Co Treatment With Biologic Agents and Immunotherapy in the Setting of irAEs of Difficult Management

Adverse drugs reaction; Immune check-point inhibitors therapy; Immunosuppression therapyReacción adversa a medicamentos; Terapia con inhibidores del punto de control inmunitario; Terapia inmunosupresoraReaccions adverses als fàrmacs; Teràpia amb inhibidors del punt de control immune; Teràpia d'immunosupressióIn recent years, immunotherapy has become an important pillar of cancer treatment, with high response rates regardless of tumor histology or baseline mutations, sometime in patients without any alternative of treatment. Moreover, these treatments are moving from later line therapies to front-line therapies in the metastasic setting. However, immune activation associated with immune check-point inhibitors (ICI) is not selective and a large variety of immune-related adverse events, with an increasing frequency, have been associated with anti-PD1, anti-PD-1/L-1 and anti-CTLA-4 agents. In clinical trials, and sometimes also in real life practice, patients who develop severe toxicities on ICI-based therapies are usually not allowed to resume ICI once their disease progresses, because of the chance of developing severe irAEs on rechallenge with immunotherapies. Moreover, patients with irAEs suffer important side effects due to the high dose corticosteroids that are used to treat them. Therapy with ICI is sometimes the only alternative for certain patients, and for this reason co treatment with classic (DMARDS) or biologic immunosuppression therapy and ICI must be considered. Co-treatment with this type of immunosuppressant drugs, apart from allowing the maintenance of ICI therapy, drive to a lesser use of corticosteroids, with an improvement of the safety and quality of life of the patients. Such a tailored scheme of treatment is mostly an expert opinion based on recommendation and currently there is scarce evidence supporting it. Herein we present comprehensive, current recommendations and real-world data on the use of co-treatment with ICI and DMARDS and biologic immunosuppression

Evaluación de la sensibilidad en distintas viníferas blancas: mildiu, oídio y botrytis

6 páginas, 6 figuras.--Trabajo publicado en revista de divulgación científica.Peer reviewe

Variability of the stomata among 'Albariño' (Vitis vinifera L.) clones and its relationship with susceptibility to downy mildew

In grapevines the stomata are located on the abaxial epidermis of the leaves, arranged in no specific order. As in other plants, they regulate the communication between the internal tissues and the external atmosphere, playing a critical role in both photosynthesis and transpiration processes. Moreover, stomata are the main entrance for pathogens such as Plasmopara viticola (Berk & Curt.)Berl. & de Toni, the causal agent of downy mildew, one of the most widespread fungal diseases of grapevines. Due to this and the fact that downy mildew causes large losses in yield and quality of grapes, there is a great interest to determine the causes of the different degree of susceptibility to this pathogen. Some authors have searched for anatomical features that might be related to the penetration and development of P. viticola in the mesophyll of grapevine leaves, such as the density of leaf hairs (KORTEKAMP and ZYPRIAN, 1999) or the ultrastructure of stomata (JÜRGES et al. 2009). Other authors have examined the differences concerning the number of stomata in different grapevine cultivars (DÜRING 1980, PALLIOTTI et al. 2000, BEN SALEM-FNAYOU et al. 2005), but none had evaluated the differences for this aspect between clones of the same cultivar. Recently some authors have found a strong correlation between the number and size of stomata and the susceptibility to downy mildew (LU et al. 2010). The aim of this work is to determine whether different clones of 'Albariño' differ in terms of their number and size of stomata and its possible relation with the different susceptibility to P. viticola of these same clones.Financial support from the Xunta de Galicia Research Projects (07MRU024403PR).Peer reviewe

Direct and indirect costs of Multiple Sclerosis in Baix Llobregat (Catalonia, Spain), according to disability

BACKGROUND: Multiple sclerosis (MS) is an incurable chronic disease that predominantly affects young adults. It has a high socio-economic impact which increases as disability progresses. An assessment of the real costs of MS may contribute to our knowledge of the disease and to treat it more efficiently. Our objective is to assess the direct and indirect costs of MS from a societal perspective, in patients monitored in our MS Unit (Baix Llobregat, Catalonia) and grouped according to their disability (EDSS). METHODS: We analysed data from 200 MS patients, who answered a questionnaire on resource consumption, employment and economical status. Mean age was 41.6 years, mean EDSS 2.7, 65.5% of patients were female, 79.5% had a relapsing-remitting course, and 67.5% of them were receiving immunomodulatory treatment (IT). Patients were grouped into five EDSS stages. Data from the questionnaires, hospital charts, Catalan Health Service tariffs, and figures from Catalan Institute of Statistics were used to calculate the direct and indirect costs. The cost-of-illness method, and the human capital approach for indirect costs, were applied. Sensitivity analyses were performed to strengthen results. RESULTS: The mean total annual cost of MS per patient results 24272 euros. This cost varied according to EDSS: 14327 euros (EDSS = 0), 18837 euros (EDSS = 1–3), 27870 euros (EDSS = 3.5–5.5), 41198 euros (EDSS = 6–7) and 52841 euros (EDSS>7.5). When the mean total annual costs was adjusted by the mean % of patients on IT in our Unit (31%) the result was 19589 euros. The key-drivers for direct costs were IT in low EDSS stages, and caregiver costs in high stages. Indirect costs were assessed in terms of the loss of productivity when patients stop working. Direct costs accounted for around 60% of total costs in all EDSS groups. IT accounts from 78% to 11% of direct costs, and decreased as disability progressed. CONCLUSION: The total mean social costs of MS in a cohort from Baix Llobregat (Catalonia) were estimated at 24272 euros per patient/year, and ranged between 14327 euros (EDSS = 0) and 52841 euros (EDSS = 7.5–9.5). Total costs, and particularly informal and direct costs, increased as the disability progressed. IT should be able to delay the progression of disability to be efficient and not only effective

Melatonin modulation of crosstalk among malignant epithelial, endothelial and adipose cells in breast cancer (Review)

Melatonin, the main secretory product of the pineal gland, is an oncostatic agent that reduces the growth and development of various types of tumors, particularly mammary tumors whose growth is dependent on estrogens. Previous in vivo and in vitro studies point to the hypothesis that melatonin interplays with estrogen signaling pathways at three different levels: i) an indirect mechanism, by interfering with the hypothalamic‑pituitary‑reproductive axis in such way that the level of plasma estrogens synthesized by the gonadal glands are downregulated; ii) a direct mechanism of the pineal gland at the cell cancer level, disrupting the activation of estradiol receptors, therefore behaving as a selective estrogen receptor modulator; and iii) by regulating the enzymes involved in the biosynthesis of estrogens in other tissues, thus behaving as a selective estrogen enzyme modulator. The intratumoral metabolism and synthesis of estrogens, as a result of the interactions of various enzymes, is more important than blood uptake to maintain mammary gland estrogen levels in menopausal females. Additionally, estrogens are considered to play an important role in the pathogenesis and development of hormone‑dependent breast carcinoma. Paracrine interactions among malignant epithelial cells and proximal adipose and endothelial cells, through cytokines and growth factors produced by breast tumor cells, modulate estrogen production at the mammary tumor level and, as a consequence, the genesis and development of mammary tumors. The aim of the present review is to summarize the recent findings describing the mechanisms by which melatonin is able to modulate the crosstalk among malignant epithelial, endothelial and adipose cells in breast cancer

The use of poplar and willow to produce biomass for energy

En esta revisión, se describen las principales características del uso de Salicáceas (álamos y sauces) en plantaciones de rotación corta para producir biomasa para energía. Se analizan distintos tipos de plantaciones para producir biomasa y la sustentabilidad de las mismas. Se resumen los resultados del mejoramiento de sauces y álamos para producir biomasa en distintos países. Finalmente, se discuten aspectos que será necesario investigar para el desarrollo de plantaciones de rotación corta con Salicáceas para producir biomasa en Argentina.In this revision, the characteristics of short rotation biomass plantations with Salicaceae (poplars and willows) are discussed. Different types of biomass plantations are described and their sustainability is discussed. The results obtained in breeding of poplar and willows for biomass production in different countries are summarized. Finally, there is a discussion of the research needed to develop short rotation bioenergy plantations in Argentina using Salicaceae.Facultad de Ciencias Agrarias y Forestale

Cost-Analysis of Subcutaneous vs Intravenous Administration of Natalizumab Based on Patient Care Pathway in Multiple Sclerosis in Spain

Análisis de costes; Administración subcutánea; Esclerosis múltipleAnàlisi de costos; Administració subcutània; Esclerosi múltipleCost-analysis; Subcutaneous administration; Multiple sclerosisIntroduction A subcutaneous (SC) formulation of natalizumab has been recently authorised for multiple sclerosis patients. This study aimed to assess the implications of the new SC formulation, and to compare the annual treatment costs of SC versus intravenous (IV) natalizumab therapy from both the Spanish healthcare system (direct health cost) and the patient (indirect cost) perspectives. Methods A patient care pathway map and a cost-minimisation analysis were developed to estimate SC and IV natalizumab annual costs over a 2-year time horizon. Considering the patient care pathway and according to natalizumab experience (IV) or estimation (SC), a national expert panel involving neurologists, pharmacists, and nurses provided information/data regarding resource consumption for drug and patient preparation, administration, and documentation. One hour of observation was applied to the first six (SC) or 12 (IV) doses, and 5 min for successive doses. The Day hospital (infusion suite) facilities at a reference hospital were considered for IV administrations and the first six SC injections. For successive SC injections, either a reference hospital or regional hospital in a consulting room was considered. Productivity time associated with travel (56 min to reference hospital, 24 min to regional hospital) and waiting time pre- and post-treatment (SC 15 min, IV 25 min) were assessed for patients and caregivers (accompanying 20% of SC and 35% of IV administrations). National salaries for healthcare professionals were used for cost estimation (€, year 2021). Results At years 1 and 2, total time and cost savings (excluding drug acquisition cost) per patient, driven by saving on administration and patient and caregiver productivity for SC at a reference hospital versus IV at a reference hospital, were 116 h (a reduction of 54.6%) and €3682.82 (a reduction of 66.2%). In the case of natalizumab SC at a regional hospital, the total time and cost saving were 129 h (a reduction of 60.6%) and €3883.47 (a reduction of 69.8%). Conclusions Besides the potential benefits of convenient administration and improving work–life balance, as suggested by the expert panel, natalizumab SC was associated with cost savings for the healthcare system by avoiding drug preparation, reducing administration time, and freeing up infusion suite capacity. Additional cost savings could be derived with regional hospital administration of natalizumab SC by reducing productivity loss

Sustained Drug Release from Biopolymer-Based Hydrogels and Hydrogel Coatings

Biopolymer based hydrogels are three-dimensional physically or chemically crosslinked polymeric networks based on natural polymers, with an intrinsic hydrophilic character due to their functional groups. They display high water content, softness, flexibility, permeability, and biocompatibility and possess a very high affinity for biological fluids. These properties resemble those of many soft living tissues, which opens up many opportunities in the biomedical field. In this regard, hydrogels provide fine systems for drug delivery and sustained release of drugs. Moreover, biopolymer based hydrogels can be applied as coatings on medical implants in order to enhance the biocompatibility of the implants and to prevent medical conditions. In this chapter we review the latest achievements concerning the use of biopolymeric physical and chemically crosslinked hydrogels as well as hydrogel coatings as sustained drug release platforms

Drug Delivery from Hyaluronic Acid-BDDE Injectable Hydrogels for Antibacterial and Anti-Inflammatory Applications

Hyaluronic acid (HA) injectable biomaterials are currently applied in numerous biomedical areas, beyond their use as dermal fillers. However, bacterial infections and painful inflammations are associated with healthcare complications that can appear after injection, restricting their applicability. Fortunately, HA injectable hydrogels can also serve as drug delivery platforms for the controlled release of bioactive agents with a critical role in the control of certain diseases. Accordingly, herein, HA hydrogels were crosslinked with 1 4-butanediol diglycidyl ether (BDDE) loaded with cefuroxime (CFX), tetracycline (TCN), and amoxicillin (AMX) antibiotics and acetylsalicylic acid (ASA) anti-inflammatory agent in order to promote antibacterial and anti-inflammatory responses. The hydrogels were thoroughly characterized and a clear correlation between the crosslinking grade and the hydrogels’ physicochemical properties was found after rheology, scanning electron microscopy (SEM), thermogravimetry (TGA), and differential scanning calorimetry (DSC) analyses. The biological safety of the hydrogels, expected due to the lack of BDDE residues observed in 1H-NMR spectroscopy, was also corroborated by an exhaustive biocompatibility test. As expected, the in vitro antibacterial and anti-inflammatory activity of the drug-loaded HA-BDDE hydrogels was confirmed against Staphylococcus aureus by significantly decreasing the pro-inflammatory cytokine levels.This research was funded by the i+Med S. Coop., Basque Government (FRONTIERS project, ELKARTEK program, HAZITEK program: IMABI exp number ZE-2019/00012), and the Department of Development and Infrastructures of the Basque Country. Jon Andrade del Olmo thanks the Basque Government for the “Program of Industrial Doctorates. Bikaintek 2018” (exp. number 01-AF-W2-2018-00002)

Melatonin modulation of radiation-induced molecular changes in MCF-7 human breast cancer cells

Radiation therapy is an important component of cancer treatment scheduled for cancer patients, although it can cause numerous deleterious effects. The use of adjuvant molecules aims to limit the damage in normal surrounding tissues and to enhance the effects of radiation therapy either killing tumor cells or slowing down their growth. Melatonin, an indoleamine released by the pineal gland, behaves as a radiosensitizer in breast cancer since it enhances the therapeutic effects of ionizing radiation and mitigates side effects on normal cells. However, the molecular mechanisms through which melatonin modulates the molecular changes triggered by radiotherapy remain mostly unknown. Here we report that melatonin potentiated the antiproliferative effect of radiation in MCF-7 cells. Treatment with ionizing radiation induced changes in expression of many genes. Out of a total of twenty-five genes altered by radiation, melatonin potentiated changes in thirteen of them, whereas reverted the effect in another ten cases. Among them, melatonin elevated the levels of PTEN and NME1, whereas counteracted the induction by radiation of SNAI2, ERBB2, AKT, SERPINE1, SFN, PLAU, ATM and N3RC1. We also analyzed the expression of several microRNAs and found that melatonin enhanced the effect of radiation on the levels of miR-20a, miR-19a, miR-93, miR-20b, miR-29a. Rather surprisingly, radiation induced miR-17, miR-141 and miR-15a but melatonin treatment prior to radiation counteracted this stimulatory effect. Radiation alone enhanced the expression of the cancer suppressor miR-34a, and melatonin strongly stimulated this effect. Melatonin further enhanced the radiationmediated inhibition of Akt. Finally, in an in vivo assay, melatonin restrained new vascularization in combination with ionizing radiation. Our results confirm that melatonin blocks many of the undesirable effects of ionizing radiation in MCF-7 cells and enhances changes that lead to optimed treatment resultsAcknowledgments: The present study was funded by grants from the Spanish Economy and Competitiveness Ministry (SAF2016-77103-P), from Universidad de Cantabria (Proyectos Puente 2020) with the participation of the Consejería de Universidades, Igualdad, Cultura y Deporte del Gobierno de Cantabria, and from Instituto de Investigación Sanitaria Valdecilla (IDIVAL) (APG/12)