Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With ...this aim, we studied the immunophenotypic and transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response.
PBMCs were obtained from 22 RRMS patients at baseline and 12 months of DMF treatment. Lymphocyte and monocyte subsets, and gene expression were assessed by flow cytometry and next-generation RNA sequencing, respectively. Clinical response was evaluated using the composite measure "no evidence of disease activity" NEDA-3 or "evidence of disease activity" EDA-3 at 2 years, classifying patients into responders (n=15) or non-responders (n=7), respectively.
In the whole cohort, DMF produced a decrease in effector (TEM) and central (TCM) memory T cells in both the CD4+ and CD8+ compartments, followed by an increase in CD4+ naïve T cells. Responder patients presented a greater decrease in TEM lymphocytes. In addition, responder patients showed an increase in NK cells and were resistant to the decrease in the intermediate monocytes shown by non-responders. Responder patients also presented differences in 3 subpopulations (NK bright, NK dim and CD8 TCM) at baseline and 4 subpopulations (intermediate monocytes, regulatory T cells, CD4 TCM and CD4 TEMRA) at 12 months. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes).
Responder patients to DMF exhibit differences in monocyte and lymphocyte subpopulations and a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.
The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for ...MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.
The photoelectrochemical reduction of CO2 to value-added products represents a promising strategy for mitigating CO2 emissions. However, further research efforts need to be undertaken to enable the ...technology for scale-up, including the design and fabrication of efficient photoelectrodes capable of yielding substantial photogenerated current densities. In this work, a photoanode combining a commercial calcium titanate perovskite (CaTiO3) and BiVO4 layers coated onto a transparent FTO substrate by automated spray pyrolysis is proposed. Different photoanode configurations are tested, with the most favourable results achieved when BiVO4 is positioned as the top layer with back illumination. The optimization of the catalytic loading is also assessed, finding an optimal at 1 mg cm−2 of CaTiO3 and 3 mg cm−2 of BiVO4, resulting in an impressive current density of –71 mA cm−2 at –1.8 V vs. Ag/AgCl. This optimal photoanode is then integrated into an electrolyzer for continuous visible light-driven CO2 reduction in the gas phase to formate, obtaining a concentration of 63.8 g L−1, with a Faradaic Efficiency of 79.1 %, and solar-to-fuel conversion efficiency of 7.6 %. These results represent a significant advancement in the development of photoanodes, offering promise for the future scalability of photoelectrochemical CO2 reduction processes.
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•A perovskite-based photoanode has been successfully developed for the PEC CO2 reduction to formate.•The p-n junction of CaTiO3 and BiVO4 exhibits promising photoactivity results.•The optimal configuration involves placing BiVO4 as the top layer with back-illumination.•A current density of –71 mA cm−2 is reached using 1 mg cm−2 of CaTiO3 and 3 mg cm−2 of BiVO4.•A concentration of 63.8 g L−1 of formate is obtained for CO2 reduction in gas phase.
The objective of the FeminFER project was to assess the value of ferric carboxymaltose following a multicriteria decision analysis in obstetrics and gynaecology in Spain.
Ferric carboxymaltose (FCM) ...and ferrous sulphate were evaluated using the EVIDEM framework. Ten stakeholders participated to collect different perspectives. The framework was adapted considering evidence retrieved with a PICO-S search strategy and grey literature. Criteria/subcriteria were weighted by level of relevance and an evidence-based decision-making exercise was developed in each criterion; weights and scores were combined to obtain the value of intervention relative to each criterion/subcriterion, that were further combined into the Modulated Relative Benefit-Risk Balance (MRBRB).
The most important criterion favouring FCM was Compared Efficacy/Effectiveness (0.183 ± 0.07), followed by Patient Preferences (0.059 ± 0.10). Only Direct medical costs criterion favoured FS (-0.003 ± 0.03). MRBRB favoured FCM; 0.45 ± 0.19; in a scale from -1 to + 1.
In conclusion, considering the several criteria involved in the decision-making process, participants agreed with the use of FCM according to its MRBRB.
Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the ...lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment.
Samples were obtained from relapsing-remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics.
Fingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod.
MS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker.
The current scenario of global warming has resulted in considerable uncertainty regarding the capacity of forest trees to adapt to increasing drought. Detailed ecophysiological knowledge would ...provide a basis to forecast expected species dynamics in response to climate change. Here, we compare the water balance (stomatal conductance, xylem water potential, needle osmotic adjustment) of Abies pinsapo, a relict drought-sensitive Mediterranean fir, along an altitudinal gradient. We related these variables to soil water and nutrient availability, air temperature, atmospheric water potential, and vapour pressure deficit during two consecutive years. Our results indicate that A. pinsapo closed stomata rapidly over a very narrow range of soil water availability and atmospheric dryness. This isohydric response during water stress suggests that this relict conifer relied on the plant hormone abscisic acid to maintain closed stomata during sustained drought, instead of needle desiccation to passively drive stomatal closure, needle osmotic adjustment or a plastic response of the xylem to different levels of water availability. Both the soil and foliar nutrient contents suggest that the studied populations are not limited by nutrient deficiencies, and drought was stronger in the warmer low-elevation areas.
Recent studies have addressed the changes in endocannabinoid ligands and receptors that occur in multiple sclerosis, as a way to explain the efficacy of cannabinoid compounds to alleviate spasticity, ...pain, tremor, and other signs of this autoimmune disease. Using Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we recently found a decrease in cannabinoid CB
1 receptors mainly circumscribed to the basal ganglia, which could be related to the motor disturbances characteristic of these rats. In the present study, using the same model, we explored the potential changes in several neurotransmitters in the basal ganglia that might be associated with the motor disturbances described in these rats, but we only found a small increase in glutamate contents in the globus pallidus. We also examined whether the motor disturbances and the changes of CB
1 receptors found in the basal ganglia of EAE rats disappear after the treatment with rolipram, an inhibitor of type IV phosphodiesterase able to supress EAE in different species. Rolipram attenuated clinical decline, reduced motor inhibition, and normalized CB
1 receptor gene expression in the basal ganglia. As a third objective, we examined whether EAE rats also exhibited changes in endocannabinoid levels as shown for CB
1 receptors. Anandamide and 2-arachidonoylglycerol levels decreased in motor related regions (striatum, midbrain) but also in other brain regions, although the pattern of changes for each endocannabinoid was different. Finally, we hypothesized that the elevation of the endocannabinoid activity, following inhibition of endocannabinoid uptake, might be beneficial in EAE rats. AM404, arvanil, and OMDM2 were effective to reduce the magnitude of the neurological impairment in EAE rats, whereas VDM11 did not produce any effect. The beneficial effects of AM404 were reversed by blocking TRPV1 receptors with capsazepine, but not by blocking CB
1 receptors with SR141716, thus indicating the involvement of endovanilloid mechanisms in these effects. However, a role for CB
1 receptors is supported by additional data showing that CP55,940 delayed EAE progression. In summary, our data suggest that reduction of endocannabinoid signaling is associated with the development of EAE in rats. We have also proved that the reduction of CB
1 receptors observed in these rats is corrected following treatment with a compound used in EAE such as rolipram. In addition, the direct or indirect activation of vanilloid or cannabinoid receptors may reduce the neurological impairment experienced by EAE rats, although the efficacy of the different compounds examined seems to be determined by their particular pharmacodynamic and pharmacokinetic characteristics.
A substantial influence of a magnetic field on the third-order nonlinear optical properties exhibited by aggregated networks of aligned carbon nanotubes (CNT) is reported by systematic measurements. ...A two-wave mixing was employed to explore and modulate the refractive index in the nanostructures in the nanosecond and picosecond regime. The presence of a magnetic field was able to modify the optical transmittance in the sample and the potentiality to generate structured light was proposed. Numerical simulations were conducted to analyze the magnetic field phenomena and the oscillations of the electric field in the studied sample. We discussed theoretical concepts, experimental methods, and computational tools employed to evaluate the third-order nonlinear optical properties of CNT in film form. Immediate applications of the system to modulate structured light can be contemplated.
Structured influence of a vectorial magnetic field on the ultrafastthird-order optical properties exhibited by carbon nanostructures are presented.
We describe and illustrate Magnolia nuevoleonensis A. Vázquez & Domínguez‐Yescas, a new deciduous tree species that belongs to M. sect. Macrophylla Figlar & Nooteboom. It is morphologically similar ...to M. ashei Weath., but differs from the latter in being a larger tree, with smaller flowers, larger and broadly ovoid (vs cylindrical to ellipsoid) fruits, prominently beaked (vs shortly beaked) carpels, and firm and short (vs flexible and elongated) styles.
Breast cancer (BC) is a major public health issue. More than one out of five women treated for breast cancer will develop lymphedema in an upper extremity. Current evidence advocates ...transdisciplinary oncological rehabilitation. Therefore, research in this area is necessary since limited consensus having been reached with regard to the basic essential components of this rehabilitation. Consensus has, however, been reached on the use of decongestive lymphedema therapy (DLT), but due to a lack of tests, the necessary dosages are unknown and its level is moderately strong. This study attempts to verify both the efficacy of activity-oriented proprioceptive antiedema therapy (TAPA), as compared to conventional treatments such as DLT or Complex Physical Therapy (CPT), as well as its efficiency in terms of cost-effectiveness, for patients affected by breast cancer-related arm lymphedema.
Controlled, randomized clinical trial with dual stratification, two parallel arms, longitudinal and single blind. 64 women with breast cancer-related arm lymphedema will take part in the study. The experimental group intervention will be the same for stage I and II, and will consist of neuro-dynamic exercises oriented to the activity, proprioceptive neuromuscular facilitation activities and proprioceptive anti-edema bandaging. The control group intervention, depending on the stage, will consist of preventive measures, skin care and exercise-prescribed training in the lymphedema workshop as well as compression garments (Stage I) or conservative Complex Decongestive Therapy treatment (skin care, multi-layer bandaging, manual lymphatic drainage and massage therapy) (Stage II).
Sociodemographic and clinical variables will be collected for the measurement of edema volume and ADL performance. Statistical analysis will be performed on intent to treat.
It has been recommended that patient training be added to DLT, as well as a re-designing of patient lifestyles and the promotion of health-related aspects. In addition, clinical trials should be undertaken to assess neural mobilization techniques and proprioceptive neuromuscular facilitation should be included in the therapy. Cohesive bandaging will also be performed as an early form of pressotherapy. The proposed study combines all of these aspects in order to increased comfort and promote the participation of individuals with lymphedema in everyday situations.
The authors have proposed the assessment of the experimental treatment for stages I and II. One possible limitation is the lack of awareness of whether or not this treatment would be effective for other stages as well as the concern for proper hand cleansing during use of bandages, given the current COVID-19 pandemic situation.
This trial was registered in ClinicalTrials.gov ( NCT03762044 ). Date of registration: 23 November 2018. Prospectively Registered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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