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Functionality of a bicistronic construction containing HEXA and HEXB genes encoding β-hexosaminidase A for cell-mediated therapy of GM2 gangliosidoses

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Neural Regeneration Research 2022年第1期17卷 122-129页

作者： Alisa A.Shaimardanova Daria S.Chulpanova Valeriya V.Solovyeva Aleksandr M.Aimaletdinov albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia

Tay-Sachs disease and Sandhoff disease are severe hereditary neurodegenerative disorders caused by a deficiency ofβ-hexosaminidase A(HexA)enzyme,which results in the accumulation of GM2 gangliosides in the nervous system *** this work,we analyzed the efficacy and safety of cell-mediated gene therapy for Sandhoff disease and Sandhoff disease using a bicistronic lentiviral vector encoding cDNA of HexAα-andβ-subunit genes separated by the nucleotide sequence of a P2A peptide(HEXA-HEXB).The functionality of the bicistronic construct containing the HEXA-HEXB genetic cassette was analyzed in a culture of HEK293T cells and human umbilical cord blood mononuclear cells(hUCBMCs).Our results showed that the enzymatic activity of HexA in the conditioned medium harvested from genetically modified HEK293T-HEXA-HEXB and hUCBMCs-HEXA-HEXB was increased by 23 and 8 times,respectively,compared with the conditioned medium of native *** blot analysis showed that hUCBMCs-HEXA-HEXB secreted both completely separated HEXA and HEXB proteins,and an uncleaved protein containing HEXA+HEXB linked by the P2A *** injection of genetically modified hUCBMCs-HEXA-HEXB to laboratory Wistar rats was carried out,and the HexA enzymatic activity in the blood plasma of experimental animals,as well as the number of live cells of immune system organs(spleen,thymus,bone marrow,lymph nodes)were determined.A significant increase in the enzymatic activity of HexA in the blood plasma of laboratory rats on days 6 and 9(by 2.5 and 3 times,respectively)after the administration of hUCBMCsHEXA-HEXB was *** the same time,the number of live cells in the studied organs remained ***,the functionality of the bicistronic genetic construct encoding cDNA of the HEXA and HEXB genes separated by the nucleotide sequence of the P2A peptide was shown in vitro and in *** hypothesize that due to the natural ability of hUCBMCs to overcome biological barriers,such a strategy can rest

关键词： bicistronic vector cell-mediated gene therapy GM2 gangliosidosis P2A peptide Sandhoff disease Tay-Sachs disease umbilical cord blood mononuclear cells β-hexosaminidase

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Successful management of vaccine-induced immune thrombotic thrombocytopenia-related cerebral sinus venous thrombosis after ChAdOx1 nCov-19 vaccination

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Stroke & Vascular Neurology 2022年第1期7卷 86-88页

作者： Thomas Gattringer Paul Gressenberger Thomas Gary albert Wöfler Markus Kneihsl Reinhard Bernd Raggam Neurology Medical University of GrazGrazAustria Divison of Angiology Department of Internal MedicineMedical University of GrazGrazAustria Divison of Haematology Department of Internal MedicineMedical University of GrazGrazAustria

Very recently,unusual thrombotic events in combination with severe thrombocytopenia have been reported 1–2 weeks following SARS-CoV-2 vaccination with ChAdOx1 nCov-19(AstraZeneca).This condition,termed VITT(vaccine-induced immune thrombotic thrombocytopenia),has been related to high risk of fatal outcome with both ischaemic and haemorrhagic complications.12 Optimal treatment strategies still need to be elucidated—especially in case of cerebral sinus venous thrombosis(CSVT)with associated brain haemorrhage as the underlying thrombotic *** here report our clinical experience with two young women diagnosed with VITT-associated CSVT,treated with high-dose intravenous immunoglobulins(IVIGs),corticosteroids and argatroban in the hyperacute phase,followed by dabigatran resulting in excellent outcome.

关键词： vaccination thrombotic cerebral

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Difficult treatment decisions in autoimmune hepatitis

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World Journal of Gastroenterology 2010年第8期16卷 934-947页

作者： albert J Czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine

Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations,uncertainties about its natural history,evolving opinions regarding treatment end points,varied nature of refractory disease,and plethora of alternative immu-nosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in au-toimmune hepatitis were identifi ed by Medline search up to October 2009 and 32 years of personal experi-ence. Autoimmune hepatitis may have an acute severe presentation,mild in? ammatory activity,lack autoan-tibodies,exhibit atypical histological changes (centri-lobular zone 3 necrosis or bile duct injury),or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early,applied despite the absence of symptoms,or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point,but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy,preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empiricaltherapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment,pursuing realistic goals,applying appropriate salvage regimens,and identifying problematic patients early.

关键词： Autoimmune hepatitis Fulminant hepatitis Salvage therapy Treatment end points

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Pedestrian walking speed at un-signalized midblock crosswalk and its impact on urban street segment performance

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Journal of Traffic and Transportation Engineering(English Edition) 2021年第1期8卷 57-69页

作者： albert Forde Janice Daniel Division of Statewide Planning New Jersey Department of TransportationTrentonNJ 08625USA Department of Civil and Environmental Engineering New Jersey Institute of TechnologyNewarkNJ 07102USA

The Urban Street Segment Chapter of the Highway Capacity Manual(HCM)includes a methodology for evaluating the level of service urban street segments provide to automobile *** methodology does not account for pedestrian activity at un-signalized midblock crosswalk on an urban street *** activity at un-signalized midblock crosswalk on urban street segments causes friction conditions between automobiles and *** a consequence,the average time it takes vehicles to travel along the segment is *** segment running time decreases both the travel speed of automobiles and the level of service provided to automobile *** is an inverse relationship between the delay incurred by interrupted vehicles and the speeds at which pedestrians walk while crossing at *** account for this delay,there is a need to investigate pedestrian walking speeds at un-signalized midblock *** study measured pedestrian walking speeds by age-group at two un-signalized midblock crosswalks on urban street *** first objective of this paper is to perform statistical analyses to examine the measured free-flow pedestrian walking *** second objective is to demonstrate how the findings of this study can be incorporated into the Urban Street Segment Analysis Chapter of the *** walking speeds were recorded and analyzed for 2937 *** results show teenagers walk at an average speed of 1.45 m/s,young adults walk at an average speed of 1.55 m/s,middle age pedestrians walk at a speed of 1.45 m/s,older pedestrians walk at speed of 1.09 m/s,and elderly or physically disabled pedestrians walk at a speed of 1.04 m/s.

关键词： Midblock Pedestrian Walking speed HCM Urban Street

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Elevated 5-hydroxymethycytosine and cell apoptosis induced by tetrachloro-1,4-benzoquinone in mouse embryonic stem cells

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Journal of Environmental Sciences 2017年第1期29卷 1-4页

作者： albert Zuehlke Hongquan Zhang Division of Analytical and Environmental Toxicology Department of Laboratory Medicine and PathologyUniversity of AlbertaEdmontonAlbertaT6G 2G3Canada

Pentachlorophenol（PCP）has been extensively used as a fungicide,bactericide,herbicide,*** and insecticide worldwide（Ahlborg and Thunberg,1980：Choudhury et al.,1986）.Although PCP is primarily used as a preservative for wood and wood products,it has been also used in a variety of other products,including adhesives,construction materials,leather and paper.

关键词： Tetrachloro-1 4-benzoquinone (TCBQ) DNA methylation 5-hydroxymethylcytosine(5hmC) Apoptosis Stem cells

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Regulation of expression of drug-metabolizing enzymes by oncogenic signaling pathways in liver tumors: a review

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Acta Pharmaceutica Sinica B 2020年第1期10卷 113-122页

作者： albert Braeuning Michael Schwarz German Federal Institute for Risk Assessment Dept.Food SafetyBerlin 10589Germany Eberhard Karls University of Tu¨bingen Inst.of Pharmacology and ToxicologyDept.of ToxicologyTu¨bingen 72074Germany

Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell *** regulation of genes related to cell growth,survival,and death has been extensively studied,much less is known on the regulation of drug-metabolizing enzymes(DMEs)by oncogenic ***,a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phasesⅠandⅡof xenobiotic *** few data are available with respect to DME regulation by p53-dependent signaling,telomerase expression or altered chromatin *** contrast,DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase(MAPK)cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth,demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negativeregulatory effects of MAPK *** studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver *** of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.

关键词： Xenobiotic metabolism Hepatocytes WNT/b-catenin signaling RAS/MAPK signaling Gene mutation Cytochrome P450

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ON THE DIFFUSION PHENOMENON OF QUASILINEAR HYPERBOLIC WAVES

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Chinese Annals of Mathematics,Series B 2000年第1期21卷 63-70页

作者： YANG HAN albert MILANI Department of Applied Mathematics South West Jiaotong University Chengdu China Department of Mathematics University of Wisconsin-Milwaukee Milwaukee USA

The authors consider the asymptotic behavior of solutions of the quasilinear hyperbolic equation with linear damping u_tt+ u_t - div (a(u)u) = 0, and show that, at least when n ≥ 3, they tend, as t - +∞, to those of the nonlinear parabolic equation v_t - div (a(v)v) = 0, in the sense that the norm ||u(., t) - v(., t) ||L∞ (R^n) of the difference u - v decays faster than that of either u or v. This provides another example of the diffusion phenomenon of nonlinear hyperbolic waves, first observed by Hsiao, L. and Liu Taiping (see [1, 2]).

关键词：扩散拟线性双曲波动方程解柯西问题

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Old and new concepts based on coherent structures for understanding sediment transport

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International Journal of Sediment Research 2011年第3期26卷 376-384页

作者： albert GYR Inst.of Hydromechanics and Water Resources Management Swiss Federal Institute of TechnologyCH-8093Swiss

Coherent structures develop due to an instability process on smooth beds under turbulent flow conditions and they are relevant for the incipient motion of fine sand *** flow structures were found to be relevant for the sediment transport under rough wall conditions,but an instability process could not explain *** this article we show that rough walls produce a new class of A-vortices,these vortices develop from separations on the grains,and are new relevant flow structures.

关键词： Sediment transport Incipient motion Coherent structures Turbulence Separations

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On the material dependence of experimental shear fracture orientation

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Science China Earth Sciences 2015年第12期58卷 2357-2362页

作者： Enrique GOMEZ-RIVAS albert GRIERA Department of Geology and Petroleum Geology School of Geosciences King’s College University of Aberdeen Departament de Geologia Universitat Autònoma de Barcelona

It is not uncommon to observe shear fractures in ductile rocks oriented at more than 45° with respect to the maximum compression direction. Since these orientations cannot be explained with the classic Mohr-Coulumb or Tresca yield criteria, Zheng et al.(Journal of Structural Geology, 35: 1394–1405, 2011) proposed the maximum effective moment(MEM) failure criterion. This rule suggests that shear fractures in ductile rocks form at ?55° with the maximum compression axis and that this orientation is material-independent and, therefore, universal. Zheng et al.(Science China: Earth Sciences, 57(11): 2819–2824, 2014) used data from our own experiments as supporting evidence of their failure criterion. In this contribution we discuss why shear fracture formation in ductile rocks indeed strongly depends on the mechanical properties of the deforming medium, and why experimental data should not be taken to prove the validity of the MEM criterion. The formation mechanisms and orientations of shear fractures in our experiments significantly vary depending on the material strength and degree and type of anisotropy(composite and intrinsic). We therefore demonstrate using experimental data that a universal failure angle in ductile and anisotropic rocks does not apply. Additionally, we highlight some inconsistencies of the MEM criterion.

关键词：剪切断裂复合材料实验性断裂方向 Tresca屈服准则依赖性断裂韧性破坏准则

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Superior mesenteric venous thrombosis: Endovascular management and outcomes

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World Journal of Clinical Cases 2022年第1期10卷 217-226页

作者： Khaled Alnahhal Beau B Toskich Samuel Nussbaum Zhuo Li Young Erben albert G Hakaim Houssam Farres Department of Surgery Division of Vascular SurgeryMayo Clinic FloridaJacksonvilleFL 32224United States Department of Radiology Mayo Clinic FloridaJacksonvilleFL 32224United States Department of Biostatistics Mayo Clinic FloridaJacksonvilleFL 32224United States

BACKGROUND Superior mesenteric venous thrombosis(SMVT)is a rare but fatal condition that is typically treated initially with anticoagulation therapy,and if this fails,with endovascular ***,due to its rarity,there are not many studies that have explored the effectiveness of anticoagulation and endovascular therapies in treating *** To evaluate patients diagnosed with SMVT who received endovascular therapy in addition to anticoagulation and report technical and clinical *** A retrospective analysis of the patients who underwent endovascular treatment for SMVT at Mayo Clinic from 2000-2019 was *** success was defined as angiographic improvement in SMV flow after *** patency was defined as the interval from reestablishing mesenteric venous flow until the first repeat thrombotic event or need for additional *** patency was defined as successful restoration of flow after repeat intervention until rethrombosis or last *** adverse events were reported through Clavien-Dindo *** Twenty-four patients were included for *** median age at intervention was 60 years(35-74 years)and 16(67%)were *** patients presented with acute thrombosis(79.2%)and 5 with chronic thrombosis with acute manifestations(20.8%).The most commonly used endovascular modalities were thrombectomy in 12 patients(50.0%)and catheter-directed thrombolysis in 10 patients(41.7%).Technical success was achieved in 18 patients(75%).The 14-d and 30-d primary patency rates were 88.9%and 83.3%,*** events were reported in two patients(8.3%),one marked as grade IIIB,and 1 death marked as grade ***-year overall survival rate was 82%(58%-100%).CONCLUSION Endovascular intervention with anticoagulation appears to be effective for managing *** treatment combination may be considered as first-line therapy for SMVT management in select patients.

关键词： Superior mesenteric venous thrombosis Endovascular Anticoagulation Retrospective Thrombectomy Mesenteric Thrombolysis

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