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self-assembling protein nanocarrier for selective delivery of cytotoxic polypeptides to CXCR4^(+) head and neck squamous cell carcinoma tumors

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Acta Pharmaceutica sinica B 2022年第5期12卷 2578-2591页

作者： Elisa Rioja-Blanco Irene Arroyo-solera Patriciaálamo Isolda Casanova Alberto Gallardo Ugutz Unzueta Naroa serna laura sánchez-garcía.miquel quer Antonio Villaverde Esther Vázquez Ramon Mangues Lorena Alba-Castellón Xavier León Institut d'InvestigacióBiomèdica sant Pau(IIB-sant Pau) Barcelona 08041Spain Institut de Recerca contra la Leucèmia Josep Carreras Barcelona 08025Spain CIBER de Bioingeniería Biomateriales y Nanomedicina(CIBER-BBN)Madrid 28029Spain Department of Pathology Hospital de la Santa Creu i Sant PauBarcelona 08041Spain Institut de Biotecnologia i de Biomedicina Universitat Autònoma de BarcelonaBellaterra 08193Spain Departament de Genètica i de Microbiologia Universitat Autònoma de BarcelonaBellaterra 08193Spain Department of Otorhinolaryngology Hospital de la Santa Creu i Sant PauBarcelona 08041Spain

Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma(HNsCC) mortality. The overexpression of chemokine receptor 4(CXCR4) in HNsCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4^(+)tumors in a HNsCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4^(+)HNsCC cells, achieving a high accumulation in CXCR4^(+)tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4^(+)cells in HNsCC. Remarkably, to our knowledge, this is the first study testing targeted proteinonly nanoparticles in this cancer type, which may represent a novel treatment approach for HNsCC patients.

关键词： Targeted drug delivery Protein nanoparticles CXCR4 receptor HNsCC Cell targeting Recombinant proteins Nanotoxins Cancer therapy

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Chinese Multinationals and Entry Mode Choice： Institutional, Transaction and Firm-specific Factors

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Frontiers of Business Research in China 2012年第1期6卷 1-24页

作者： Diego quer Enrique Claver laura Rienda Department of Management University of Alicante Alicante 03690 Sant Spain

Foreign direct investment （FDI） ownership decision is one of the most researched topics in the international business literature. However, little is known about the extent to which this knowledge can be applied to emerging-economy multinationals. Building on the institutional, transaction cost and resource-based view perspectives, this paper analyzes the determining factors of FD! mode choice between wholly-owned subsidiary （WOs） and joint venture （JV） by Chinese firms. Based on a sample of 139 outward FDI decisions made by large Chinese firms between 2002 and 2009, our results show certain characteristics that differ from the conventional wisdom of the multinational enterprise （MNE）. A host country＇s political risk and cultural distance do not affect FDI ownership decisions of Chinese MNEs, while firm size is negatively related with WOs. However, from a more conventional point of view, technological intensity of the industry is positively associated with WOs.

关键词： FDI ownership decision Chinese firms determining factors

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The Janus face of N-terminal lysines in α-synuclein

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Neural Regeneration Research 2020年第10期15卷 1840-1841页

作者： Ana Belén Uceda laura Mari?o miquel Adrover Institut Universitari d’Investigació en Ciències de la salut (IUNICs) Institut d’Investigació Sanitària Illes Balears (Id ISBa) Departament de Química Universitat de les Illes Balears

Parkinson’s disease(PD)is the second most prevalent progressive neurodegenerative disorder after Alzheimer’s *** usually starts with a tremor in the extremities(usually in the hands)and gradually evolves with other symptoms such as bradykinesia,muscle stiffness,impaired posture,loss of automatic movements or speech *** symptoms worsen as the condition progresses and eventually lead to death.

关键词： impaired Alzheimer eventually

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Melatonin in the seasonal response of the aphid Acyrthosiphon pisum

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Insect science 2020年第2期27卷 224-238页

作者： miquel Barbera laura Escriva Jorge Mariano Collantes-Alegre Giuseppe Meca Ezio Rosato David Martinez-Torres Institut de Biologia Integrativa de sistemes&Institut Cavanilles de Biodiversitati Biologia Evolutiva Parc Cientific Universitat de ValenciaC/Catedmtico Jose Beltran n°246980PaternaValenciaSpain Laboratory of Food Chemistry and Toxicology Faculty of PharmacyUniversitat de ValenciaBurjassotSpain Department of Genetics University of LeicesterLeicesterLE17RHUK

Aphids display life cycles largely determined by the *** the warm long-day *** aphid species reproduce by viviparous *** shortening of the photoperiod in autumn induces a switch to sexual *** and sexual females mate to produce overwintering resistant *** addition to this full life cycle(holocycle),there are anholocyelic lineages that do not respond to changes in photoperiod and reproduce continuously by *** molecular or hormonal events that trigger the scasonal response(i.c,induction of the sexual phenotypes)are still *** circadian synthesis of melatonin is known to play a key role in vertebrate photoperiodism,the involvement of the circadian clock and/or of the hor-mone melatonin in insect seasonal responses is not so well *** we show that melatonin levels in the aphid Acyrthosiphon pisum are significantly higher in holocyclice aphids reared under short days than under long days,while no differences were found between anholoeyelic aphids under the same *** also found that melatonin is localized in the aphid suboesophageal ganglion(sOG)and in the thoracic ganglionic mass(TGM).In analogy to vertcbrates,insect-type arylalkxylamine N-acetyltransferases(i-AANATs)are thought to play a key role in melatonin *** measured the expression of four I-AANAT genes identified in *** and localized two of them in situ in the insect central nervous systems(CNs).Levels of expression of these genes were compatible with the quantities of melatonin ***,like melatonin,expression of these genes was found in the sOG and the TGM.

关键词： AANAT aphid in situ hybridization melatonin photoperiodism quantification

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Cost-effectiveness of enhanced liver fibrosis test to assess liver fibrosis in chronic hepatitis C virus and alcoholic liver disease patients

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World Journal of Gastroenterology 2017年第17期23卷 3163-3173页

作者： Marcelo soto laura sampietro-Colom Luis Lasalvia Aurea Mira Wladimiro Jiménez miquel Navasa FundacióClínic per a la Recerca Biomèdica Health Technology Assessment Unit Hospital Clínic siemens Healthcare Department of Clinical Microbiology Hospital Clínic Department of Biomedicine University of Barcelona IDIBAPs7.Liver Unit Hospital Clínic

AIM To assess liver fibrosis(LF) in hepatitis C virus(HCV) and alcoholic liver disease(ALD), estimate health outcomes and costs of new noninvasive testing strategies METHODs A Markov model was developed to simulate LF progression in HCV and ALD for a cohort of 40-yearold men with abnormal levels of transaminases. Three different testing alternatives were studied: a single liver biopsy; annual Enhanced liver fibrosis(ELF?) followed by liver stiffness measurement(LsM) imaging as a confirmation test if the ELF test is positive; and annual ELF test without LsM. The analysis was performed from the perspective of a university hospital in *** data were obtained from published literature. Costs were sourced from administrative databases of the hospital. Deterministic and probabilistic sensitivity analyses were *** In HCV patients, annual sequential ELF test/LsM and annual ELF test alone prevented respectively 12.9 and 13.3 liver fibrosis-related deaths per 100 persons tested, compared to biopsy. The incremental costeffectiveness ratios(ICERs) were respectively €13400 and €11500 per quality-adjusted life year(QALY). In ALD, fibrosis-related deaths decreased by 11.7 and 22.1 per 100 persons tested respectively with sequential ELF test/LsM and annual ELF test alone. ICERs were €280 and €190 per QALY, *** The use of the ELF test with or without a confirmation LsM are cost-effective options compared to a single liver biopsy for testing liver fibrosis in HCV and ALD patients in spain.

关键词： Cost-effectiveness analysis Liver fibrosis Noninvasive diagnostic assessment Alcoholic liver disease Hepatitis C

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Chinese Outward Foreign Direct Investment： A Review of Empirical Research

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Frontiers of Business Research in China 2015年第3期9卷 326-370页

作者： Diego quer Enrique Claver laura Rienda 1. Department of Management University of Alicante Alicante 03080 Spain2. Department of Management University of Alicante Alicante 03080 Spain3. Department of Management University of Alicante Alicante 03080 Spain

In the past decade, Chinese outward foreign direct investment （OFDI） has become a major element of global capital flows. As a consequence, recent years have witnessed an increasing growth in the number of papers focusing on Chinese companies ＂going global.＂ This paper reviews 112 empirical papers focusing on Chinese OFDI that were published in major scholarly journals between 2002 and 2014. We report on individual and institutional contributions, citations, the theories and methods used and the research topics. We also identify the research gaps and discuss the implications of our literature review for future theory building.

关键词： Chinese outward foreign direct investment (OFDI) literature review,empirical papers

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Current trends in access to treatment for hepatitis B in immigrants vs non-immigrants

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Gastroenterology Report 2020年第5期8卷 362-366,I0002页

作者： Mireia.miquel Albert Pardo Montse Forné Gemma Martínez-Alpin AdriàRodríguez-Castellano Meritxell Casas MercèRosinach MercèRoget Blai Dalmau Rocío Temiño Joan Carlos quer Jordi sanchez-Delgado Jordi Ortiz Mercedes Vergara Liver Unit Gastroenterology DepartmentParc TaulíUniversity HospitalInstitut d’Investigacio i InnovacióParc TaulíI3PTAutonomous University of BarcelonaSabadellSpain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas(CIBERehd) Instituto de Salud Carlos IIIMadridSpain Gastroenterology Department University Hospital Joan XXIIITarragonaSpain Liver Unit Gastroenterology DepartmentUniversity Hospital Mútua TerrassaBarcelonaSpain Liver Unit Gastroenterology DepartmentConsorci Sanitari de TerrassaTerrassaSpainó

Background:Universal vaccination for hepatitis B virus(HBV)and migratory movements have changed the demographic characteristics of this disease in spain and in ***,we evaluated the characteristics of the disease and the possible differences according to origin(immigrants vs non-immigrants)and access to ***:This is a multicenter cross-sectional study(June 2014 to May 2015)in which outpatients with a positive HBsAg were seen and followed in four Hepatology *** and clinical data and indication and access to treatment were collected in two different regions of Catalonia(spain)where there are no barriers to treatment due to a comprehensive coverage under the National Health ***:A total of 951 patients were evaluated(48.1%men).Of these,46.6%were immigrants(58.7%of them were born in Africa)and were significantly younger compared to *** proportions of patients with alcohol consumption,being overweight,and other indicators of metabolic co-morbidities were significantly higher in *** the 937 patients receiving HBeAg examination,91.7%were *** HBeAg-positive infection was significantly higher in immigrants(3.9%vs 0.6%,P=0.001)and chronic HBeAg-negative hepatitis was higher non-immigrants(31.7%vs 21.4%,Ps the proportion of patients who met treatment criteria significantly higher among nonimmigrants(38.4%vs 29.2%,P=0.003),but also the proportion of those with indication of effectively receiving therapy at the time of data collection(83.2%vs 57.8%,Psions:The immigrant population with HBV is younger and has a lower prevalence of metabolic co-morbidities and a higher frequency of chronic HBeAg *** having access to care and an indication for treatment,some do not get adequately treated due to several factors including local adaptation that precludes access to treatment.

关键词： hepatitis B prevalence immigration access to treatment

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New real-time-PCR method to identify single point mutations in hepatitis C virus

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World Journal of Gastroenterology 2016年第43期22卷 9604-9612页

作者： Qian Chen Irene Belmonte Maria Buti Leonardo Nieto Damir garcia-Cehic Josep Gregori Celia Perales laura Ordeig Meritxell Llorens Maria Eugenia soria Rafael Esteban Juan Ignacio Esteban Francisco Rodriguez-Frias Josep quer Liver Unit Internal Medicine Lab. Malalties Hepàtiques Vall d’Hebron Institut Recerca-Hospital Universitari Vall d’ Hebron08035 Barcelona Spain Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas Instituto de Salud Carlos Ⅲ28029 madrid Spain Liver Pathology Unit Departments of Biochemistry and Microbiology Hospital Universitari Vall d’Hebron Autonomous University of Barcelona 08035 Bareelona Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas del Instituto de salud Carlos Ⅲ 28029 Madrid Spain Universitat Autònoma de Barcelona 08193 Bareelona Spain

AIM To develop a fast, low-cost diagnostic strategy to identify single point mutations in highly variable genomes such as hepatitis C virus(HCV).METHODs In patients with HCV infection, resistance-associated amino acid substitutions within the viral quasispecies prior to therapy can confer decreased susceptibility to direct-acting antiviral agents and lead to treatment failure and virological relapse. One such naturally occurring mutation is the Q80 K substitution in the HCV-Ns3 protease gene, which confers resistance to PI inhibitors, particularly simeprevir. Low-cost, highly sensitive techniques enabling routine detection of these single point mutations would be useful to identify patients at a risk of treatment failure. Light Cycler methods, based on real-time PCR with sequencespecific probe hybridization, have been implemented in most diagnostic laboratories. However, this technique cannot identify single point mutations in highly variable genetic environments, such as the HCV genome. To circumvent this problem, we developed a new method to homogenize all nucleotides present in a region except the point mutation of interest. REsULTs Using nucleotide-specific probes Q, K, and R substitutions at position 80 were clearly identified at a sensitivity of 10%(mutations present at a frequency of at least 10% were detected). The technique was successfully applied to identify the Q80 K substitution in 240 HCV G1 serum samples, with performance comparable to that of direct sanger sequencing, the current standard procedure for this purpose. The new method was then validated in a Catalonian population of 202 HCV G1-infected individuals. Q80 K was detected in 14.6% of G1 a patients and 0% of G1 b in our setting. CONCLUsION A fast, low-cost diagnostic strategy based on real-time PCR and fluorescence resonance energy transfer probe melting curve analysis has been successfully developed to identify single point mutations in highly variable genomes such as hepatitis C virus. This

关键词： Hepatitis C virus Resistance-associated amino acid substitutions Low-cost test single-point mutations Q80K

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sUMOylation Inhibition Mediated by Disruption of sUMO El-E2 Interactions Confers Plant susceptibility to Necrotrophic Fungal Pathogens

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Molecular Plant 2017年第5期10卷 709-720页

作者： laura Castano-miquel Abraham Mas Ines Teixeira Josep segui Anna Perearnau Bhagyasree N. Thampi Arnaldo L. schapire Natalia Rodrigo Gaelle La Verde silvia Manrique Maria Coca L. Maria Lois Center for Research in Agricultural Genomics - CRAG Edifici CRAG-Campus UAB Bellaterra (Cerdanyola del Vall~s) 08193 Barcelona Spain

Protein modification by sUMO modulates essential biological processes in eukaryotes. sUMOylation is facilitated by sequential action of the El-activating, E2-conjugating, and E3-1igase enzymes. In plants, sUMO regulates plant development and stress responses, which are key determinants in agricultural productivity. To generate additional tools for advancing our knowledge about the sUMO biology, we have developed a strategy for inhibiting in vivo sUMO conjugation based on disruption of sUMO El-E2 interactions through expression of E1 sAE2uFDct domain. Targeted mutagenesis and phylogenetic analyses revealed that this inhibition involves a short motif in sAE2uFDct highly divergent across kingdoms. Transgenic plants expressing the sAE2UFDCt domain displayed dose-dependent inhibition of sUMO conjugation, and have revealed the existence of a post-transcriptional mechanism that regulates sUMO E2 conjugating enzyme levels. Interestingly, these transgenic plants displayed increased suscep- tibility to necrotrophic fungal infections by Botrytis cinerea and Plectosphaerella cucumerina. Early after fungal inoculation, host sUMO conjugation was post-transcriptionally downregulated, suggesting that targeting sUMOylation machinery could constitute a novel mechanism for fungal pathogenicity. These findings support the role of sUMOylation as a mechanism involved in plant protection from environmental stresses. In addition, the strategy for inhibiting sUMO conjugation in vivo described in this study might be applicable in important crop plants and other non-plant organisms regardless of their genetic complexity.

关键词： sUMQ inhibition development flowering necrotrophic fungi El-activating enzyme El-E2interaction disruption

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Facial nerve palsy following parotid gland surgery:A machine learning prediction outcome approach

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World Journal of Otorhinolaryngology-Head and Neck surgery 2023年第4期9卷 271-279页

作者： Carlos M.Chiesa‐Estomba Jose A.González‐garcía Ekhiñe Larruscain Jon A.sistiaga suarez miquel quer Xavier León Paula Martínez‐Ruiz de Apodaca Celia López‐Mollá Miguel Mayo‐Yanez Alfonso Medela Department of Otorhinolaryngology—Headand Neck surgery Donostia University HospitalDonosti‐San SebastiánSpain Head&Neck study Group of Young‐Otolaryngologists of the International Federations of Oto‐rhino‐laryngological societies(YO‐IFOs) ParisFrance Biodonostia Health Research Institute San SebastiánSpain Department of Otorhinolaryngology Hospital Santa Creu I Sant PauUniversitatAutònoma de BarcelonaBarcelonaSpain Department of Otorhinolaryngology Doctor Peset University HospitalValenciaSpain Otorhinolaryngology—Head and Neck surgery Department Complexo Hospitalario Universitario A Coruña(CHUAC)A CoruñaGaliciaSpain Clinical Research in Medicine International Center for Doctorate and Advanced Studies(CIEDUS)Universidade de Santiago deCompostela(USC)Santiago de CompostelaGaliciaSpain LEGIT Health BilbaoSpain

Introduction:Machine learning (ML)‐based facial nerve injury (FNI) forecasting grounded on multicentric data has not been released up to *** distinct ML models,random forest (RF),K‐nearest neighbor,and artificial neural network (ANN),for the prediction of FNI were evaluated in this ***:A retrospective,longitudinal,multicentric study was performed,including patients who went through parotid gland surgery for benign tumors at three different university ***:seven hundred and thirty‐six patients were *** most compelling aspects related to risk escalation of FNI were as follows:(1) location,in the mid‐portion of the gland,near to or above the main trunk of the facial nerve and at the top part,over the frontal or the orbital branch of the facial nerve;(2) tumor volume in the anteroposterior axis;(3) the necessity to simultaneously dissect more than one level;and (4) the requirement of an extended resection compared to a lesser extended *** contrast,in accordance with the ML analysis,the size of the tumor (>3 cm),as well as gender and age did not result in a determining favor in relation to the risk of ***:The findings of this research conclude that ML models such as RF and ANN may serve evidence‐based predictions from multicentric data regarding the risk of ***:Along with the advent of ML technology,an improvement of the information regarding the potential risks of FNI associated with patients before each procedure may be achieved with the implementation of clinical,radiological,histological,and/or cytological data.

关键词： gland machine learning parotid personalized medicine surgery

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