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Pharmacokinetic drug interactions in liver disease:Anupdate

World Journal of Gastroenterology 2016年第3期22卷 1260-1278页

作者： Pietro Palatini sara de martin department of Pharmaceutical and Pharmacological Sciences University of Padova35131 PadovaItaly

Inhibition and induction of drug-metabolizing enzymes are the most frequent and dangerous drugdrug interactions. They are an important cause of serious adverse events that have often resulted in early termination of drug development or withdrawal of drugs from the market. Management of such interactions by dose adjustment in clinical practice is extremely difficult because of the wide interindividual variability in their magnitude. This review examines the genetic, physiological, and environmental factors responsible for this variability, focusing on an important but so far neglected cause of variability, liver functional status. Clinical studies have shown that liver disease causes a reduction in the magnitude of interactions due to enzyme inhibition, which is proportional to the degree of liver function impairment. The effect of liver dysfunction varies quantitatively according to the nature, reversible or irreversible, of the inhibitory interaction. The magnitude of reversible inhibition is more drastically reduced and virtually vanishes in patients with advanced hepatocellular insufficiency. Two mechanisms, in order of importance, are responsible for this reduction: decreased hepatic uptake of the inhibitory drug and reduced enzyme expression. The extent of irreversible inhibitory interactions is only partially reduced, as it is only influenced by the decreased expression of the inhibited enzyme. Thus, for appropriate clinical management of inhibitory drug interactions, both the liver functional status and the mechanism of inhibition must be taken into consideration. Although the inducibility of drugmetabolizing enzymes in liver disease has long been studied, very conflicting results have been obtained, mainly because of methodological differences. Taken together, the results of early animal and human studies indicated that enzyme induction is substantially preserved in compensated liver cirrhosis, whereas no definitive conclusion as to whether it is significantly reduced in the decompensated state of cirrhos

关键词： Pharmacokinetic interactions Enzymeinhibition Enzyme induction Liver disease Plasmaprotein binding

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pregnane X receptor and constitutive androstane receptor modulate differently CYp3A-mediated metabolism in earlyand late-stage cholestasis

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World Journal of Gastroenterology 2017年第42期23卷 7519-7530页

作者： Daniela Gabbia Arianna Dalla Pozza Laura Albertoni Roberta Lazzari Giorgia Zigiotto Maria Carrara Vincenzo Baldo Tatjana Baldovin Annarosa Floreani sara de martin department of Pharmaceutical and Pharmacological Sciences University of Padova department of Medicine General Pathology and Cytopathology UnitUniversity of Padova department of Cardiac Thoracicand Vascular SciencesHygiene and Public Health UnitUniversity of Padova department of Surgery Oncology and GastroenterologyUniversity of Padova

AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.

关键词： Cholestasis CYP3A Drug metabolism Pregnane X receptor Constitutive androstane receptor

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Multi-tissue transcriptomics of a unique monozygotic discordant twin case of severe progressive osseous heteroplasia

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Genes & Diseases 2024年第3期11卷 22-25页

作者： Alberto Gomez-Carballa Maria Jose Curras-Tuala sara Pischedda Miriam Cebey-Lopez Jose Gomez-Rial Irene Rivero-Cale Jacobo Pardo-seco Xabier Bello Sandra Viz-Lasheras Antonio Justicia-Grande Julian Montoto-Louzao Alba Camino-Mera Isabel Ferreiros-Vidal Maximo Fraga Jose RAntunez Rodolfo Gomez Federico martinon-Torres Antonio Salas Genetics Vaccines and Infections Research Group(GENVIP)Instituto de Investigacion Sanitaria de SantiagoSantiagode CompostelaGalicia 15706Spain Translational Pediatrics and Infectious Diseases Department of PediatricsHospital Clinico Universitario de Santiago de CompostelaServicio Galego de Saude(SERGAS)Galicia 15706Spain Laboratorio de Inmunologia Servicio de Andlisis ClinicosHospital Clinico Universitario de Santiago de CompostelaServicio Galego de Saude(SERGAS)Galicia 15706Spain Unidade de Xenetica Instituto de Ciencias Forenses(INCIFOR)Facultade de MedicinaUniversidade de Santiago de Compostelaand GenPoB Research GroupInstituto de Investigacion SanitariaHospital Clinico Universitario de Santiago de CompostelaServicio Galego de Saude(SERGAS)Galicia 15706Spain Musculoskeletal Pathology Group Instituto de Investigacion Sanitaria de SantiagoServicio Galego de Saude(SERGAS)Santiago de CompostelaGalicia 15706Spain department of Pathology Hospital Clinico Universitario de Santiago de Compostela(SERGAS)Galicia 15706Spain Unidad Integrada de BiobancosBiomodelos 3D y Modelos Animales IDIS(lnstituto de Investigacion Sanitaria de Santiagode Compostela)Galicia15706Spain Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias(CIBER-ES) MadridSpain

Progressive osseous heteroplasia(POH)is an ultra-rare autosomal dominant disabling disorder characterized by heterotopic ossification(HO).It is caused by heterozygous inactivating mutations in the GNAS(guanine nucleotide-binding protein alpha-stimulating activity polypeptide)gene.However,the molecular mechanisms underlying HO remain poorly understood.As a treatment for POH is not yet available,the identification of the mechanisms driving POH in affected tissues using gene expression may be of great help to underestand the molecular basis of POH and develop new therapeutic approaches.

关键词： stimulating driving asi

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Auricular embryonal rhabdomyosarcoma

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World Journal of Pediatrics 2022年第5期18卷 358-360页

作者： Javier Arredondo Montero Monica Bronte Anaut sara Hernandez-martin Juan Carlos Lopez-Gutierrez Pediatric Surgery department Complejo Hospitalario de NavarraCalle Irunlarrea 331008 PamplonaNavarraSpain Pathology department Complejo Hospitalario de NavarraPamplonaSpain Pediatric Surgery department Hospital Universitario La PazMadridSpain

A 13-month-old girl presented with a red-violaceous tumor of 13 mm in diameter on the inner side of the root of the right helix,with increased temperature and cystic consistency(Fig.1).No pulse was palpable in the lesion.An ultrasonography was performed,showing a 1.6 cm rounded lesion with well-defined margins,hypoechogenic and homogeneous,compatible with hemangioma.Empirical treatment with oral propranolol was started without improve-ment.

关键词： sarcoma ultrasonography showing

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A screen for bacterial endosymbionts in the model organisms Tribolium castaneum, T. confusum, Callosobruchus maculatus, and related species

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Insect Science 2015年第2期22卷 165-177页

作者： sara L. Goodacre Claudia Fricke Oliver Y. martin School of Biology University of Nottingham Queen's Medical Centre Nottingham NG7 2UH United Kingdom Institute for Evolution and Biodiversity University of Muenster Muenster D-48 149 Germany ETH ZOrich Experimental Ecology Institute for IntegrativeBiology D-USYS CH-8092 ZOrich Switzerland

Reproductive parasites such as Wolbachia are extremely widespread amongst the arthropods and can have a large influence over the reproduction and fitness of their hosts. Undetected infections could thus confound the results of a wide range of studies that focus on aspects of host behavior, reproduction, fitness, and degrees of reproductive isolation. This potential problem has already been underlined by work investigating the in- cidence of Wolbachia infections in stocks of the model system Drosophila melanogaster. Here we survey a range of lab stocks of further commonly used model arthropods, fo- cusing especially on the flour beetles Tribolium castaneum and Tribolium confusum, the cowpea weevil Callosobruchus maculatus and related species （Coleoptera： Tenebrionidae and Bruchidae）. These species are widespread stored product pests so knowledge of infec- tions with symbionts further has potential use in informing biocontrol measures. Beetles were assessed for infection with 3 known microbial reproductive parasites： Wolbachia, Rickettsia, Spiroplasma. Infections with some of these microbes were found in some of the lab stocks studied, although overall infections were relatively rare. The consequences of finding infections in these or other species and the type of previous studies likely to be affected most are discussed.

关键词： Coleoptera reproductive isolation reproductive parasite sexual conflict sexual selection Wolbachia

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Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

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World Journal of Gastroenterology 2010年第38期16卷 4823-4831页

作者： Inti Zlobec Francesca Molinari Vittoria martin Luca Mazzucchelli Piercarlo Saletti Rosangela Trezzi sara de Dosso Tatjana Vlajnic Milo Frattini Alessandro Lugli Institute for Pathology University Hospital Basel Institute of Pathology Division of Medical Oncology Institute of Southern Switzerland

AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and "high-grade" tumor budding was defi ned as 15 buds/high-power f ield.RESULTS: Tumor buds and K-RAS mutation both correctly classif ied 68% of patients. All patients with K-RAS mutation (n=7) or high-grade tumor budding (n=11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P=0.008)].CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting.

关键词： Anti-epidermal growth factor receptor therapy Colorectal cancer K-RAS Prognosis Tumor budding

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Trading in your spindles for blebs： the amoeboid tumor cell phenotype in prostate cancer

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Asian Journal of Andrology 2014年第4期16卷 530-535页

作者： Samantha Morley martin H Hager sara G Poilan Beatrice Knudsen Dolores Di Vizio Michael R Freeman Division of Cancer Biology and Therapeutics Departments of Surgery Medicine and Biomedical Sciences and The Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center Los Angeles CA Urological Diseases Research Center Boston Children's Hospital Boston MA department of Surgery Harvard Medical School Boston MA department of Medicine David Geffen School of Medicine University of California Los Angeles CA USA.

Prostate cancer （PCa） remains a principal cause ofmortalityin developed countries.Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor ceils reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, ＇amoeboid＇ phenotype is increasingly appreciated as relevant to human cancer.

关键词： SIGNALING COOPERATE RHO GTPASES INVASION MOTILITY MIGRATION TRANSITION PLASTICITY ROCK METASTASIS ACTIVATION

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Selective silencing of 2Cys and type-ⅡB Peroxiredoxins discloses their roles in cell redox state and stress signaling

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Journal of Integrative Plant Biology 2015年第6期57卷 591-601页

作者： Patrícia Vidigal Ana Montserrat martin-Hernandez Cèlia Guiu-Aragonés sara Amncio Luísa Carvalho departamento de Recursos Naturais Ambiente e Território (DRAT)/Centro de Botanica Aplicada à Agricultura (CBAA)Institute of AgronomyUniversity of Lisbon Institut de Recercai Tecnologia Agroalimentàries (IRTA) Centre for Research in Agricultural Genomics (CSIC-IRTA-UAB-UB) Campus Universitat Autonoma de Barcelona (UAB)Edificio Center for Research in Agricultural Genomics (CRAG)

Peroxiredoxins （Prx） catalyse the reduction of hydrogen peroxide （H2O2） and, in association with catalases and other peroxidases, may participate in signal transduction by regulating intercel ular H2O2 concentration that in turn can control gene transcription and cel signaling. Using virus-induced-gene-silencing （VIGS）, 2-Cys Peroxiredoxin （2CysPrx） family and type-II Peroxiredoxin B （PrxI B） gene were silenced in Nicotiana benthamiana, to study the impact that the loss of function of each Prx would have in the antioxidant system under control （22℃） and severe heat stress conditions （48 ℃）. The results showed that both Prxs, although in different organel es, influence the regeneration of ascorbate to a significant extent, but with different purposes. 2CysPrx affects abscisic acid （ABA） biosynthesis through ascorbate, while PrxIIB does it probably;through the xanthophyl cycle. Moreover, 2CysPrx is key in H2O2 scavenging and in consequence in the regulation of ABA signal-ing downstream of reactive oxygen species and PrxIIB provides an important assistance for H2O2 peroxisome scavenges.

关键词： 2-Cys Peroxiredoxin abscisic acid ascorbate heat stress hydrogen peroxide peroxisome type-Ⅱ Peroxiredoxin B

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Ocular Toxoplasmosis: A Case Report

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International Journal of Clinical Medicine 2013年第1期4卷 1-4页

作者： sara Ortiz Raul martin Victoria de Juan Optometry Research Group IOBA-Eye Institute University of Valladolid Valladolid Spain

Report a case of a male patient with a macular scar compatible with ocular toxoplasmosis (OT) in right eye (RE) and review the relevant literature on this disease. A patient, who attended for a routine contact lens follow up, presented with amblyopic exotropia without any ocular disease. Best-corrected visual acuity of the affected eye was 20/40 with constant and mono-fixation exotropia. Ophthalmoscopic assessment revealed a macular scar compatible with OT. OT is the leading cause of infection in the posterior segment. Inactive cases could be asymptomatic and diagnosis requires a complete eye examination, providing a correct diagnosis and patient management.

关键词： Toxoplasmosis Retinochoroiditis Ophthalmoscopy Posterior Uveitis

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Biochar and sugar cane filter cake interaction on physical and hydrological soil properties under tropical field conditions

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Biochar 2020年第2期2卷 195-210页

作者： sara de Jesus Duarte Bruno Glaser Blanca Lucia Prado Pano Carlos Eduardo Pellegrino Cerri Soil and Plant Nutrition Luiz de Queiroz College of AgricultureUniversity of São PauloAvenida Pádua Dias11-AgronomiaPiracicabaSP 13418-900Brazil Soil Biogeochemistry Martin Luther University Halle-WittenbergVon-Seckendorff-Platz 306120 HalleGermany Instituto de Geología Universidad Nacional Autónoma de MéxicoMéxicoD.F.Mexico

Biochar is known for its effects on carbon sequestration and soil fertility.However,there is a lack of information about its effects on soil physical and hydraulic properties for tropical soils.We assessed the effects of biochar(BC)plus sugar cane filter cake(FC)rate,and time of interaction on soil physical and hydraulic properties under humid tropical conditions.For this purpose,a field experiment was installed at a loamy sandy soil with five treatments and four replicates:control(only soil),25 Mg ha^(−1) sugar cane filter cake,and 25 Mg ha^(−1) sugar cane filter cake plus 6.25,12.5,and 25 Mg ha^(−1) Miscanthus biochar,respectively,two soil depths(0-10 and 10-20 cm)and two times of interaction(9 and 18 months).Physical prop-erties(aggregate stability,bulk density,total porosity,pores size distribution)and hydraulic properties(soil water holding capacity,hydraulic conductivity,plant-available water holding capacity)were measured after nine and eighteen months.The bulk density decreased slightly,and the porosity increased after nine months,for the biochar plus sugar cane filter cake(both 25 Mg ha^(−1)).After 18 months,biochar plus filter cake interaction increase micropores,aggregate stability,and plant-available water content.Saturated hydraulic conductivity was not influenced by sugar cane filter cake.However,biochar significantly reduced saturated hydraulic conductivity when combined with sugar cane filter cake after 18 months.We concluded that sugar cane filter cake in combination with biochar modified the pore size distribution,slightly increased plant-available water holding capacity,and significantly decreased saturated hydraulic conductivity.

关键词： Water retention Hydraulic conductivity Miscanthus biochar Soil physics

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