Effects of 3D nanocomposite bioceramic scaffolds on the immune response

The interaction of new nanocomposite mesoporous glass/hydroxyapatite (MGHA) scaffolds with immune cells involved in both innate and acquired immunity has been studied in vitro as an essential aspect of their biocompatibility assessment. Since the immune response can be affected by the degradation products of bioresorbable scaffolds and scaffold surface changes, both processes have been evaluated. No alterations in proliferation and viability of RAW-264.7 macrophage-like cells were detected after culture on MGHA scaffolds which did not induce cell apoptosis. However, a slight cell size decrease and an intracellular calcium content increase were observed after contact of this cell line with MGHA scaffolds or their extracts. Although no changes in the percentages of RAW cells with low and high contents of reactive oxygen species (ROS) are observed by the treatment with 7 day extracts, this study has revealed modifications of these percentages after direct contact with scaffolds and by the treatment with 24 h extracts, related to the high reactivity/bioactivity of this MGHA nanocomposite at initial times. Furthermore, when normal fresh murine spleen cells were used as an experimental model closer to physiological conditions, no significant alterations in the activation of different immune cell subpopulations were detected in the presence of 24 h MGHA extract. MGHA scaffolds did not affect either the spontaneous apoptosis or intracellular cytokine expression (IL-2, IL-10, IFN-gamma, and TNF-alpha.) after 24 h treatment. The results obtained in the present study with murine immune cell subpopulations (macrophages, lymphocytes B, lymphocytes T and natural killer cells) support the biocompatibility of the MGHA material and suggest an adequate host tissue response to their scaffolds upon their implantation

Determination of the cardiac drug amiodarone and its N-desethyl metabolite in sludge samples

This is the postprint (accepted manuscript) version of the article published in Journal of Chromatography A http://doi.org/10.1016/j.chroma.2015.03.024 This manuscript version is made available under de CC-BY-NC-ND 4.0 licenseFor the first time, a procedure for the simultaneous determination of the iodinated drug amiodarone and its major metabolite, N-desethylamiodarone, in sludge from urban sewage treatment plants (STPs) is proposed. Matrix solid-phase dispersion (MSPD) followed by on-line cationic exchange clean-up, in mod- ular configuration, was used as sample preparation technique. Liquid chromatography with tandem mass spectrometry (LC–MS/MS), based on a hybrid quadrupole time-of-flight (QTOF) system, was employed for the selective determination of target compounds. The optimized procedure provided exhaustive recov- eries with little effect of the sample matrix in the efficiency of electrospray ionization (ESI). The overall recoveries of the method ranged between 95 and 111%, for samples spiked at different concentration levels. The achieved limits of quantification (LOQs) remained below 10 ng g−1 for both compounds, and the linear response range extended up to 2500 ng g−1. Amiodarone and N-desethylamiodarone were ubiquitous in sludge samples, from different STPs located in the Northwest of Spain, with maximum concentrations above 300 ng g−1 referred to the freeze-dried matrix. They were also present in stabilized sludge (mixed with lime and thermally dehydrated), which is mostly disposed in agriculture fields as fertilizer. Furthermore, mono-iodinated analogues of amiodarone and N-desethylamiodarone were also tentatively identified in some samples from their accurate MS and MS/MS spectraThis study has been supported by the Spanish Government and E.U. FEDER funds (project CTQ2012-33080) and the Xunta de Galicia (Excellence Research Groups Programme). R.M. acknowledges a post-doctoral “Juan de la Cierva” contract from the Spanish Ministry of Economy and Competitiveness.S

La pérdida específica de células T de la subunidad catalítica p110? de PI-3-linasa da como resultado una producción mejorada de citocinas y una respuesta antitumoral

Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110? and p110? are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110? PI3K in normal or pathological immune responses is well established, yet the importance of p110? subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110? conditionally deleted in CD4+ and CD8+ T lymphocytes (p110??/??T) were used. p110??/??T mice show normal development of T cell subsets, but slightly reduced numbers of CD4+ T cells in the spleen. “In vitro,” TCR/CD3 plus CD28 activation of naive CD4+ and CD8+ p110??/??T T cells showed enhanced effector function, particularly IFN-? secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110??/??T cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110??/??T CD8+ T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110??/??T iTreg cells was diminished. Also, p110??/??T mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-?, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110??/??T mice inoculated with B16.F10 melanoma showed delayed tumor progression. The percentage of CD8+ T lymphocytes was higher and the percentage of Treg cells lower in the spleen of tumor-bearing p110??/??T mice. Also, IFN-? production in tumor antigen-activated spleen cells was enhanced. Thus, PI3K p110? plays a significant role in antigen activation and differentiation of CD4+ and CD8+ T lymphocytes modulating antitumor immunity

A holistic index-based framework to assess urban resilience: Application to the Madrid Region, Spain

Resilience is considered to be a component of sustainability and is addressed in the 17 Sustainable Development Goals adopted by all United Nations Member States. Resilience in this context is mainly oriented to climate change adaptation and disaster risk reduction. However, a holistic approach, considering urban systems as a whole and resilience to all kind of disturbances, is needed for a better understanding of the complexity of urban resilience. To advance in this direction we have proposed an Urban Resilience Index and applied it to 81 cities in the Madrid Region, Spain. The index comprises 42 indicators that measure six resilience characteristics: diversity, self-sufficiency and autonomy, polycentric governance, social cohesion, learning and innovation, and social-ecological justice, in five urban dimensions: socio-cultural, economic, ecological, physical and technological, and governance system. Our results showed that the ecological dimension in the Madrid Region is largely determined by the geomorphological characteristics and the associated ecosystems, but municipalities compensate it with resilience strategies focused on social and physical aspects. The most resilient municipalities are also in general the most sustainable, but not always. We propose to use the Urban Resilience Index in combination with the Sustainable Development Goals Index to develop resilient strategies towards sustainabilityProgram H2019/HUM-5744 CM-INCLUSIVA-C

1,4-Dihydropyridine as a Promising Scaffold for Novel Antimicrobials Against Helicobacter pylori

The increasing occurrence of multidrug-resistant strains of the gastric carcinogenic bacterium Helicobacter pylori threatens the efficacy of current eradication therapies. In a previous work, we found that several 1,4-dihydropyridine (DHP)-based antihypertensive drugs exhibited strong bactericidal activities against H. pylori by targeting the essential response regulator HsrA. To further evaluate the potential of 1,4-DHP as a scaffold for novel antimicrobials against H. pylori, we determined the antibacterial effects of 12 novel DHP derivatives that have previously failed to effectively block L- and T-type calcium channels. Six of these molecules exhibited potent antimicrobial activities (MIC ≤ 8 mg/L) against three different antibiotic-resistant strains of H. pylori, while at least one compound resulted as effective as metronidazole. Such antimicrobial actions appeared to be specific against Epsilonproteobacteria, since no deleterious effects were appreciated on Escherichia coli and Staphylococcus epidermidis. The new bactericidal DHP derivatives targeted the H. pylori regulator HsrA and inhibited its DNA binding activity according to both in vitro and in vivo analyses. Molecular docking predicted a potential druggable binding pocket in HsrA, which could open the door to structure-based design of novel anti-H. pylori drugs

An immunological approach to the biocompatibility of mesoporous SiO2-CaO nanospheres.

Mesoporous bioactive glass nanospheres (NanoMBGs) have high potential for clinicalapplications. However, the impact of nanoparticles on the immune system needs to be addressed. In this study, the biocompatibility of SiO2-CaO NanoMBGs was evaluated on different mouse immune cells, including spleen cells subsets, bone marrow-derived dendritic cells (BMDCs), or cell lines likevSR.D10 Th2 CD4+ lymphocytes and DC2.4 dendritic cells. Flow cytometry and confocal microscopy show that the nanoparticles were rapidly and efficiently taken up in vitro by T and B lymphocytes or by specialized antigen-presenting cells (APCs) like dendritic cells (DCs). Nanoparticles were not cytotoxic and had no effect on cell viability or proliferation under T-cell (anti-CD3) or B cell (LPS) stimuli. Besides, NanoMBGs did not affect the balance of spleen cell subsets, or the production of intracellular or secreted pro- and anti-inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-6, IL-10) by activated T, B, and dendritic cells (DC), as determined by flow cytometry and ELISA. T cell activation surface markers (CD25, CD69 and Induced Costimulator, ICOS) were not altered by NanoMBGs. Maturation of BMDCs or DC2.4 cells in vitro was not altered by NanoMBGs, as shown by expression of Major Histocompatibility Complex (MHC) and costimulatory molecules (CD40, CD80, CD86), or IL-6 secretion. The effect of wortmannin and chlorpromazine indicate a role for phosphoinositide 3-kinase (PI3K), actin and clathrin-dependent pathways in NanoMBG internalization. We thus demonstrate that these NanoMBGs are both non-toxic and non-inflammagenic for murine lymphoid cells and myeloid DCs despite their efficient intake by the cells

Phase II clinical trial of nab-paclitaxel plus gemcitabine in elderly patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma: the BIBABRAX study

[Purpose] To evaluate the health-related quality of life (HRQoL), global health status (GHS), and deterioration-free survival of an elderly population (> 70 years) with unresectable locally advanced (LAPC) or metastatic pancreatic cancer (mPC) treated with nab-paclitaxel in combination with gemcitabine.[Methods] In this open-label, single-arm, multicenter, phase II trial, patients received 4-week cycles of intravenous (i.v.) nab-paclitaxel at a dose of 125 mg/m2, followed by i.v. injections of gemcitabine at a dose of 1000 mg/m2 on days 1, 8 and 15 until disease progression or unacceptable toxicity was observed. The primary outcome was the HRQoL (deterioration-free rate at 3 months as evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30.[Results] Eighty patients (median age: 74.6 years) were enrolled (56 with mPC, 24 with LAPC). The percentage of patients who had not experienced deterioration at 3 months was 54.3% (95% CI 41.6–67.0%). The median (interquartile range) time until definite deterioration was 1.6 (1.1–3.7) months. The objective response rate and clinical benefit rate were achieved by 11 (13.8%, 95% CI 6.2–21.3%) and 54 patients (67.5%, 95% CI 57.2–77.8%), respectively. The median overall survival was 9.2 months (95% CI 6.9–11.5), and the median progression-free survival was 7.2 months (95% CI 5.8–8.5). Only fatigue and neutropenia demonstrated a grade 3–4 toxicity incidence > 20%.[Conclusions] Our study confirms the clinical benefit of the combination of nab-paclitaxel and gemcitabine in an elderly population with pancreatic cancer in terms of improved survival and clinical response. However, we were unable to confirm a benefit in terms of quality-of-life.The BIBABRAX study was funded by Celgene. Medical writing assistance in the preparation of this paper was provided by Apices with financial support from Celgene.Peer reviewe

Algunos resultados de la aplicación del nuevo Plan de Estudios

Este dossier coordinado por Alfredo Alvar Ezquerra contiene los siguientes artículos: La inclusa de Madrid; El protocolo 258 y Madrid hacia 1562; Evolución de dos casas panadería en el Madrid de la época moderna; Canencia: un ejercicio de demografía histórica.Este artículo está sujeto a una licencia CC BY 4.0Peer reviewe

Recovery of uninvolved heavy/light chain pair immunoparesis in newly diagnosed transplant-eligible myeloma patients complements the prognostic value of minimal residual disease detection

Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite (R) assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant -eligible (NDMM-TE) patients with intensive treatment and its association with minimal residual disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA /GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next -generation flow cytometry after consolidation (sensitivity level 2x10 (-6 )). We found no differences in progression -free survival (PFS) between patients who recovered and patients who didn't recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (95% confidence interval [CI]: 0.21-0.81; P =0.008). Multivariate analysis with Cox proportional -hazards re - gression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C -statistic of 0.05 (95% CI: -0.04 to 0.14; P <0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recov - ery from uHLC IP after 1 year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment ( clinicaltrials gov. Identifiers: NCT01916252 and NCT02406144 )

Prognostic Value of Serum Paraprotein Response Kinetics in Patients With Newly Diagnosed Multiple Myeloma

Response kinetics is not well-established as a prognostic marker in multiple myeloma (MM). We developed a mathematical model to assess the prognostic value of serum monoclonal component (MC) response kinetics during 6 induction cycles in 373 newly diagnosed MM patients. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent, dividing the patients into two kinetics categories with significantly different progression-free survival (PFS). Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent. Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P =.02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P =.02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P <.002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies. (C) 2022 The Authors. Published by Elsevier Inc