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1.
PLoS One ; 15(4): e0231633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353864

RESUMO

Arginine deprivation cancer therapy targets certain types of malignancies with positive result in many studies and clinical trials. NEI-01 was designed as a novel arginine-depleting enzyme comprising an albumin binding domain capable of binding to human serum albumin to lengthen its half-life. In the present work, NEI-01 is shown to bind to serum albumin from various species, including mice, rat and human. Single intraperitoneal administration of NEI-01 to mice reduced plasma arginine to undetectable level for at least 9 days. Treatment of NEI-01 specifically inhibited cell viability of MIA PaCa-2 and PANC-1 cancer cell lines, which were ASS1 negative. Using a human pancreatic mouse xenograft model, NEI-01 treatment significantly reduced tumor volume and weight. Our data provides proof of principle for a cancer treatment strategy using NEI-01.

2.
Cancer Med ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32351024

RESUMO

Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal disorders of the bone marrow, and are associated with a high disease burden, reduced quality of life (QOL), and shortened survival. This multinational, multicenter, non-interventional registry "MERGE" was initiated with an objective to collect data on the epidemiological indices of classical Ph-MPNs, existing treatment patterns, and impact of MPNs on health-related QOL in various countries/regions in Asia, including the Middle East, Turkey, and Algeria. Of the 884 eligible patients with MPNs, 169 had myelofibrosis (MF), 301 had polycythemia vera (PV), 373 had essential thrombocythemia (ET), and 41 had unclassified MPNs. The median age was 58 years (range, 47-66 years), and 50% of patients were males. The prevalence and incidence of MPNs were estimated to be 57-81 and 12-15 per 100 000 hospital patients per year over the last 4 years, respectively, in these countries. Total symptom score (mean [standard deviation; SD]) at baseline was highest in patients with MF (23.5 [17.47]) compared with patients with ET (14.6 [14.26]) and PV (16.6 [14.84]). Patients with ET had a lower mean (SD) number of inpatient visits (0.9 [0.77] days), and patients with MF had more outpatient visits (5.2 [3.17] days) on an average, compared with the entire MPN group. The study showed that patients with MPNs have a severe disease burden and reduced QOL. A discordance between physician and patient perception of symptom assessment was observed in this study (International clinical trials registry ID: CTRI/2014/05/004598).

3.
Transl Stroke Res ; 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32430797

RESUMO

Transient receptor potential melastatin 7 (TRPM7), a calcium-permeable, ubiquitously expressed ion channel, is critical for axonal development, and mediates hypoxic and ischemic neuronal cell death in vitro and in vivo. However, the downstream mechanisms underlying the TRPM7-mediated processes in physiology and pathophysiology remain unclear. In this study, we employed a mouse model of hypoxic-ischemic brain cell death which mimics the pathophysiology of hypoxic-ischemic encephalopathy (HIE). HIE is a major public health issue and an important cause of neonatal deaths worldwide; however, the available treatments for HIE remain limited. Its survivors face life-long neurological challenges including mental retardation, cerebral palsy, epilepsy and seizure disorders, motor impairments, and visual and auditory impairments. Through a proteomic analysis, we identified calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphatase calcineurin as potential mediators of cell death downstream from TRPM7 activation. Further analysis revealed that TRPM7 mediates cell death through CaMKII, calmodulin, calcineurin, p38, and cofilin cascade. In vivo, we found a significant reduction of brain injury and improvement of short- and long-term functional outcomes after HI after administration of specific TRPM7 blocker waixenicin A. Our data demonstrate a molecular mechanism of TRPM7-mediated cell death and identifies TRPM7 as a promising therapeutic and drug development target for HIE.

4.
Cardiovasc Res ; 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251516

RESUMO

AIMS: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. METHODS AND RESULTS: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1x106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. CONCLUSIONS: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy. TRANSLATIONAL PERSEPCTIVE: The recognition that cardioreparative effects of adult stem cells are attributed to their salutary paracrine activity is driving the recent paradigm shift to harness stem cell paracrine effects for effective cardiac repair. However, poor cell engraftment post-transplantation limits the release of paracrine factors over time and thus their therapeutic efficacy. This study demonstrates sustained delivery of the secretome from cardiac stem cells using an immune-isolation device, implanted subcutaneously, to produce cardioreparative effects following myocardial infarction. This innovative delivery method is minimally invasive and clinically adaptable for other stem cell types with a high secretory profile and for other cardiovascular diseases.

6.
Asia Pac J Ophthalmol (Phila) ; 9(2): 67-77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32349113

RESUMO

The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory coronavirus-2, was first reported in December 2019. The World Health Organization declared COVID-19 a pandemic on March 11, 2020 and as of April 17, 2020, 210 countries are affected with >2,000,000 infected and 140,000 deaths. The estimated case fatality rate is around 6.7%. We need to step up our infection control measures immediately or else it may be too late to contain or control the spread of COVID-19. In case of local outbreaks, the risk of infection to healthcare workers and patients is high. Ophthalmic practice carries some unique risks and therefore high vigilance and special precautions are needed. We share our protocols and experiences in the prevention of infection in the current COVID-19 outbreak and the previous severe acute respiratory syndrome epidemic in Hong Kong. We also endeavor to answer the key frequently asked questions in areas of the coronaviruses, COVID-19, disease transmission, personal protection, mask selection, and special measures in ophthalmic practices. COVID-19 is highly infectious and could be life-threatening. Using our protocol and measures, we have achieved zero infection in our ophthalmic practices in Hong Kong and China. Preventing spread of COVID-19 is possible and achievable.


Assuntos
Infecções por Coronavirus/prevenção & controle , Controle de Infecções/métodos , Máscaras , Oftalmologia/normas , Pandemias/prevenção & controle , Equipamento de Proteção Individual , Pneumonia Viral/prevenção & controle , Betacoronavirus , China , Higiene das Mãos , Hong Kong , Humanos , Ventiladores Mecânicos
7.
Cancer Med ; 9(10): 3371-3382, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32187883

RESUMO

Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18- to 65-year-old AML patients refractory to first-line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high-dose cytarabine consolidation, with clofarabine (30 mg/m2 /d, Days 1-5), cytarabine (750 mg/m2 /d, Days 1-5), and mitoxantrone (12 mg/m2 /d, Days 3-5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mutational profile of a 69-gene panel was evaluated. Twenty-six men and 26 women at a median age of 46 (22-65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty-two CR/CRi patients underwent allo-HSCT. The 2-year overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo-HSCT (P = .005), and superior RFS and EFS were associated with allo-HSCT (P < .001). Remarkably, CR after CLAM and allo-HSCT resulted in 2-year OS of 84.3% and 90%, respectively. Karyotypic aberrations and genetic mutations did not influence responses or survivals. Grade 3/4 neutropenia/thrombocytopenia and grade 3 febrile neutropenia occurred in all cases. Other nonhematologic toxicities were mild and uncommon. There was no treatment-related mortality and the performance of allo-HSCT was not compromised. Clofarabine, cytarabine, and mitoxantrone was highly effective and safe in refractory/relapsed AML. This study was registered at ClinicalTrials.gov (NCT02686593).

8.
PLoS Pathog ; 16(2): e1008307, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32069328

RESUMO

The ability of HIV-1 to evolve resistance to combined antiretroviral therapies (cARTs) has stimulated research into alternative means of controlling this infection. We assayed >60 modulators of RNA alternative splicing (AS) to identify new inhibitors of HIV-1 RNA processing-a segment of the viral lifecycle not targeted by current drugs-and discovered compound N-[4-chloro-3-(trifluoromethyl)phenyl]-7-nitro-2,1,3-benzoxadiazol-4-amine (5342191) as a potent inhibitor of both wild-type (Ba-L, NL4-3, LAI, IIIB, and N54) and drug-resistant strains of HIV-1 (IC50: ~700 nM) with no significant effect on cell viability at doses tested. 5342191 blocks expression of four essential HIV-1 structural and regulatory proteins (Gag, Env, Tat, and Rev) without affecting total protein synthesis of the cell. This response is associated with altered unspliced (US) and singly-spliced (SS) HIV-1 RNA accumulation (~60% reduction) and transport to the cytoplasm (loss of Rev) whereas parallel analysis of cellular RNAs revealed less than a 0.7% of host alternative splicing (AS) events (0.25-0.67% by ≥ 10-20%), gene expression (0.01-0.46% by ≥ 2-5 fold), and protein abundance (0.02-0.34% by ≥ 1.5-2 fold) being affected. Decreased expression of Tat, but not Gag/Env, upon 5342191 treatment was reversed by a proteasome inhibitor, suggesting that this compound alters the synthesis/degradation of this key viral factor. Consistent with an affect on HIV-1 RNA processing, 5342191 treatment of cells altered the abundance and phosphorylation of serine/arginine-rich splicing factor (SRSF) 1, 3, and 4. Despite the activation of several intracellular signaling pathways by 5342191 (Ras, MEK1/2-ERK1/2, and JNK1/2/3), inhibition of HIV-1 gene expression by this compound could be reversed by pre-treatment with either a G-protein α-subunit inhibitor or two different MEK1/2 inhibitors. These observations demonstrate enhanced sensitivity of HIV-1 gene expression to small changes in host RNA processing and highlights the potential of modulating host intracellular signaling as an alternative approach for controlling HIV-1 infection.

10.
J Mech Behav Biomed Mater ; 103: 103584, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32090915

RESUMO

Owing to the poor load-bearing ability and apparent cytotoxicity of polymeric and ceramic materials, magnesium-based materials can be an ideal substitute for bone repair applications. Magnesium is bioresorbable, unlike other metallic materials like titanium and stainless steel, has excellent biocompatibility, compressive strengths and elastic modulus similar to the natural bone, which circumvents the need for secondary surgery post-implantation in vivo. Against this background, in this study, magnesium-based nanocomposites were developed by using hydroxyapatite bioceramic as a nano reinforcement. Magnesium-based alloys were synthesized using selective alloying elements and hydroxyapatite incorporated nanocomposites were processed using the disintegrated melt deposition technique. The microstructure characterization revealed that the addition of hydroxyapatite resulted in superior grain refinement of the magnesium alloy matrix. The addition of hydroxyapatite improved the yield strength of the alloy matrix and displayed superior strength and ductility retention post corrosion for 21 days, under compression loading. The presence of hydroxyapatite improved the hydrophilicity of the alloy matrix thereby aiding the biocompatibility properties with improved corrosion resistance, level 0 cytotoxicity, and high cell attachment. Hence, the present study strongly suggests that magnesium alloy-based hydroxyapatite nanocomposites can be a suitable candidate for bone repair applications.

11.
Eur J Ophthalmol ; : 1120672120908719, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32103680

RESUMO

PURPOSE: To evaluate the choroidal vascularity index of eyes for acute and chronic central serous chorioretinopathy patients using swept-source optical coherence tomography generated en-face scans. METHODS: This was a retrospective study, in which slabs of en-face optical coherence tomography scans, at 5 µm intervals, spanning from the retina to choroid, were binarized using a validated algorithm to calculate choroidal vascularity index. The choroidal vascularity index was defined as the ratio between the choroidal vascular luminal area and the total choroidal area. Choroidal vascularity index was calculated for all the slabs of every subject in both the groups. RESULTS: A total of 30 eyes for each acute and chronic central serous chorioretinopathy groups were recruited. The mean choroidal vascularity index of the acute group was 45.21% ± 2.25% at the choriocapillaris, which increased to the maximal value of 48.35% ± 2.06% at 75% depth of the choroidal thickness and 45.31% ± 3.27% at the choroidoscleral interface; whereas for the chronic group, the mean choroidal vascularity index was 44.76% ± 2.60% at the choriocapillaris, which maximized at 50% choroidal depth (48.70% ± 1.32%) and then returned to 45.41% ± 6.02% at the choroidoscleral interface. CONCLUSION: For both groups, the choroidal vascularity index increased from choriocapillaris to maximum values at mid-choroid and returned to almost the choriocapillaris value at the choroidoscleral interface.

12.
Stem Cell Res Ther ; 11(1): 32, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964413

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) hold great potential as a therapy for stroke and have previously been shown to promote recovery in preclinical models of cerebral ischaemia. MSCs secrete a wide range of growth factors, chemokines, cytokines and extracellular vesicles-collectively termed the secretome. In this study, we assessed for the first time the efficacy of the IL-1α-primed MSC-derived secretome on brain injury and functional recovery after cerebral ischaemia. METHODS: Stroke was induced in male C57BL/6 mice using the intraluminal filament model of middle cerebral artery occlusion. Conditioned medium from IL-1α-primed MSCs or vehicle was administered at the time of reperfusion or at 24 h post-stroke by subcutaneous injection. RESULTS: IL-1α-primed MSC-derived conditioned medium treatment at the time of stroke led to a ~ 30% reduction in lesion volume at 48 h and was associated with modest improvements in body mass gain, 28-point neurological score and nest building. Administration of MSC-derived conditioned medium at 24 h post-stroke led to improved nest building and neurological score despite no observed differences in lesion volume at day 2 post-stroke. CONCLUSIONS: Our results show for the first time that the administration of conditioned medium from IL-1α-primed MSCs leads to improvements in behavioural outcomes independently of neuroprotection.

13.
J Am Chem Soc ; 142(5): 2310-2316, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31927922

RESUMO

Unexpected phenomena displayed by low-boron-doped diamond (BDD) electrodes are disclosed in the present work. Generally, the presence of sp2 nondiamond carbon impurities in BDD electrodes causes undesirable electrochemical properties, such as a reduced potential window and increased background current, etc. However, we found that the potential window and redox reaction in normally doped (1%) BDD and low-doped (0.1%) BDD exhibited opposite tendencies depending on the extent of sp2 carbon. Moreover, we found that contrary to the usual expectations, low-doped BDD containing sp2 carbon hinders electron transfer, whereas in line with expectations, normally doped BDD containing sp2 exhibits enhanced electron transfer. Surface analyses by X-ray/ultraviolet photoelectron spectroscopy (XPS/UPS) and electrochemical methods are utilized to explain these unusual phenomena. This work indicates that the electrochemical properties of low-doped BDD containing sp2 might be due partially to the high level of surface oxygen, the large work function, the low carrier density, and the existence of different types of sp2 carbon.

14.
J Cell Physiol ; 235(5): 4594-4604, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31637708

RESUMO

Gliomas are a group of brain cancers with high mortality and morbidity. Understanding the molecular mechanisms is important for the prevention or treatment of gliomas. The present study was to investigate the effects and mechanisms of long noncoding RNA TRPM2-AS in gliomas proliferation, migration, and invasion. We first compared the levels of TRPM2-AS in 111 patients with glioma to that of the normal control group by a quantitative polymerase chain reaction. The results indicated a significant increase of TRPM2-AS in patients with glioma (2.43 folds of control, p = .0135). MTT methods, wound healing assays, transwell analysis, and clone formation analysis indicated the overexpression of TRPM2-AS promoted the proliferation, migration, and invasion of U251 and U87 cells, while downregulation of TRPM2-AS inhibited the cell proliferation, migration, and invasion significantly (p < .05). To further uncover the mechanisms, bioinformatics analysis was conducted on the expression profiles, GSE40687 and GSE4290, from the Gene Expression Omnibus database. One hundred fifty-six genes were differentially expressed in both datasets (FC > 2.0; p = .05). Among these differentially expressed genes, the level of RGS4 messenger RNA was drastically regulated by TRPM2-AS. Further western-blot analysis indicated the increase of RGS4 protein expression and decrease of p-JNK/JNK and p-c-Jun/c-Jun ratio after TRPM2-AS overexpression. On the other hand, inhibition of TRPM2-AS by small interfering RNA suppressed the expression of RGS4 and promoted the ratios of p-JNK/JNK and p-c-Jun/c-Jun. The present work indicated the mechanisms of the participation of TRPM2-AS in the progression of gliomas might, at least partly, be related to JNK, c-Jun, and RGS4. Our work provided new insights into the underlying mechanisms of glioma cellular functions.

15.
J Mech Behav Biomed Mater ; 103: 103548, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31783282

RESUMO

INTRODUCTION: Mandibular endoprostheses have been explored extensively as potential methods of alloplastic reconstruction. Studies, however, have demonstrated that for segmental mandibular defects, there are challenges associated with loosening. Another method recently introduced in clinical settings is popular as a design for patient-specific implants for segmental mandibular defect and involves a tray (filled with bone) over the defect with wings on both sides secured with screws. Our aim was to investigate which design better withstands the forces of function since studies have presented favourable results with regard to the wing design. MATERIALS AND METHODS: Two designs, an endoprosthesis with stems and wings were modelled. Finite element analysis was performed, and geometric data obtained from a human-sized mandible. A continuity defect of 20 mm was created digitally at the right mandibular molar region and the modelled segments combined with the endoprosthesis. Boundary conditions were set, and 300-N vertical loads applied in the incisor region. The stress concentrations and displacements were evaluated for the titanium alloy (Group 1-Stem) (Group 2-Wing) and the polycaprolactone (PCL) (Group 3 with stem, Group 4 wing design). RESULTS: For the titanium stem (Group 1), the stress values were in the 557-803 MPa range. The titanium wing (Group 2) design showed markedly reduced stress values in the 20-68 MPa range. The stresses observed for the PCL(Group 3) were in the 66-110 MPa range, and the stress concentration in the PCL wing (Group 4) was observed in the wing and body regions of the scaffolds in the 8-42 MPa range. CONCLUSION: The wing design decreased the areas of stress concentrations significantly compared to an endoprosthesis. PCL alone did not have adequate strength to withstand forces applied even in a design that reduced stress concentrations significantly.

16.
Sci Rep ; 9(1): 18656, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31796843

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

17.
Blood Adv ; 3(22): 3780-3817, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31770441

RESUMO

Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

18.
J Neuroinflammation ; 16(1): 222, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727174

RESUMO

BACKGROUND: Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1ß (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531-3543, 2017; Hill et al., Lancet Neurol 11:942-950, 2012; Amaro et al., Stroke 47:2874-2876, 2016). METHODS: Transient stroke was induced in mice via one of two methods. One group of mice were subjected to tandem ipsilateral common carotid artery and middle cerebral artery occlusion, while another group underwent the filament-based middle cerebral artery occlusion. We have recently developed an animal model of intra-arterial (IA) drug administration after recanalization (Maniskas et al., J Neurosci Met 240:22-27, 2015). Sub groups of the mice were treated with either saline or Il-1α, wherein the drug was administered either acutely (immediately after surgery) or subacutely (on the third day after stroke). This was followed by behavioral and histological analyses. RESULTS: We now show in the above-mentioned mouse stroke models (transient tandem ipsilateral common carotid artery (CCA) and middle cerebral artery occlusion (MCA) occlusion, MCA suture occlusion) that IL-1α is neuroprotective when acutely given either intravenously (IV) or IA at low sub-pathologic doses. Furthermore, while IV administration induces transient hemodynamic side effects without affecting systemic markers of inflammation, IA delivery further improves overall outcomes while eliminating these side effects. Additionally, we show that delayed/subacute IV IL-1α administration ameliorates functional deficit and promotes neurorepair. CONCLUSIONS: Taken together, our present study suggests for the first time that IL-1α could, unexpectedly, be an effective ischemic stroke therapy with a broad therapeutic window.

19.
ACS Nano ; 13(11): 12470-12486, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31693858

RESUMO

The development of effective therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies, and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5 and 4 h) and delayed (24 and 48 h) time points, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal colocalization within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages toward brain repair. These findings demonstrate the capability of liposomes to maximize selective translocation into the brain after stroke and identify two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of stroke treatments.

20.
Clin Chem Lab Med ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31584871

RESUMO

Background Eltrombopag is a thrombopoietin receptor agonist used for the treatment of thrombocytopenic conditions. It can cause pH-dependent discoloration of plasma/serum. Eltrombopag is potentially hepatotoxic. It can affect the assessment of hyperbilirubinemia because of its (i) absorbance at ~450 nm (bilirubin), (ii) absorbance at ~550 nm (diazo-bilirubin) and (iii) it can cause yellowish discoloration of the eyes at normal circulating bilirubin levels. Methods We collected 66 samples from patients on a range of eltrombopag dosages up to 150 mg daily. Bilirubin was measured using multiple routine spectrophotometric analyzers, the Doumas reference method and high-performance liquid chromatography (HPLC). Plasma/serum eltrombopag concentrations were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS). Spike-in and admixture experiments delineated the effects of eltrombopag and its metabolites. Results Forty-nine of 52 samples from patients on ≥50 mg daily eltrombopag therapy showed significantly discrepant inter-analyzer total bilirubin results, a difference up to 64 µmol/L (3.7 mg/dL). In one sample, total bilirubin varied from 8 to 65 µmol/L (0.4-3.8 mg/dL) by different routine analyzers, with direct bilirubin ≤4 µmol/L (0.2 mg/dL). There was a positive correlation between total bilirubin difference and plasma eltrombopag concentration (r = 0.679), and spike-in experiments demonstrated that Beckman AU and Doumas reference methods were susceptible to positive interference. HPLC can quantify bilirubin after separating eltrombopag, and results suggest different analyzers are affected to varying degrees by eltrombopag and its metabolites. Conclusions Eltrombopag and its metabolites can cause positive interference to the spectrophotometric measurements of total bilirubin. Accurate measurements of total bilirubin may improve our understanding of the prevalence of hyperbilirubinemia in patients on eltrombopag therapy.

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