Primate Center37077 GöttingenGermany Hearing Genomics Group Institute for Auditory Neuroscience and InnerEarLabUniversity Medical Center Göttingen37075 GöttingenGermany Institute of Human Genetics University Medical Center Göttingen37075 GöttingenGermany

Dear Editor,Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in Supplementary Materials).Otoferlin is a key player in this machinery and its defects cause human auditory synaptopathy(Moser and Starr,2016).Otoferlin,a tail-anchored(Vogl et al.,2016)multi-C_(2)-domain protein(Fig.1Ai)specific to hair cells(Roux et al.,2006),is a member of the ferlin protein family involved in membrane trafficking and repair that are of major disease relevance(Pangršičet al.,2012),also see Supplementary Materials.Otoferlin is distributed broadly within IHCs(Fig.2Ai-Aiii;Pangrsic et al.,2010;Roux et al.,2006).

关键词： auditory hair

Combined Oxidative Phosphorylation Deficiency-20-Exome as a Diagnostic Implement

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Journal of Biosciences and Medicines 2024年第6期12卷 7-12页

作者： Paulo Roberto Matos-Neto Lucas Antonissen Lima Verde Airton Ferreira da Ponte-Filho Luís Eduardo Oliveira Matos Amandha Espavier Trés Paulo Roberto Lacerda Leal Gerardo Cristino-Filho regina Coeli de Carvalho Porto Carneiro Faculty of Medicine Federal University of Cear Sobral Cear Brazil Department of Neurosurgery Federal University of Cear Sobral Cear Brazil Department of Neuropediatrics Federal University of Cear Sobral Cear Brazil

Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.

关键词： Oxidative Phosphorylation Epilepsy Exome Mitochondrial Defect VARS2

What is driving gender inequalities in physical activity among adolescents?

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Journal of Sport and Health Science 2022年第4期11卷 424-426页

作者： regina Guthold Juana Willumsen Fiona Claire Bull Adolescent and Young Adult Health Unit MaternalNewbornChild and Adolescent Health and Ageing DepartmentWorld Health OrganizationGeneva CH-1211Switzerland Physical Activity Unit Health Promotion DepartmentWorld Health OrganizationGeneva CH-1211Switzerland

In most countries around the globe,adolescent girls are less physically active than boys.However,the majority of studies have been conducted in high-income countries,while there is less evidence from low-and middle-income countries.1 The reasons for this gender difference in physical activity(PA)participation are poorly understood.A recently published article by Ricardo et al.2 on gender inequalities in adolescent PA from 64 global south countries seeks to close this knowledge gap.

关键词： inequalities physically income

Manual and alternative therapies as non-pharmacological interventions for pain and stress control in newborns:a systematic review

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World Journal of Pediatrics 2023年第1期19卷 35-47页

作者： Leva A.Shayani Vera regina F.da S.Maraes University of Brasilia BrasiliaBrazil

Background Supporting therapies that provide stress and pain control of preterm and term newborns infants contribute positively to the neuropsychomotor development.Non-pharmacological interventions that involve manual techniques are described,considering protocols that can be reproduced by physical therapists,with positive and negative outcomes reports.Data sources Systematic review follows PRISMA 2020 statements guidelines.Primary and specific health sciences databases(Science Direct,Pubmed,Scielo,Embase and Scopus)were consulted between October 2021 and May 2022.Articles con-sidered were clinical trials,randomized or not,that included descriptions of the type of intervention as non-pharmacological and that studied the following outcomes:"pain"and"stress".Results Fifteen articles were selected for analysis,reaching a methodological quality of at least 3 on the Jadad Scale for the Quality of Researched Sources.The non-pharmacological therapies most applied in isolation were massage,swaddling or wrapping,gentle touch and kinesthetic stimulation,and the combined therapies were non-nutritive sucking and swad-dling,oral sucrose and swaddling,sensory stimulation and familiar odors,and sensory saturation.The outcomes found were relaxation,pain,and stress reduction after the application of painful procedures.The behavioral changes included crying,grimacing,yawning,sneezing,jerky arm or leg movements,startles,and finger flaring.The vital signs included heart rate,blood oxygen saturation level,and pulse respiration.Conclusions Combined techniques lead to better results in controlling neonatal pain when compared to isolated techniques.They can be applied both in preterm and term infants in a safe way and are reproducible in any health unit in a simple and economical way.

关键词： Newborn Non-pharmacological interventions Pain Premature neonate Stress

Promotional effects of Ru and Fe on Ni/ZrO_(2) catalyst during CO_(2) methanation:A comparative evaluation of the mechanism

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Journal of Energy Chemistry 2023年第11期86卷 351-361,I0008页

作者： Jie Ren Feng Zeng Chalachew Mebrahtu Zhandong Wang regina Palkovits Institute for Technical and Macromolecular Chemistry RWTH Aachen UniversityWorringerweg 252074 AachenGermany Department of Thermal Science and Energy Engineering University of Science and Technology of ChinaHeifei 230026AnhuiChina State Key Laboratory of Materials-Oriented Chemical Engineering College of Chemical EngineeringNanjing Tech UniversityNanjing 211816JiangsuChina National Synchrotron Radiation Laboratory University of Science and Technology of ChinaHefei 230029AnhuiChina

Ni-based catalysts are widely investigated non-noble metal-based systems for CO_(2)methanation.However,their industrial application is still limited due to lower activity at low-temperature and catalyst deactivation.Incorporating a second metal such as Ru and Fe is considered as a successful strategy to overcome these challenges through alloy formation or the synergies provided by the interplay of two adjacent metallic sites.Nonetheless,their promotional effect on the CO_(2)methanation mechanism under similar conditions has not been reported yet.In this work,Fe and Ru-promoted Ni/ZrO_(2)catalysts were investigated to evaluate their promotional effect on the mechanism.The Ni/Fe ratio was first optimized and a CO_(2)conversion rate of 37.7 mmolCO_(2)/(molNi+Fes)and 96.3%CH^(4)selectivity was obtained over the Ni_(0.8)Fe_(0.2)/ZrO_(2)catalyst.In comparison with Ni_(0.8)Fe_(0.2)/ZrO_(2),Ni_(0.8)Ru_(0.2)/ZrO_(2)prepared with the same composition showed higher activity and stability in CO_(2)methanation.Characterization results indicate alloys formation and H spillover for Ni_(0.8)Ru_(0.2)/ZrO_(2)to be responsible for promotion.Besides,in situ DRIFTS studies evidenced the occurrence of both CO_(2)dissociative and associative pathways over Ni_(0.8)Ru_(0.2)/ZrO_(2)catalyst,while solely the CO_(2)associative pathway occurred for Ni_(0.8)Fe_(0.2)/ZrO_(2)

关键词： Ni-based catalyst Alloy formation H spillover CO_(2) methanation Methanation mechanism

Stability and deactivation of OER electrocatalysts: A review

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Journal of Energy Chemistry 2022年第6期31卷 301-329,I0009页

作者： Feng Zeng Chalachew Mebrahtu Longfei Liao Anna Katharina Beine regina Palkovits State Key Laboratory of Materials-Oriented Chemical Engineering College of Chemical EngineeringNanjing Tech UniversityNanjing 211816JiangsuChina Institute of Technical and Macromolecular Chemistry RWTH Aachen UniversityWorringerweg 252074 AachenGermany Max Planck Institute for Chemical Energy Conversion Stiftstraße.34–3645470 Mülheim an der RuhrGermany

Recently, H_(2) has attracted increasing attention as green energy carrier holding the possibility to replace fossil fuel-based energy sources and thereby reduce CO_(2) emissions. Green hydrogen can be generated by water electrolysis using renewable energies like wind and solar power. When it is combusted, only water forms as by-product. However, the efficiency of water electrolysis is hampered by the anodic oxygen evolution reaction(OER) because of the slow kinetics which leads to a high overpotential. Therefore, many catalysts have been developed for OER to facilitate the kinetics and reduce the overpotential. In addition to electrocatalytic activity, the stability of the catalysts is imperative for industrial application and has been intensively studied. In this review, we cover recent findings on the stability and deactivation mechanisms of OER catalysts. We discuss the correlation between OER activity and stability, methodologies and experimental techniques to study the stability and deactivation as well as the deactivation mechanisms, together with factors influencing stability. Furthermore, strategies for stabilizing and regenerating OER catalysts as well as methods to predict stability are summarized. Finally, the review highlights emerging methodologies yet to be explored and future directions of stability studies and the design of highly stable OER catalysts.

关键词： Oxygen evolution OER Stability Durability Deactivation

Periprosthetic knee joint infection caused by Brucella melitensis which was first-osteoarticular brucellosis or osteoarthrosis:A case report

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World Journal of Clinical Cases 2023年第3期11卷 677-683页

作者： Thomas Stumpner regina Kuhn Josef Hochreiter Reinhold Ortmaier Department of Orthopaedic Surgery Ordensklinikum Linz Barmherzige SchwesternLinz 4010Austria

BACKGROUND Brucellosis is the most common zoonosis worldwide and is endemic in the Middle East,Africa,Asia,and Latin America.However,it is uncommon in Central Europe,and periprosthetic infections caused by Brucella are therefore rare.Due to the low prevalence and nonspecific clinical presentation of the disease,accurate diagnosis can be challenging;no gold standard currently exists for treating brucellosis.CASE SUMMARY Here,we present a 68-year-old Afghan woman living in Austria with a periprosthetic knee infection caused by Brucella melitensis.The interval from total knee arthroplasty to septic loosening was five years.A profound medical history and examinations suggested that the patient had been suffering from unrecognized chronic osteoarticular brucellosis prior to total knee arthroplasty.She was successfully treated by two-stage revision surgery and combined antibiotic therapy over three months.CONCLUSION Clinicians should consider brucellosis as a possible cause of chronic arthralgia and periprosthetic infection in patients originating from countries with a high brucellosis burden.

关键词： Brucellosis Arthroplasty Infection Osteoarticular Knee Case report

Genetic analysisofsuicide:asamplestudyinTuscany(CentralItaly)

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Forensic Sciences Research 2022年第4期7卷 790-797页

作者： Martina Focardi Barbara Gualco Vilma Pinchi Norelli Gian-Aristide regina Rensi Elisabetta Pelo Ilaria Carboni Ugo Ricci Division of Genetic Diagnostics University Hospital“Careggi”FlorenceItaly

Many studies have examined the genetic contribution to suicide.However,data on suicide in the Italian population are scarce.We therefore aimed to address this gap by investigating a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence,Italy between 2007 and 2017.This cohort included 86 men and 25 women.DNA samples were obtained from tissues or blood,and 22 genes from multiple neurobiological pathways previously shown to be associated with the pathogenesis of suicide were analysed.Next-generation sequencing was used to compare these gene sequences with those from a large,normal population.In this study,we identified 19 gene variants that were present at significantly lower frequencies in our Italian cohort than in the general population.In addition,four missense mutations were identified in four different genes:Monoamine Oxidase A(MAOA),5-Hydroxytryptamine Receptor 2 A(HTR2A),Sodium Voltage-Gated Channel Alpha Subunit 8(SCN8A),and Nitric Oxide Synthase 3(NOS3).Our study identified several potential genetic links with suicide in a cohort of Italians and supports a relationship between specific genetic variants and suicidal behaviour in this population.

关键词： Forensic sciences forensic genetics suicide MAOA HTR2A SCN8A NOS3