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1.
Phys Rev Lett ; 127(14): 147201, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34652169

RESUMO

We demonstrate a nanoscale materials design path that allows us to bypass universality in thin ferromagnetic films and enables us to tune the critical exponents of ferromagnetic phase transitions in a very wide parameter range, while at the same time preserving scaling in an extended phase space near the Curie temperature. Our detailed magnetometry results reveal that single crystal CoRu alloy films, in which the predefined depth dependent exchange coupling strength follows a V-shaped profile, exhibit critical scaling behavior over many orders of magnitude. Their critical exponents, however, can be designed and controlled by modifying their specific nanoscale structures, thus demonstrating full tunability of critical behavior. The reason for this tunability and the disappearance of universality is shown to be the competing relevance of collective versus interface propagating progression of ferromagnetic phase transitions, whose balance we find to be dependent on the specifics of the underlying exchange coupling strength profile.

2.
Am J Gastroenterol ; 116(9): 1924-1928, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465694

RESUMO

INTRODUCTION: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. METHODS: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). RESULTS: Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. DISCUSSION: Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Falência Renal Crônica/terapia , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Esquema de Medicação , Feminino , Fluorenos/administração & dosagem , Hepatite C/complicações , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento
3.
Artigo em Inglês | MEDLINE | ID: mdl-34347431

RESUMO

Electrically induced ionic motion offers a new way to realize voltage-controlled magnetism, opening the door to a new generation of logic, sensor, and data storage technologies. Here, we demonstrate an effective approach to magneto-ionically and electrically tune the exchange bias in Gd/Ni1-xCoxO thin films (x = 0.50 and 0.67), where neither of the layers alone is ferromagnetic at room temperature. The Gd capping layer deposited onto antiferromagnetic Ni1-xCoxO initiates a solid-state redox reaction that reduces an interfacial region of the oxide to ferromagnetic NiCo. An exchange bias is established after field cooling (FC), which can be enhanced by up to 35% after a voltage conditioning and subsequently reset with a second FC. These effects are caused by the presence of an interfacial ferromagnetic NiCo layer, which further alloys with the Gd layer upon FC and voltage application, as confirmed by electron microscopy and polarized neutron reflectometry studies. These results highlight the viability of the solid-state magneto-ionic approach to achieve electric control of exchange bias, with potential for energy-efficient magneto-ionic devices.

4.
Clin Pharmacokinet ; 60(5): 569-583, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33782830

RESUMO

Remdesivir (RDV, Veklury®) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug-drug interaction potential based on available in vitro and clinical data in healthy volunteers. Following single-dose intravenous administration over 2 h of an RDV solution formulation across the dose range of 3-225 mg in healthy participants, RDV and its metabolites (GS-704277and GS-441524) exhibit linear pharmacokinetics. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. Based on pharmacokinetic bridging from animal data and available human data in healthy volunteers, the RDV clinical dose regimen of a 200-mg loading dose on day 1 followed by 100-mg maintenance doses for 4 or 9 days was selected for further evaluation of pharmacokinetics and safety. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. Mathematical drug-drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug-drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Adulto , Alanina/farmacocinética , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Antivirais/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Interações Medicamentosas , Furanos/metabolismo , Meia-Vida , Humanos , Taxa de Depuração Metabólica , Pirróis/metabolismo , SARS-CoV-2 , Triazinas/metabolismo
5.
Clin Pharmacol Ther ; 109(4): 1116-1124, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33501997

RESUMO

Severe coronavirus disease 2019 (COVID-19) disease, including multisystem inflammatory syndrome, has been reported in children. This report summarizes development of a remdesivir physiologically-based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. The adult PBPK model was applied to predict pediatric remdesivir and metabolites steady-state exposures using the Pediatric Population Model in SimCYP and incorporated the relevant physiologic and mechanistic information. Model development was based on adult phase I exposure data in healthy volunteers who were administered a 200-mg loading dose of remdesivir intravenous (IV) over 0.5 hours on Day 1, then 100-mg daily maintenance doses of IV over 0.5 hours starting on Day 2 and continuing through Days 5 or 10. Simulations indicated that use of the adult therapeutic remdesivir dosage regimen (200-mg loading dose on Day 1 then 100-mg daily maintenance dose starting on Day 2) in pediatric patients ≥ 40 kg and a weight-based remdesivir dosage regimen (5-mg/kg loading dose on Day 1 then 2.5-mg/kg daily maintenance dose starting on Day 2) in pediatric patients weighing 2.5 to < 40 kg is predicted to maintain therapeutic exposures of remdesivir and its metabolites. The comprehensive PBPK model described in this report supported remdesivir dosing in planned pediatric clinical studies and dosing in the emergency use authorization and pediatric compassionate use programs that were initiated to support remdesivir as a treatment option during the pandemic.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/administração & dosagem , Antivirais/farmacocinética , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/uso terapêutico , Adolescente , Alanina/administração & dosagem , Alanina/farmacocinética , Alanina/uso terapêutico , Antivirais/uso terapêutico , Área Sob a Curva , Peso Corporal , Criança , Pré-Escolar , Simulação por Computador , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Lactente , Masculino , Modelos Biológicos , Pandemias , SARS-CoV-2
6.
Clin Pharmacol Ther ; 109(5): 1334-1341, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33141923

RESUMO

Firsocostat (FIR: previously GS-0976), a highly sensitive OATP substrate, reduces hepatic de novo lipogenesis (DNL) by inhibiting acetyl-CoA carboxylases (ACC). Measuring the pharmacodynamic (PD) efficacy of FIR on DNL provides a unique opportunity to determine optimal dosing strategies for liver-targeted OATP substrates in settings of altered OATP function. A randomized, four-way crossover drug-drug interaction study was conducted. Hepatic DNL, a marker for ACC activity, was measured in 28 healthy volunteers after reference, single dose FIR 10 mg, FIR 10 mg plus the OATP inhibitor rifampin (RIF) 300 mg i.v., or RIF 300 mg i.v. (control for DNL effect of RIF), each separated by a 7-day washout. Samples were collected for pharmacokinetic (PK) and PD assessments through 24 hours after each treatment. Hepatic DNL and its inhibition by FIR were assessed. Twenty-four subjects completed the study. All adverse events were mild. RIF alone increased hepatic DNL area under the effect curve from time of administration up to the time of the last quantifiable concentration (AUEClast ; 35.7%). Despite a 5.2-fold increase in FIR plasma exposure (area under the concentration-time curve from zero to infinity (AUCinf )) when administered with RIF, FIR alone, and FIR + RIF had the same hepatic PD effect, 37.1% and 34.9% reduction in DNL AUEClast , respectively, compared with their respective controls. These findings indicate that large decreases in OATP activity do not alter hepatic intracellular exposure (as inferred by no change in PD) for drugs that are primarily eliminated hepatically and permeability rate-limited, such as FIR. These results support PK theory that has been difficult to test and provide practical guidance on administration of liver-targeted drugs in settings of reduced OATP function.

7.
Lancet Microbe ; 1(5): e200-e208, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32939459

RESUMO

Background: Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women. Methods: This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir-sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks' gestation and had a 12-week course of oral ledipasvir-sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25-26, 29-30, and 33-34 weeks' gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir-sofosbuvir area under the concentration-time curve of the dosing interval (AUCtau) during pregnancy compared with the reference group by geometric mean ratio. This study is registered with ClinicalTrials.gov, NCT02683005. Findings: From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUCtau ledipasvir 89·3% [90% CI 68·7-116·1]; sofosbuvir 91·1% [78·0-106·3]). Interpretation: Ledipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women. Funding: National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women's Health, and Gilead Sciences.

8.
Lancet Gastroenterol Hepatol ; 5(10): 918-926, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32531259

RESUMO

BACKGROUND: There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. METHODS: This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov, number NCT01958281, and is completed. FINDINGS: This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12-74) of ten patients in cohort 1 and six (60%, 26-88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82-100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. INTERPRETATION: In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4-5 chronic kidney disease who were not on dialysis. FUNDING: Gilead Sciences.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Ensaios Clínicos Controlados não Aleatórios como Assunto/métodos , Insuficiência Renal Crônica/complicações , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Uridina Monofosfato/análogos & derivados , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Quimioterapia Combinada/métodos , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Fluorenos/farmacocinética , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Insuficiência Renal Crônica/classificação , Insuficiência Renal Crônica/fisiopatologia , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Ribavirina/farmacocinética , Segurança , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Sofosbuvir/farmacocinética , Resultado do Tratamento , Estados Unidos/epidemiologia , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/uso terapêutico , Carga Viral/efeitos dos fármacos
9.
Phys Rev E ; 101(3-1): 032125, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32289981

RESUMO

In this paper, we describe the unification and extension of multiple kinematic theories on the advection of colloidal particles through periodic obstacle lattices of arbitrary geometry and infinitesimally small obstacle size. We focus specifically on the particle displacement lateral to the flow direction (termed "deterministic lateral displacement") and the particle-obstacle interaction frequency, and develop methods for describing these as a function of particle size and lattice parameters for arbitrary lattice geometries. We then demonstrate design algorithms for microfluidic devices consisting of chained obstacle lattices of this type that approximate any lateral displacement function of size to arbitrary accuracy with respect to multiple optimization metrics, prove their validity mathematically, and compare the generated results favorably to designs in the literature with respect to metrics such as accuracy, device size, and complexity.

10.
Sci Adv ; 6(15): eaay0114, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32300646

RESUMO

Engineering magnetic anisotropy in two-dimensional systems has enormous scientific and technological implications. The uniaxial anisotropy universally exhibited by two-dimensional magnets has only two stable spin directions, demanding 180° spin switching between states. We demonstrate a previously unobserved eightfold anisotropy in magnetic SrRuO3 monolayers by inducing a spin reorientation in (SrRuO3)1/(SrTiO3) N superlattices, in which the magnetic easy axis of Ru spins is transformed from uniaxial 〈001〉 direction (N < 3) to eightfold 〈111〉 directions (N ≥ 3). This eightfold anisotropy enables 71° and 109° spin switching in SrRuO3 monolayers, analogous to 71° and 109° polarization switching in ferroelectric BiFeO3. First-principle calculations reveal that increasing the SrTiO3 layer thickness induces an emergent correlation-driven orbital ordering, tuning spin-orbit interactions and reorienting the SrRuO3 monolayer easy axis. Our work demonstrates that correlation effects can be exploited to substantially change spin-orbit interactions, stabilizing unprecedented properties in two-dimensional magnets and opening rich opportunities for low-power, multistate device applications.

11.
ACS Appl Mater Interfaces ; 12(4): 4741-4748, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31880904

RESUMO

Solid-state ionic approaches for modifying ion distributions in getter/oxide heterostructures offer exciting potentials to control material properties. Here, we report a simple, scalable approach allowing for manipulation of the superconducting transition in optimally doped YBa2Cu3O7-δ (YBCO) films via a chemically driven ionic migration mechanism. Using a thin Gd capping layer of up to 20 nm deposited onto 100 nm thick epitaxial YBCO films, oxygen is found to leach from deep within the YBCO. Progressive reduction of the superconducting transition is observed, with complete suppression possible for a sufficiently thick Gd layer. These effects arise from the combined impact of redox-driven electron doping and modification of the YBCO microstructure due to oxygen migration and depletion. This work demonstrates an effective step toward total ionic tuning of superconductivity in oxides, an interface-induced effect that goes well into the quasi-bulk regime, opening-up possibilities for electric field manipulation.

12.
Nano Lett ; 19(12): 8381-8387, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31665887

RESUMO

We report on the emergent magnetic state of (111)-oriented CoCr2O4 ultrathin films sandwiched between Al2O3 spacer layers in a quantum confined geometry. At the two-dimensional crossover, polarized neutron reflectometry reveals an anomalous enhancement of the total magnetization compared to the bulk value. Synchrotron X-ray magnetic circular dichroism measurements demonstrate the appearance of a long-range ferromagnetic ordering of spins on both Co and Cr sublattices. Brillouin function analyses and ab-initio density functional theory calculations further corroborate that the observed phenomena are due to the strongly altered magnetic frustration invoked by quantum confinement effects, manifested by the onset of a Yafet-Kittel-type ordering as the magnetic ground state in the ultrathin limit, which is unattainable in the bulk.

13.
J Phys Chem Lett ; 10(23): 7531-7536, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31743030

RESUMO

Electronic polarization effects play an important role in the interactions of charged species in biologically relevant aqueous solutions, such as those involving salt ions, proteins, nucleic acids, or phospholipid membranes. Explicit inclusion of electronic polarization in molecular modeling is tedious both from the point of view of force field parametrization and actual performance of the simulations. Therefore, the vast majority of biomolecular simulations is performed using nonpolarizable force fields, which can lead to artifacts such as dramatically overestimated ion pairing, particularly when polyvalent ions are involved. Here, we show that many of these issues can be remedied without extra computational costs by including electronic polarization in a mean field way via charge rescaling. We also lay the solid physical foundations of this approach and reconcile from this perspective the microscopic versus macroscopic natures of nonpolarizable force fields.

14.
Phys Rev Lett ; 123(12): 128001, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31633960

RESUMO

Colloidal suspensions in industrial processes often exhibit shear thickening that is difficult to control actively. Here, we use piezoelectric transducers to apply acoustic perturbations to dynamically tune the suspension viscosity in the shear-thickening regime. We attribute the mechanism of dethickening to the disruption of shear-induced force chains via perturbations that are large relative to the particle roughness scale. The ease with which this technique can be adapted to various flow geometries makes it a powerful tool for actively controlling suspension flow properties and investigating system dynamics.

15.
J Am Soc Nephrol ; 30(10): 1980-1990, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506292

RESUMO

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells resulting from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent. METHODS: In a phase 2 trial evaluating selonsertib's safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 weeks. RESULTS: Selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 weeks, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 weeks. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 weeks (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 weeks (therapeutic effect) with higher doses of selonsertib. A post hoc analysis (excluding data for 20 patients from two sites with Good Clinical Practice compliance-related issues) found that between 4 and 48 weeks, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 ml/min per 1.73 m2 annualized over 1 year; 95% confidence interval, 0.10-6.13; nominal P=0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. CONCLUSIONS: Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.


Assuntos
Benzamidas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Idoso , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Resultado do Tratamento
16.
J Hepatol ; 71(4): 660-665, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31195062

RESUMO

BACKGROUND & AIMS: Although off-label use of sofosbuvir-containing regimens occurs regularly in patients with hepatitis C virus (HCV) infection undergoing dialysis for severe renal impairment or end-stage renal disease (ESRD), these regimens are not licensed for this indication, and there is an absence of dosing recommendations in this population. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir in patients with HCV infection with ESRD undergoing dialysis. METHODS: In this phase II, single-arm study, 59 patients with genotype 1-6 HCV infection with ESRD undergoing hemodialysis or peritoneal dialysis received open-label sofosbuvir/velpatasvir (400 mg/100 mg) once daily for 12 weeks. Patients were HCV treatment naive or treatment experienced without cirrhosis or with compensated cirrhosis. Patients previously treated with any HCV NS5A inhibitor were not eligible. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response (SVR) 12 weeks after discontinuation of treatment (SVR12). The primary safety endpoint was the proportion of patients who discontinued study drug due to adverse events. RESULTS: Overall, 56 of 59 patients achieved SVR12 (95%; 95% CI 86-99%). Of the 3 patients who did not achieve SVR12, 2 patients had virologic relapse determined at post-treatment Week 4 (including 1 who prematurely discontinued study treatment), and 1 patient died from suicide after achieving SVR through post-treatment Week 4. The most common adverse events were headache (17%), fatigue (14%), nausea (14%), and vomiting (14%). Serious adverse events were reported for 11 patients (19%), and all were deemed to be unrelated to sofosbuvir/velpatasvir. CONCLUSIONS: Treatment with sofosbuvir/velpatasvir for 12 weeks was safe and effective in patients with ESRD undergoing dialysis. LAY SUMMARY: Sofosbuvir/velpatasvir is a combination direct-acting antiviral that is approved for treatment of patients with hepatitis C virus (HCV) infection. Despite the lack of dosing recommendations, sofosbuvir-containing regimens (including sofosbuvir/velpatasvir) are frequently used for HCV-infected patients undergoing dialysis. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir for 12 weeks in patients with HCV infection who were undergoing dialysis. Treatment with sofosbuvir/velpatasvir was safe and well tolerated, resulting in a cure rate of 95% in patients with HCV infection and end-stage renal disease. Clinical Trial Number: NCT03036852.


Assuntos
Carbamatos , Hepatite C Crônica , Compostos Heterocíclicos de 4 ou mais Anéis , Falência Renal Crônica , Diálise Renal/métodos , Sofosbuvir , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento
17.
Sci Adv ; 5(3): eaav5050, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30944859

RESUMO

The coexistence and coupling of ferroelasticity and magnetic ordering in a single material offers a great opportunity to realize novel devices with multiple tuning knobs. Complex oxides are a particularly promising class of materials to find multiferroic interactions due to their rich phase diagrams, and are sensitive to external perturbations. Still, there are very few examples of these systems. Here, we report the observation of twin domains in ferroelastic LaCoO3 epitaxial films and their geometric control of structural symmetry intimately linked to the material's electronic and magnetic states. A unidirectional structural modulation is achieved by selective choice of substrates having twofold rotational symmetry. This modulation perturbs the crystal field-splitting energy, leading to unexpected in-plane anisotropy of orbital configuration and magnetization. These findings demonstrate the use of structural modulation to control multiferroic interactions and may enable a great potential for stimulation of exotic phenomena through artificial domain engineering.

18.
Small ; 15(22): e1901666, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31021500

RESUMO

A new class of solvent free, lyotropic liquid crystal nanocomposites based on gold nanorods (AuNRs) with high nanorod content is reported. Application of shear results in switchable, highly ordered alignment of the nanorods over several centimeters with excellent storage stability for months. For the synthesis, AuNRs are surface functionalized with a charged, covalently tethered corona, which induces fluid-like properties. This honey-like material can be deposited on a substrate and a high orientational order parameter of 0.72 is achieved using a simple shearing protocol. Switching shearing direction results in realignment of the AuNRs. For a film containing 75 wt% of AuNRs the alignment persists for several months. In addition to the lyotropic liquid crystal characteristics, the AuNRs films also exhibit anisotropic electrical conductivity with an order of magnitude difference between the conductivities in direction parallel and perpendicular to the alignment of the AuNRs.

19.
Anal Biochem ; 577: 26-33, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30790546

RESUMO

Capture and analysis of circulating tumor cells (CTCs) holds promise for diagnosing and guiding treatment of pancreatic cancer. To accurately monitor disease progression, capture platforms must be robust to processes that increase the phenotypic heterogeneity of CTCs. Most CTC-analysis technologies rely on the recognition of epithelial-specific markers for capture and identification, in particular the epithelial cell-adhesion molecule (EpCAM) and cytokeratin. As the epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance are both associated with loss of epithelial markers and characteristics, the effect of these processes on the expression of commonly used CTC markers, specifically EpCAM, EGFR and cytokeratin, requires further exploration. To determine this effect, we developed an in vitro model of EMT and acquired gemcitabine resistance in human pancreatic cancer cell lines. Using this model, we show that EMT-induction and acquired chemoresistance decrease EpCAM expression and microfluidic anti-EpCAM capture performance. Furthermore, we find that EGFR capture is more robust to these processes. By measuring the expression of known mediators of chemoresistance in captured cells using automated imaging and image processing, we demonstrate the ability to resistance-profile cells on-chip. We expect that this approach will allow for the development of improved non-invasive biomarkers of pancreatic cancer progression.


Assuntos
Biomarcadores Tumorais/análise , Molécula de Adesão da Célula Epitelial/análise , Células Neoplásicas Circulantes/metabolismo , Neoplasias Pancreáticas/diagnóstico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Receptores ErbB/análise , Humanos
20.
Clin Cancer Res ; 25(6): 1880-1888, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30301829

RESUMO

PURPOSE: Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. The presence or absence of androgen receptor (AR) splice variants, AR-V7 and ARv567es, in mCRPC patient circulating tumor cells (CTC) may be associated with taxane treatment outcomes.Experimental Design: A novel digital droplet PCR (ddPCR) assay assessed AR-splice variant expression in CTCs from patients receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353). Patient outcomes were examined according to AR-splice variant expression, including prostate-specific antigen (PSA)50 response and progression-free survival (PFS). RESULTS: Of the 54 evaluable patients, 36 (67%) were AR-V7+, 42 (78%) were ARv567es+, 29 (54%) were double positive, and 5 (9%) were double negative. PSA50 response rates at any time were numerically higher for AR-V7- versus AR-V7+ (78% vs. 58%; P = 0.23) and for ARv567es- versus ARv567es+ (92% vs. 57%; P = 0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from cycle 1 day 1 to day 8 (n = 24), AR-V7+ patients (n = 16) had a 0.4% decrease versus a 12.9% and 26.7% decrease in AR-V7-/ARv567es- (n = 3) and AR-V7-/ARv567es+ (n = 5) patients, respectively, suggesting a dominant role for AR-V7 over ARv567es. Median PFS was 12.02 versus 8.48 months for AR-V7- versus AR-V7+ (HR = 0.38; P = 0.01), and 12.71 versus 7.29 months for ARv567es- versus ARv567es+ (HR = 0.37; P = 0.02). For AR-V7+, AR-V7-/ARv567es+, and AR-V7-/ARv567es- patients, median PFS was 8.48, 11.17, and 16.62 months, respectively (P = 0.0013 for trend). CONCLUSIONS: Although detection of both CTC-specific AR-V7 and ARv567es by ddPCR influenced taxane outcomes, AR-V7 primarily mediated the prognostic impact. The absence of both variants was associated with the best response and PFS with taxane treatment.See related commentary by Dehm et al., p. 1696.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Células Neoplásicas Circulantes/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Prednisona/farmacologia , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Taxoides/uso terapêutico , Resultado do Tratamento
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