Publications by authors named "Pedro Miranda"

116 Publications

A comprehensive analysis of the impact of head model extent on electric field predictions in transcranial current stimulation.

J Neural Eng 2021 Mar 1. Epub 2021 Mar 1.

Institute of Biophysics and Biomedical Engineering, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal, Campo Grande, 1749-016, Lisboa, Portugal, Lisbon, 1749-016, PORTUGAL.

Objective: MRI-based head models are used to predict the electric field (E-field) in the brain in Transcranial Current Stimulation (tCS). The standard field of view (FOV) of clinical MRI often only covers the head down to the skull base, which has usually lead to models truncated at the nose. Although recent pipelines can artificially extend the head model to the neck, the need for implementing full head models preserving skull holes such as the foramen magnum remains controversial. The objective is to analyze the impact of head model extent on E-field accuracy, with emphasis on specific electrode montages.

Approach: A full head model containing an open foramen magnum and a cut head model with closed skull were compared in terms of predicted E-field. Several electrode montages, including fronto-occipital montages used in validation studies, were simulated. Local and global metrics were used to evaluate the error for both E-field magnitude and distribution, along with tangential and normal components over different cortical areas. The percentage of current flowing through the truncation level was also computed.

Results: Regarding E-field magnitude, small relative differences below 7% were found in gray matter for classical montages. Although considerably higher relative differences near 50% were found for fronto-occipital montages, absolute errors of 0.1 V/m were only found in non-targeted regions such as the cerebellum. Differences in tangential and normal E-fields were similar and followed the trend observed for E-field magnitude. Our results also showed a high correlation between the percentage of current shunted through the truncation level and the absolute E-field differences.

Significance: The influence of head model extent on E-field accuracy depends on electrode montage. Standard cut head models provide sufficiently accurate predictions for both E-field magnitude and distribution in targeted brain areas. Fronto-occipital montages exhibited larger errors, which might be considered in further validation studies.
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http://dx.doi.org/10.1088/1741-2552/abeab7DOI Listing
March 2021

A Blockchain-Based Consent Platform for Active Assisted Living: Modeling Study and Conceptual Framework.

J Med Internet Res 2020 12 4;22(12):e20832. Epub 2020 Dec 4.

School of Public Health and Health Systems, University of Waterloo, Waterloo, ON, Canada.

Background: Recent advancements in active assisted living (AAL) technologies allow older adults to age well in place. However, sensing technologies increase the complexity of data collection points, making it difficult for users to consent to data collection. One possible solution for improving transparency in the consent management process is the use of blockchain, an immutable and timestamped ledger.

Objective: This study aims to provide a conceptual framework based on technology aimed at mitigating trust issues in the consent management process.

Methods: The consent management process was modeled using established methodologies to obtain a mapping of trust issues. This mapping was then used to develop a conceptual framework based on previous monitoring and surveillance architectures for connected devices.

Results: In this paper, we present a model that maps trust issues in the informed consent process; a conceptual framework capable of providing all the necessary underlining technologies, components, and functionalities required to develop applications capable of managing the process of informed consent for AAL, powered by blockchain technology to ensure transparency; and a diagram showing an instantiation of the framework with entities comprising the participants in the blockchain network, suggesting possible technologies that can be used.

Conclusions: Our conceptual framework provides all the components and technologies that are required to enhance the informed consent process. Blockchain technology can help overcome several privacy challenges and mitigate trust issues that are currently present in the consent management process of data collection involving AAL technologies.
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http://dx.doi.org/10.2196/20832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748951PMC
December 2020

Bioinspired channeled, rhBMP-2-coated β-TCP scaffolds with embedded autologous vascular bundles for increased vascularization and osteogenesis of prefabricated tissue-engineered bone.

Mater Sci Eng C Mater Biol Appl 2021 Jan 22;118:111389. Epub 2020 Aug 22.

Department of Anaesthesia, Sun Yet-sen Memorial Hospital, Sun Yet-sen University, Yanjiang Road 120, Guangzhou 510120, China. Electronic address:

To date, the recovery of large bone defects is a major clinical challenge despite the availability of numerous therapeutic procedures including tissue engineering. Although there is a pressing need for large tissue-engineered constructs, inadequate vascularization remains an insurmountable barrier for successful clinical translation. Considering that vascularization is a prerequisite for osteogenesis, we proposed an advanced design of large customized porous β-tricalcium phosphate (TCP) scaffolds with biomimetic vascular hierarchy which upon embedding of femoral axial vascular bundles significantly improved overall vascularity of the scaffolds. Such scaffolds also promoted osteogenesis when they were coated with recombinant bone morphogenetic protein-2 (rhBMP-2). Compared to the conventional TCP scaffolds (S), the newly designed multi-channeled β-TCP (CS) scaffolds led to adequate blood vessels and bone-like tissue formation throughout their porous hierarchy within 4 weeks of implantation. Especially, the scaffolds coated with rhBMP-2 and embedded with flow-through vascular bundle (FVB) were able to form more uniform vascularized bone within 2 weeks post-implantation. Based on the clinical, radiographic, angiographic and histological assessments, the newly designed multi-channeled scaffolds were found to be promising for successful recovery of large bone defects.
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http://dx.doi.org/10.1016/j.msec.2020.111389DOI Listing
January 2021

The impact of the uncertainty of biological tissue thermal parameters on the estimated maximum temperature during TTFields treatment.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:2283-2286

In this work we evaluated the maximum temperature reached by the head tissues and transducers during TTFields treatment when the thermal parameters were changed. We used Pennes' equation to obtain the temperature distribution and we ran our studies using COMSOL Multiphysics. We observed that, among the parameters we tested, changes in the scalp thermal conductivity and grey matter blood perfusion were the ones that led to the highest temperature variations.Clinical Relevance- This work shows that the uncertainty regarding the thermal parameters of biological tissues might lead to significant changes in the temperature distribution when modeling heat transfer during TTFields therapy.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175372DOI Listing
July 2020

Heat transfer during TTFields treatment: Influence of the uncertainty of the electric and thermal parameters on the predicted temperature distribution.

Comput Methods Programs Biomed 2020 Nov 12;196:105706. Epub 2020 Aug 12.

Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.

Background And Objectives: Tumor Treating Fields (TTFields) is a technique currently used in the treatment of glioblastoma. It consists in applying an electric field (EF) with a frequency of 200 kHz using two pairs of transducer arrays placed on the head. Current should be injected at least 18 h/day and induce a minimum EF intensity of 1 V/cm at the tumor bed for the treatment to be effective. To avoid scalp burns, Optune, the device used to apply this technique in patients, monitors the temperature of the transducers and keeps them below 41 °C by reducing the injected current. The goal of this study was to quantify the impact of the uncertainty associated with the electric and thermal parameters on the predicted temperature of the transducers and of each tissue when TTFields were applied.

Methods: We used a realistic head model, added the two pairs of transducers arrays on the scalp and a virtual lesion, mimicking a glioblastoma tumor in the right hemisphere. Minimum, standard and maximum values for the electric and thermal properties of each tissue were taken from the literature after an extensive review. We used finite element methods (COMSOL Multiphysics) to solve Laplace's equation for the electric potential and Pennes' equation for the temperature distribution.

Results: We observed that the electric conductivity of the scalp and skull, as well as scalp's blood perfusion and thermal conductivity were the parameters to which tissue and transducers temperature were most sensitive to. Considering all simulations, scalp's maximum temperature was around 43.5 °C, skull's 42 °C, CSF's 41.2 °C and brain's 39.3 °C. According to the literature, for this temperature range, some physiological changes are predicted only for the brain. The average temperature of the transducers varied between 38.1 °C and 41.6 °C which suggests that modelling TTFields current injection is very sensitive to the parameters chosen.

Conclusions: Better knowledge of the physical properties of tissues and materials and how they change with the temperature is needed to improve the accuracy of these predictions. This information would likely decrease the predicted temperature maxima in the brain and thus help ascertaining TTFields safety from a thermal point of view.
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http://dx.doi.org/10.1016/j.cmpb.2020.105706DOI Listing
November 2020

A Computational Analysis of the Electric Field Components in Transcranial Direct Current Stimulation.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:5913-5917

Realistic electric field (E-field) models of the brain have cast doubt on classical targeting approaches used in transcranial direct current stimulation (tDCS). In apparent contradiction with physiological results, modeling studies predict similar or even higher E-field values in regions between the electrodes distant to the presumed targeted areas. As an explanation, not only the magnitude, but the direction of the E-field over specific cortical structures, have been shown to be determinant for the stimulation outcome. This work examines the magnitude and distribution of tangential and normal E-field components over different cortical areas in a representative brain atlas for various electrode montages commonly used in clinical applications. We have confirmed a general trend in the distribution of tangential and normal E-fields on gyri and sulci areas, respectively, partially independent of electrode configuration. The differences found between the various montages are also discussed.
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http://dx.doi.org/10.1109/EMBC.2019.8857382DOI Listing
July 2019

Temperature control in TTFields therapy of GBM: impact on the duty cycle and tissue temperature.

Phys Med Biol 2019 11 21;64(22):225008. Epub 2019 Nov 21.

Institute of Biophysics and Biomedical Engineering, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal. Author to whom correspondence should be addressed.

In TTFields therapy, Optune is used to deliver the electric field to the tumor via 4 transducer arrays. This device monitors the temperature of the transducers and reduces the current whenever a transducer reaches 41 °C. Our aim is to quantify Optune's duty cycle and to predict the steady-state temperature distribution in the head during GBM treatment. We used a realistic head model and the finite element method to solve Pennes equation and to simulate how Optune operates considering that current reduces to zero when the thermal limit is reached. The thermal impact was evaluated considering the maximum temperature reached by each tissue and using the CEM 43 °C metric. We observed that Optune switches the current on and off intermittently. In our model, one transducer reached the temperature limit quicker than the others and consequently it was the one that controlled current injection. This led to different duty cycles for the anterior-posterior and left-right array pairs. The thermal analysis indicated that the highest temperature in the model, 41.7 °C, was reached on the scalp under a transducer. However, TTFields may lead to significant changes only at the brain level such as BBB permeability increase, cerebral blood flow variation and changes in the concentration of some neurotransmitters. The duty cycle may be increased, e.g. by controlling the current at the transducer level. These predictions should be validated by comparison with experimental data and reconciled with the lack of evidence of thermal impact in clinical trials.
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http://dx.doi.org/10.1088/1361-6560/ab5323DOI Listing
November 2019

Cervical trans-spinal direct current stimulation: a modelling-experimental approach.

J Neuroeng Rehabil 2019 10 25;16(1):123. Epub 2019 Oct 25.

Instituto de Fisiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisbon, Portugal.

Background: Trans-spinal direct current stimulation (tsDCS) is a non-invasive technique with promising neuromodulatory effects on spinal cord (SC) circuitry. Computational studies are essential to guide effective tsDCS protocols for specific clinical applications. This study aims to combine modelling and experimental studies to determine the electrode montage that maximizes electric field (E-field) delivery during cervical tsDCS.

Methods: Current and E-field distributions in the cervical SC were predicted for four electrode montages in a human realistic model using computational methods. A double-blind crossover and randomized exploratory study was conducted using the montage that maximized E-field delivery. tsDCS was applied for 15 min in 10 healthy subjects (anodal, cathodal, sham, with polarity assigned to the cervical electrode), with a current intensity of 2.5 mA, resulting in a total current charge density delivery of 90 mC/cm. Upper limb motor (transcranial magnetic stimulation) and sensory evoked potentials (MEP, SEP), M-waves, H-reflex and F-wave responses were analysed. Central and peripheral conduction times were determined using MEP. Repeated measures ANOVA and Friedman test were used for statistical analysis (significance level α = 0.05).

Results: All montages presented higher current density and E-field magnitudes in the cervical SC region between the electrodes. However, electrodes at C3 and T3 spinous processes (C3-T3) originated the highest E-field magnitude (0.50 V/m). Using C3-T3 montage we observed significant changes in N9 SEP latency (p = 0.006), but significance did not persist in pairwise comparisons (sham-anodal: p = 0.022; sham-cathodal: p = 0.619; anodal-cathodal: p = 0.018; α = 0.017, Bonferroni corrected). MEP latency and central motor conduction time (CMCT) modified significantly on stimulation (p = 0.007 and p = 0.015, respectively). In addition, pairwise comparisons confirmed significant differences between sham and cathodal conditions after Bonferroni correction for MEP latency (sham-anodal: p = 0.868; sham-cathodal: p = 0.011; anodal-cathodal: p = 0.023) and CMCT (sham-anodal: p = 0.929; sham-cathodal: p = 0.010; anodal-cathodal: p = 0.034).

Conclusions: Computational models predicted higher E-field delivery in the cervical SC for the C3-T3 montage. Polarity-dependent effects in motor responses were reported using this montage consistent with spinal motor modulation. tsDCS experimental protocol designs should be guided by modelling studies to improve effectiveness.
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http://dx.doi.org/10.1186/s12984-019-0589-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815068PMC
October 2019

Efficacy and safety of switching from rituximab to biosimilar CT-P10 in rheumatoid arthritis: 72-week data from a randomized Phase 3 trial.

Rheumatology (Oxford) 2019 12;58(12):2193-2202

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.

Objective: To evaluate the efficacy and safety of CT-P10, a rituximab biosimilar after a single switch, during a multinational, randomized, double-blind Phase 3 trial involving patients with RA.

Methods: Patients received 48 weeks' treatment with CT-P10 or United States- or European Union-sourced reference rituximab (US-RTX and EU-RTX, respectively). Patients entering the extension period (weeks 48-72) remained on CT-P10 (CT-P10/CT-P10; n = 122) or US-RTX (US-RTX/US-RTX; n = 64), or switched to CT-P10 from US-RTX (US-RTX/CT-P10; n = 62) or EU-RTX (EU-RTX/CT-P10; n = 47) for an additional course. Efficacy endpoints included Disease Activity Score using 28 joints (DAS28), American College of Rheumatology (ACR) response rates, and quality of life-related parameters. Pharmacodynamics, immunogenicity and safety were also assessed.

Results: At week 72, similar improvements were observed by disease activity parameters including DAS28 and ACR response rate in the four extension period treatment groups. Quality of life improvements at week 72 vs baseline were similarly shown during the extension period in all groups. Newly developed anti-drug antibodies were detected in two patients following study drug infusion in the extension period. Similar pharmacodynamic and safety profiles were observed across groups.

Conclusion: Long-term use of CT-P10 up to 72 weeks was effective and well tolerated. Furthermore, switching from reference rituximab to CT-P10 in RA was well tolerated and did not result in any clinically meaningful differences in terms of efficacy, pharmacodynamics, immunogenicity and safety.

Trail Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02149121.
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http://dx.doi.org/10.1093/rheumatology/kez152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880852PMC
December 2019

Reinforcing 13-93 bioglass scaffolds fabricated by robocasting and pressureless spark plasma sintering with graphene oxide.

J Mech Behav Biomed Mater 2019 09 10;97:108-116. Epub 2019 May 10.

Abalonyx AS, Forskningsveien 1, 0373, Oslo, Norway.

13-93 bioglass (BG) scaffolds reinforced with graphene oxide (GO) were fabricated by robocasting (direct-ink-writing) technique. Composite scaffolds with 0-4 vol% content of GO platelets were printed, and then consolidated by pressureless spark plasma sintering at 650 °C. It was found that, despite hampering densification of the bioglass, the addition of GO platelets up to a certain content enhanced the mechanical performance of the 13-93 bioglass scaffolds in terms of strength and, especially, toughness. Best performance was obtained for 2 vol.% GO, which increased strain energy density (toughness) of the scaffolds by ∼894%, and their compressive strength by ∼26%. At higher contents, agglomeration of the nanoplatelets and increased porosity significantly reduced the mechanical enhancement obtained. Implications of the results on the fabrication of novel bioglass scaffolds that may find use in load-bearing bone tissue engineering applications are discussed.
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http://dx.doi.org/10.1016/j.jmbbm.2019.05.016DOI Listing
September 2019

Long-Term Efficacy and Safety of Biosimilar CT-P10 Versus Innovator Rituximab in Rheumatoid Arthritis: 48-Week Results from a Randomized Phase III Trial.

BioDrugs 2019 Feb;33(1):79-91

CELLTRION, Inc., Incheon, Republic of Korea.

Objective: The aim of this study was to investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks.

Methods: In this multinational, randomized, double-blind trial, adults with active RA received up to two courses of CT-P10, US-RTX, or EU-RTX alongside methotrexate. Efficacy endpoints included Disease Activity Score 28-joint count (DAS28) and American College of Rheumatology (ACR) response rates. Pharmacokinetics, pharmacodynamics, immunogenicity, and safety were also assessed.

Results: Of 372 patients randomized to the study drug, 330 (88.7%) completed the second treatment course. Mean change from baseline to week 48 in DAS28-C-reactive protein was comparable in the CT-P10 and combined rituximab (US-RTX and EU-RTX) groups (- 2.7 and - 2.6, respectively). ACR20, ACR50, and ACR70 response rates at week 48 indicated no differences between groups (80.6%, 55.4%, and 31.7% vs. 79.8%, 53.9%, and 33.7% in the CT-P10 and combined rituximab groups, respectively). Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, antidrug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic, pharmacodynamic, and safety profiles.

Conclusion: CT-P10 was similar to EU-RTX and US-RTX in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety up to week 48. CLINICALTRIALS.

Gov Identifier: NCT02149121.
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http://dx.doi.org/10.1007/s40259-018-00331-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373391PMC
February 2019

Oral formulation of DPP-4 inhibitor plus Quercetin improves metabolic homeostasis in type 1 diabetic rats.

Sci Rep 2018 10 17;8(1):15310. Epub 2018 Oct 17.

Laboratório de Bioquímica Metabólica (LBM), Departamento de Ciências Biológicas (DECBI), Universidade Federal de Ouro Preto (UFOP), Ouro Preto, MG, 35400-000, Brazil.

This study aimed to investigate the potential of an oral formulation (QV formulation) containing Quercetin and a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), Vildagliptin, in improving metabolic homeostasis in type 1 diabetes model. Female albino Fischer rats were divided into four groups: untreated control animals (C), untreated diabetic animals (D), diabetic animals treated with QV formulation (DQV), and diabetic animals treated with insulin (DI). Diabetes was induced by injection of alloxan (135 mg kg body mass) and confirmed by glycemic test. After the 30-day treatment period, biochemical parameters were analyzed in the pancreas, liver, and serum. Histopathological changes in pancreatic tissue were examined by Hematoxyline & Eosin staining and the insulin content in the islet measured by immunohistochemistry with anti-insulin antibody. The glycogen content in the hepatocytes was quantified by Periodic Schiff Acid staining. The QV formulation reduced the glycemia, preserved the pancreatic architecture, increased insulin levels, furthermore ameliorated lipid profile and to promote higher survival rate of animals. Together, our data suggest that the QV formulation treatment was able to normalize metabolic homeostasis in type 1 diabetic rats.
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http://dx.doi.org/10.1038/s41598-018-33727-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192983PMC
October 2018

The Odyssey's mythological network.

PLoS One 2018 30;13(7):e0200703. Epub 2018 Jul 30.

Department of Physics, State University of de Ponta Grossa, Paraná, Brazil.

In this work, we study the mythological network of Odyssey of Homer. We use ordinary statistical quantifiers in order to classify the network as real or fictional. We also introduce an analysis of communities which allows us to see how network properties shall emerge. We found that Odyssey can be classified both as real and fictional network. This statement is supported as far as mythological characters are removed, which results in a network with real properties. The community analysis indicated to us that there is a power-law relationship based on the max degree of each community. These results allow us to conclude that Odyssey might be an amalgam of myth and of historical facts, with communities playing a central role.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200703PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066224PMC
January 2019

Neuromodulation of lower limb motor responses with transcutaneous lumbar spinal cord direct current stimulation.

Clin Neurophysiol 2018 09 11;129(9):1999-2009. Epub 2018 Jul 11.

Instituto de Medicina Molecular, Instituto de Fisiologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal; Departamento de Neurociências e Saúde Mental, Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, 1649-035 Lisboa, Portugal. Electronic address:

Objective: Trans-spinal direct current stimulation (tsDCS) is a promising technique to modulate spinal circuits. Combining clinical with modelling studies can improve effectiveness of tsDCS protocols. The aim of this study is to measure the effects of lumbar tsDCS on motor spinal responses and observe if these are consistent with the electric field (E-field) predicted from a computational model.

Methods: The exploratory study design was double-blind crossover and randomized. tsDCS was delivered for 15 min (anodal, cathodal, sham) at L2 vertebra level (2.5 mA, 90 C/cm) in 14 healthy subjects. F-wave, H-reflex, cortical silent period, motor evoked potential and sympathetic skin response were analyzed. Statistical methods were applied with Bonferroni correction for multiple comparisons, a p < 0.05 was set as significant. A human volume conductor model was obtained from available databases. E-field distributions in the spinal grey matter (GM) and white matter (WM) were calculated.

Results: No tsDCS effects were observed. E-field magnitude predicted in the lumbosacral spinal GM and WM was <0.15 V/m, insufficient to ensure neuromodulation, which is consistent with the absence of effects.

Conclusion: The tsDCS protocol applied did not change motor response to delivered stimulus, thus we observed no effect on motor spinal circuits.

Significance: Future tsDCS protocols should be supported by computational models.
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http://dx.doi.org/10.1016/j.clinph.2018.07.002DOI Listing
September 2018

Synthetic molecules for disruption of the MYC protein-protein interface.

Bioorg Med Chem 2018 08 11;26(14):4234-4239. Epub 2018 Jul 11.

Department of Chemistry, BCC-582, 10550 N Torrey Pines Road, The Scripps Research Institute, La Jolla, CA 92037, United States. Electronic address:

MYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. Despite this prevalence, functional chemical probes of MYC function at the protein level have been limited. Previously, we discovered 5a, that binds to MYC with potency and specificity, downregulates the transcriptional activities of MYC and shows efficacy in vivo. However, this scaffold posed intrinsic pharmacokinetic liabilities, namely, poor solubility that precluded biophysical interrogation. Here, we developed a screening platform based on field-effect transistor analysis (Bio-FET), surface plasmon resonance (SPR), and a microtumor formation assay to analyze a series of new compounds aimed at improving these properties. This blind SAR campaign has produced a new lead compound of significantly increased in vivo stability and solubility for a 40-fold increase in exposure. This probe represents a significant advancement that will not only enable biophysical characterization of this interaction and further SAR, but also contribute to advances in understanding of MYC biology.
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http://dx.doi.org/10.1016/j.bmc.2018.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214403PMC
August 2018

Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial.

MAbs 2018 Aug/Sep;10(6):934-943. Epub 2018 Jul 16.

x Division of Rheumatology , Hanyang University Hospital for Rheumatic Diseases , Seoul , Republic of Korea.

This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration-time curve (AUC) from time zero to last measurable concentration (AUC), AUC from time zero to infinity (AUC), and maximum concentration (C) after two infusions. The primary efficacy endpoint was change from baseline to week 24 in Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP). Pharmacodynamics, immunogenicity, and safety were also assessed. 372 patients were randomly assigned to CT-P10 (n = 161) or RTX (n = 211 [US-RTX, n = 151; EU-RTX, n = 60]). For the co-primary pharmacokinetic endpoints, 90% confidence intervals (CI) for ratios of geometric means (CT-P10/US-RTX, CT-P10/EU-RTX or EU-RTX/US-RTX) all fell within the equivalence margin of 80-125%. Adjusted least squares (LS) mean (standard error) change from baseline in DAS28-CRP at week 24 was -2.13 (0.175) for CT-P10 and -2.09 (0.176) for RTX. The 95% CI (-0.29, 0.21) of the estimated treatment difference between CT-P10 and RTX (-0.04) was entirely within the efficacy equivalence margin of ±0.5. Pharmacodynamics, immunogenicity, and safety profiles were similar for CT-P10 and RTX. The pharmacokinetics of CT-P10, US-RTX, and EU-RTX were equivalent. CT-P10 and RTX were also equivalent in terms of efficacy and displayed similar pharmacodynamic, immunogenicity, and safety profiles up to week 24.
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http://dx.doi.org/10.1080/19420862.2018.1487912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152436PMC
February 2019

A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred From Computational Modeling.

IEEE Rev Biomed Eng 2018 13;11:195-207. Epub 2018 Feb 13.

Tumor-treating fields (TTFields) are a cancer treatment modality that uses alternating electric fields of intermediate frequency (∼100-500 kHz) and low intensity (1-3 V/cm) to disrupt cell division. TTFields are delivered by transducer arrays placed on the skin close to the tumor and act regionally and noninvasively to inhibit tumor growth. TTFields therapy is U.S. Food and Drug Administration approved for the treatment of glioblastoma multiforme, the most common and aggressive primary human brain cancer. Clinical trials testing the safety and efficacy of TTFields for other solid tumor types are underway. The objective of this paper is to review computational approaches used to characterize TTFields. The review covers studies of the macroscopic spatial distribution of TTFields generated in the human head, and of the microscopic field distribution in tumor cells. In addition, preclinical and clinical findings related to TTFields and principles of its operation are summarized. Particular emphasis is put on outlining the potential clinical value inferred from computational modeling.
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http://dx.doi.org/10.1109/RBME.2017.2765282DOI Listing
December 2018

Crystallography Coupled with Kinetic Analysis Provides Mechanistic Underpinnings of a Nicotine-Degrading Enzyme.

Biochemistry 2018 07 13;57(26):3741-3751. Epub 2018 Jun 13.

Program in Biomolecular Pharmacology , Boston University School of Medicine , 72 East Concord Street , Boston , Massachusetts 02118 , United States.

Nicotine oxidoreductase (NicA2) is a bacterial flavoenzyme, which catalyzes the first step of nicotine catabolism by oxidizing S-nicotine into N-methyl-myosmine. It has been proposed as a biotherapeutic for nicotine addiction because of its nanomolar substrate binding affinity. The first crystal structure of NicA2 has been reported, establishing NicA2 as a member of the monoamine oxidase (MAO) family. However, substrate specificity and structural determinants of substrate binding and/or catalysis have not been explored. Herein, analysis of the pH-rate profile, single-turnover kinetics, and binding data establish that pH does not significantly affect the catalytic rate and product release is not rate-limiting. The X-ray crystal structure of NicA2 with S-nicotine refined to 2.65 Å resolution reveals a hydrophobic binding site with a solvent exclusive cavity. Hydrophobic interactions predominantly orient the substrate, promoting the binding of a deprotonated species and supporting a hydride-transfer mechanism. Notably, NicA2 showed no activity against neurotransmitters oxidized by the two isoforms of human MAO. To further probe the substrate range of NicA2, enzyme activity was evaluated using a series of substrate analogues, indicating that S-nicotine is the optimal substrate and substitutions within the pyridyl ring abolish NicA2 activity. Moreover, mutagenesis and kinetic analysis of active-site residues reveal that removal of a hydrogen bond between the pyridyl ring of S-nicotine and the hydroxyl group of T381 has a 10-fold effect on K, supporting the role of this bond in positioning the catalytically competent form of the substrate. Together, crystallography combined with kinetic analysis provides a deeper understanding of this enzyme's remarkable specificity.
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http://dx.doi.org/10.1021/acs.biochem.8b00384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295333PMC
July 2018

Enhancing the mechanical and in vitro performance of robocast bioglass scaffolds by polymeric coatings: Effect of polymer composition.

J Mech Behav Biomed Mater 2018 08 25;84:35-45. Epub 2018 Apr 25.

Departamento de Ingeniería Mecánica, Energética y de los Materiales, Universidad de Extremadura, Escuela de Ingenierías Industriales, Avda. de Elvas s/n, 06006 Badajoz, Spain. Electronic address:

The effect of different polymeric coatings, including natural and synthetic compositions, on the mechanical performance of 45S5 bioglass robocast scaffolds is systematically analyzed in this work. Fully amorphous 45S5 bioglass robocast scaffolds sintered at 550 °C were impregnated with natural (gelatin, alginate, and chitosan) and synthetic (polycaprolactone, PCL and poly-lactic acid, PLA) polymers through a dip-coating process. Mechanical enhancement provided by these coatings in terms of both compressive strength and strain energy density was evaluated. Natural polymers, in general, and chitosan, in particular, were found to produce the greater reinforcement. The effect of these coatings on the in vitro bioactivity and degradation behavior of 45S5 bioglass robocast scaffolds was also investigated through immersion tests in simulated body fluid (SBF). Coatings from natural polymers, especially chitosan, are shown to have a positive effect on the bioactivity of 45S5 bioglass, accelerating the formation of an apatite-like layer. Besides, most coating compositions reduced the degradation (weight loss) rate of the scaffold, which has a positive impact on the evolution of their mechanical properties.
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http://dx.doi.org/10.1016/j.jmbbm.2018.04.022DOI Listing
August 2018

High salt diet exacerbates colitis in mice by decreasing Lactobacillus levels and butyrate production.

Microbiome 2018 03 22;6(1):57. Epub 2018 Mar 22.

Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: Changes in hygiene and dietary habits, including increased consumption of foods high in fat, simple sugars, and salt that are known to impact the composition and function of the intestinal microbiota, may explain the increase in prevalence of chronic inflammatory diseases. High salt consumption has been shown to worsen autoimmune encephalomyelitis and colitis in mouse models through p38/MAPK signaling pathway. However, the effect of high salt diet (HSD) on gut microbiota and on intestinal immune homeostasis, and their roles in determining vulnerability to intestinal inflammatory stimuli are unknown. Here, we investigate the role of gut microbiota alterations induced by HSD on the severity of murine experimental colitis.

Results: Compared to control diet, HSD altered fecal microbiota composition and function, reducing Lactobacillus sp. relative abundance and butyrate production. Moreover, HSD affected the colonic, and to a lesser extent small intestine mucosal immunity by enhancing the expression of pro-inflammatory genes such as Rac1, Map2k1, Map2k6, Atf2, while suppressing many cytokine and chemokine genes, such as Ccl3, Ccl4, Cxcl2, Cxcr4, Ccr7. Conventionally raised mice fed with HSD developed more severe DSS- (dextran sodium sulfate) and DNBS- (dinitrobenzene sulfonic acid) induced colitis compared to mice on control diet, and this effect was absent in germ-free mice. Transfer experiments into germ-free mice indicated that the HSD-associated microbiota profile is critically dependent on continued exposure to dietary salt.

Conclusions: Our results indicate that the exacerbation of colitis induced by HSD is associated with reduction in Lactobacillus sp. and protective short-chain fatty acid production, as well as changes in host immune status. We hypothesize that these changes alter gut immune homeostasis and lead to increased vulnerability to inflammatory insults.
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http://dx.doi.org/10.1186/s40168-018-0433-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865374PMC
March 2018

Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity.

ACS Infect Dis 2018 05 1;4(5):815-824. Epub 2018 Mar 1.

Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeutics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with antiarenaviral activity that could serve as probes to identify arenavirus-host interactions suitable for targeting, as well as lead compounds to develop future antiarenaviral drugs. Screening of a combinatorial library of Krönhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[ b][1,4] dioxin-6-yl)-4'-methoxy-[1,1'-biphenyl]-3-yl)thiophene-2-carboxamide] as having strong anti-lymphocytic choriomeningitis virus (LCMV) activity in cultured cells. KP-146 did not inhibit LCMV cell entry but rather interfered with the activity of the LCMV ribonucleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Kröhnke pyridine scaffold as a valuable source to identify compounds that could serve as tools to dissect arenavirus-host interactions, as well as lead candidate structures to develop antiarenaviral drugs.
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http://dx.doi.org/10.1021/acsinfecdis.7b00236DOI Listing
May 2018

Transcutaneous spinal direct current stimulation of the lumbar and sacral spinal cord: a modelling study.

J Neural Eng 2018 06 9;15(3):036008. Epub 2018 Feb 9.

Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal. Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.

Objective: Our aim was to perform a computational study of the electric field (E-field) generated by transcutaneous spinal direct current stimulation (tsDCS) applied over the thoracic, lumbar and sacral spinal cord, in order to assess possible neuromodulatory effects on spinal cord circuitry related with lower limb functions.

Approach: A realistic volume conductor model of the human body consisting of 14 tissues was obtained from available databases. Rubber pad electrodes with a metallic connector and a conductive gel layer were modelled. The finite element (FE) method was used to calculate the E-field when a current of 2.5 mA was passed between two electrodes. The main characteristics of the E-field distributions in the spinal grey matter (spinal-GM) and spinal white matter (spinal-WM) were compared for seven montages, with the anode placed either over T10, T8 or L2 spinous processes (s.p.), and the cathode placed over right deltoid (rD), umbilicus (U) and right iliac crest (rIC) areas or T8 s.p. Anisotropic conductivity of spinal-WM and of a group of dorsal muscles near the vertebral column was considered.

Main Results: The average E-field magnitude was predicted to be above 0.15 V m in spinal cord regions located between the electrodes. L2-T8 and T8-rIC montages resulted in the highest E-field magnitudes in lumbar and sacral spinal segments (>0.30 V m). E-field longitudinal component is 3 to 6 times higher than the ventral-dorsal and right-left components in both the spinal-GM and WM. Anatomical features such as CSF narrowing due to vertebrae bony edges or disks intrusions in the spinal canal correlate with local maxima positions.

Significance: Computational modelling studies can provide detailed information regarding the electric field in the spinal cord during tsDCS. They are important to guide the design of clinical tsDCS protocols that optimize stimulation of application-specific spinal targets.
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http://dx.doi.org/10.1088/1741-2552/aaac38DOI Listing
June 2018

Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With Rheumatoid Arthritis.

Arthritis Rheumatol 2018 05 31;70(5):679-689. Epub 2018 Mar 31.

Brigham and Women's Hospital, Boston, Massachusetts.

Objective: Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony-stimulating factor receptor α. We undertook to determine the long-term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open-label extension study (ClinicalTrials.gov identifier: NCT01712399).

Methods: In study 1071, patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate. In study 1107, patients with an inadequate response to anti-tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate. Patients entering the open-label extension study received 100 mg mavrilimumab every other week plus methotrexate. Long-term safety and efficacy of mavrilimumab were assessed.

Results: A total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open-label extension study discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient-years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1-3.3 years). The most common treatment-emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient-years) and bronchitis (n = 51; 5.68 per 100 patient-years). At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with AEs. Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <3.2, and 40.6% of patients achieved a DAS28-CRP of <2.6.

Conclusion: Long-term treatment with mavrilimumab maintained response and was well-tolerated with no increased incidence of treatment-emergent AEs. Safety data were comparable with those from both phase IIb qualifying studies.
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http://dx.doi.org/10.1002/art.40420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947536PMC
May 2018

An enzymatic advance in nicotine cessation therapy.

Chem Commun (Camb) 2018 Feb;54(14):1686-1689

Departments of Chemistry, Immunology, Microbiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

A nicotine-degrading enzyme termed NicA2 was altered (NicA2-J1) through fusion of an albumin binding domain to increase its half-life. Examination of NicA2-J1 in vivo demonstrated a complete blockade of brain nicotine access, which in turn blunted nicotine's psychoactive effects. These data further support development of pharmacokinetic nicotine cessation therapeutics.
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http://dx.doi.org/10.1039/c7cc09134fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231713PMC
February 2018

Effects of Amerindian Genetic Ancestry on Clinical Variables and Therapy in Patients with Rheumatoid Arthritis.

J Rheumatol 2017 Dec 1;44(12):1804-1812. Epub 2017 Nov 1.

From the Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Departamento de Inmunología y Reumatología, Hospital General de Occidente y Universidad de Guadalajara, Zapopan; Unidad de Investigación "Dr. Mario Alvizouri Muñoz" Hospital General "Dr. Miguel Silva," Secretaría de Salud de Michoacán, Morelia; Servicio de Reumatología del Departamento de Medicina Interna, Facultad de Medicina y Hospital Universitario "Dr. José Eleuterio González," Universidad Autonoma de Nuevo León, Monterrey; Departamento de Reumatología, Hospital General de Culiacán, Culiacán; Unidad de Reumatología, Hospital General de México "Dr. Eduardo Liceaga"; Unidad de Biología Molecular y Medicina Genómica from Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; Hospital Provincial de Rosario; Instituto Lucha Antipoliomielítica de Rosario (ILAR); Hospital Escuela Eva Perón, Granadero Baigorria; Hospital José Maria Cullen; Hospital J.B. Iturraspe, Santa Fe; Hospital San Martín, Paraná; Hospital Privado de Córdoba; Hospital Italiano de Córdoba; Instituto Reumatológico Strusberg, Córdoba; Hospital Cosme Argerich; Hospital Italiano de Buenos Aires; Organización Médica Integral; Centro de Educación Médica e Investigaciones Clínicas (CEMIC); Instituto de Rehabilitación Psicofísica (IREP); Hospital Bernardino Rivadavia; Hospital de Clínicas de Buenos Aires, Buenos Aires; H.I.G.A. San Martín, La Plata; H.I.G.A. Oscar E. Alende, Mar del Plata; Centro Medico Privado de Reumatología; FUNIPSE, San Miguel de Tucumán, Tucumán; Hospital Interzonal San Juan Bautista, Catamarca; Hospital G. Rawson, San Juan; Sanatorio Parque, Rosario, Argentina; Facultad Medicina Occidente, and Facultad de Medicina Campus Centro, Universidad de Chile, Santiago de Chile, Chile; Servicio de Reumatología, Hospital Nacional Guillermo Almenara I, EsSalud y Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú; GENYO, Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica, Granada, Spain; Unit of Chronic Inflammatory Diseases, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Objective: To define whether Amerindian genetic ancestry correlates with clinical and therapeutic variables in admixed individuals with rheumatoid arthritis (RA) from Latin America.

Methods: Patients with RA (n = 1347) and healthy controls (n = 1012) from Argentina, Mexico, Chile, and Peru were included. Samples were genotyped for the Immunochip v1 using the Illumina platform. Clinical data were obtained through interviews or the clinical history.

Results: Percentage of Amerindian ancestry was comparable between cases and controls. Morning stiffness (p < 0.0001, OR 0.05), rheumatoid factor (RF; p < 0.0001, OR 0.22), radiographic changes (p < 0.0001, OR 0.05), and higher number of criteria were associated with lower Amerindian ancestry after Bonferroni correction. Higher Amerindian ancestry correlated only with weight loss (p < 0.0001, OR 2.85). Increased Amerindian ancestry correlated with higher doses of azathioprine (p < 0.0001, OR 163.6) and sulfasalazine (p < 0.0001, OR 48.6), and inversely with methotrexate (p = 0.001, OR 0.35), leflunomide (p = 0.001, OR 0.16), and nonsteroidal antiinflammatory drugs (p = 0.001, OR 0.37). Only the presence of RF and weight loss were modified after confounders adjustment.

Conclusion: Amerindian ancestry protects against most major clinical criteria of RA, but regarding the association of RF with increased European ancestry, age, sex, and smoking are modifiers. Ancestry also correlates with the therapeutic profiles.
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http://dx.doi.org/10.3899/jrheum.160485DOI Listing
December 2017

A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis.

Arthritis Rheumatol 2018 01;70(1):49-59

Charité-University Medicine Berlin, Free University of Berlin, and Humboldt University of Berlin, Berlin, Germany.

Objective: This 24-week, phase IIb, double-blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte-macrophage colony-stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti-TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) (referred to as DMARD-IR) and/or inadequate response to other anti-TNF agents (referred to as anti-TNF-IR).

Methods: Patients with active RA and a history of DMARD-IR (≥1 failed regimen) or DMARD-IR (≥1 failed regimen) and anti-TNF-IR (1-2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate. The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures. This study was not powered to formally compare the 2 treatments.

Results: At week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, -3.5% (90% confidence interval [90% CI] -16.8, 9.8), -8.6% (90% CI -22.0, 4.8), and -9.8% (90% CI -21.1, 1.4), respectively; in the anti-TNF-IR group, 11.1% (90% CI -7.8, 29.9), -8.7% (90% CI -28.1, 10.7), and -0.7% (90% CI -18.0, 16.7), respectively. Differences in the percentage of patients achieving a DAS28-CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were -11.6% (90% CI -23.2, 0.0) in all patients, and -4.0% (90% CI -20.9, 12.9) in the anti-TNF-IR group. The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups. Treatment-emergent adverse events were reported in 51.4% of mavrilimumab-treated patients and 42.6% of golimumab-treated patients. No deaths were reported, and no specific safety signals were identified.

Conclusion: The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well-tolerated in patients who had shown an inadequate response to DMARDs and/or other anti-TNF agents.
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http://dx.doi.org/10.1002/art.40323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767745PMC
January 2018

Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro-2H-pyrans via Tandem S2'-Prins Cyclization.

Org Lett 2017 09 31;19(18):4834-4837. Epub 2017 Aug 31.

Instituto de Productos Naturales y Agrobiología, CSIC , Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain.

A new, direct, and diastereoselective synthesis of activated 2,3,4,6-tetrasubstituted tetrahydro-2H-pyrans is described. In this reaction, iron(III) catalyzed an S2'-Prins cyclization tandem process leading to the creation of three new stereocenters in one single step. These activated tetrahydro-2H-pyran units are easily derivatizable through CuAAC conjugations in order to generate multifunctionalized complex molecules. DFT calculations support the in situ S2' reaction as a preliminary step in the Prins cyclization.
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http://dx.doi.org/10.1021/acs.orglett.7b02270DOI Listing
September 2017