Oncological translational research in the Spanish national health system: the INTRO study

Under the auspices of the Foundation for Excellence and Quality in Oncology (ECO), the Translational Research in Oncology Medical Services Study (INTRO) was conducted with the aim of describing the current state of, and future expectations for translational cancer research in Spanish medical centres. The first step in the investigation was intended to analyse the current condition of the national Medical Oncology Services network by examining different aspects of the oncology research field. A descriptive and observational multicentre study was performed at a statewide level; information was collected by surveying a cross-section of all those responsible for Medical Oncology Services in Spain. The survey was completed by key informants, who were selected independently by each service, between September 2010 and April 2011. We were able to gather comprehensive data from a total of 27 Spanish hospitals. These data enabled us to describe the allocation of human and material resources devoted to clinical and translational research across the Medical Oncology Services and to describe the organisational and functional components of these services and units. These data included information pertaining to the activities developed, their funding sources, and their functional dependence on other internal or external bodies. Finally, we explored the degree of dissemination and use of some specific techniques used for the genetic diagnosis of cancer, which have recently been introduced in Medical Oncology within the Spanish healthcare system. A wide range of variability exists between different oncology services in Spanish hospitals. Time should be spent reflecting on the need and opportunities for improvement in the development of translational research within the field of oncology.Caballero, C.; Jantus-Lewintre, E.; Carrato, A.; García Foncillas, J.; Gascon, P.; Blasco, A.; Moreno Nogueira, JA.... (2014). Oncological translational research in the Spanish national health system: the INTRO study. Clinical and Translational Oncology. 16(8):686-695. doi:10.1007/s12094-013-1138-6S686695168Díaz-Rubio E. Translational research in clinical oncology: challenges and opportunities. Farm Hosp. 2010;34(Supl.1):1–7.Marincola FM. Translational medicine: a two-way road. J Transl Med. 2003;1(1):1.Ablin RJ, Marincola FM, Natali PG. The “excellence in translational medicine” and “bedside-to-bench” awards 2008–09. J Transl Med. 2010;13(8):95.García-Sáenz JA, Bueno C, SanPedro T, Díaz-Rubio E. La nueva oncología médica: aportación de la biología molecular al diagnóstico y tratamiento del cáncer. In: Díaz-Rubio E, editor. Tomo IV. Madrid: You and Us; 2006. p. 1–24.ORDEN SCO/709/2002, Boletín Oficial del Estado, 3 de abril de 2003, núm. 80, pp. 12742–12746. http://www.boe.es/boe/dias/2002/04/03/pdfs/A12742-12746.pdf . Accessed 30 sept 2013.Soto-Martínez JL, Baselga-Torres J, Carrato-Mena A. La investigación Translacional en Oncología Médica. En Primer Libro blanco de la Oncología Médica en España. Dosier 2006. Madrid: Editorial Dispublic SL; 2007. p. 177–99.Ministerio de Sanidad y Consumo. Agencia de Calidad del Sistema Nacional de Salud. Estrategia en Cáncer del Sistema Nacional de Salud. 2006. http://www.msc.es/organizacion/ sns/planCalidadSNS/docs/estratCancerSNS.pdf. Accessed 30 sept 2013.Lenfant C. Shattuck lecture–clinical research to clinical practice-lost in translation? N Engl J Med. 2003;349(9):868–74.Laurence J. Translating translational research. Transl Res. 2006;148(1):1–3.Lemieux-Charles L, McGuire WL. What do we know about health care team effectiveness? A review of the literature. Med Care Res Rev. 2006;63(3):263–300.Oandasan I, Baker RG, Barker K, Bosco C, D’Amour D, Jones L, et al. Teamwork in health care: promoting effective teamwork in healthcare in Canada; policy synthesis and recommendations. June 2006. http://www.chsrf.ca/Migrated/PDF/teamwork-synthesis-report_e.pdf . Accessed 30 Sep 2013.Mankoff SP, Brander C, Ferrone S, Marincola FM. Lost in Translation: obstacles to translational medicine. J Transl Med. 2004;2(1):14.Curran T. Lost in translation: the future of cancer research? Clin Cancer Res. 2005;11(13):4644.Valladares Y. Memoria y actas del primer congreso de investigación sobre el cáncer en España. Madrid; 1983.Vicente J. Apuntes para una historia de la Oncología en España. Los orígenes. Oncología. 2000;23(7):310–7.Legido-Quigley H, Otero L, la Parra D, Alvarez-Dardet C, Martin-Moreno JM, McKee M. Will austerity cuts dismantle the Spanish healthcare system? BMJ. 2013;13(346):f2363

Crosstalk Between LXR and Caveolin-1 Signaling Supports Cholesterol Efflux and Anti-Inflammatory Pathways in Macrophages

© 2021 Ramírez, Torrecilla-Parra, Pardo-Marqués, de-Frutos, Pérez-García, Tabraue, de la Rosa, Martín-Rodriguez, Díaz-Sarmiento, Nuñez, Orizaola, Través, Camps, Boscá and Castrillo.Macrophages are immune cells that play crucial roles in host defense against pathogens by triggering their exceptional phagocytic and inflammatory functions. Macrophages that reside in healthy tissues also accomplish important tasks to preserve organ homeostasis, including lipid uptake/efflux or apoptotic-cell clearance. Both homeostatic and inflammatory functions of macrophages require the precise stability of lipid-rich microdomains located at the cell membrane for the initiation of downstream signaling cascades. Caveolin-1 (Cav-1) is the main protein responsible for the biogenesis of caveolae and plays an important role in vascular inflammation and atherosclerosis. The Liver X receptors (LXRs) are key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages. Although the role of Cav-1 in cellular cholesterol homeostasis and vascular inflammation has been reported, the connection between LXR transcriptional activity and Cav-1 expression and function in macrophages has not been investigated. Here, using gain and loss of function approaches, we demonstrate that LXR-dependent transcriptional pathways modulate Cav-1 expression and compartmentation within the membrane during macrophage activation. As a result, Cav-1 participates in LXR-dependent cholesterol efflux and the control of inflammatory responses. Together, our data show modulation of the LXR-Cav-1 axis could be exploited to control exacerbated inflammation and cholesterol overload in the macrophage during the pathogenesis of lipid and immune disorders, such as atherosclerosis.We thank MINECO FPI predoctoral fellowship granted to MCO (BES-2015-075339). Experimental work was supported by grants from Ministerio de Ciencia, Investigación y Universidades, y Fondo Europeo de Desarrollo Regional (FEDER) Grant REF: PID2019-104284RB-I00/AEI/10.13039/501100011033 (to AC) and support from Networks of Excellence from MINECO (Nuclear Receptors in Cancer, Metabolism and Inflammation [NuRCaMeIn] SAF2017-90604-REDT to AC. Ministerio de Economía, Industria y Competitividad, Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación (SAF2017-82436-R, RTC2017-6283-1), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686 and Fondo Europeo de Desarrollo Regional (to LB). Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación Proyectos de I+D+i Retos Investigación 2018 (RTI2018-095061-B-I00); TALENTO Grant from Madrid Government, Spain (2017-T1/BMD-5333); Consejería de Ciencia, Universidades e Innovación Comunidad de Madrid, Spain (PEJD-2018-POST/BMD-8900 and PEDJ-2018-AI/BDM-9724) to CMR

Identification of novel synthetic lethal vulnerability in non small cell lung cancer by co targeting TMPRSS4 and DDR1

Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Clinical efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR)

Introduction: Bloodstream infection (BSI) due to extended-spectrum β-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although β-lactam/β-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. Methods and analysis: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. Sample size: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. Ethics and dissemination: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH)

Cost-effectiveness analysis of pemetrexed versus docetaxel in the second-line treatment of non-small cell lung cancer in Spain: results for the non-squamous histology population

BackgroundThe objective of this study was to conduct a cost-effectiveness evaluation of pemetrexed compared to docetaxel in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) for patients with predominantly non-squamous histology in the Spanish healthcare setting.MethodsA Markov model was designed consisting of stable, responsive, progressive disease and death states. Patients could also experience adverse events as long as they received chemotherapy. Clinical inputs were based on an analysis of a phase III clinical trial that identified a statistically significant improvement in overall survival for non-squamous patients treated with pemetrexed compared with docetaxel. Costs were collected from the Spanish healthcare perspective.ResultsOutcomes of the model included total costs, total quality-adjusted life years (QALYs), total life years gained (LYG) and total progression-free survival (PFS). Mean survival was 1.03 years for the pemetrexed arm and 0.89 years in the docetaxel arm; QALYs were 0.52 compared to 0.42. Per-patient lifetime costs were € 34677 and € 32343, respectively. Incremental cost-effectiveness ratios were € 23967 per QALY gained and € 17225 per LYG.ConclusionsPemetrexed as a second-line treatment option for patients with a predominantly non-squamous histology in NSCLC is a cost-effective alternative to docetaxel according to the € 30000/QALY threshold commonly accepted in Spain

Safety and effectiveness of isavuconazole in real-life non-neutropenic patients

Objectives: Information is scarce on clinical experiences with non-neutropenic patients with invasive fungal infection (IFI) receiving isavuconazole. We aimed to report the safety and effectiveness of this drug as a first-line treatment or rescue in real life. Methods: A retrospective, observational multicentric study of non-neutropenic patients who received isavuconazole as an IFI treatment at 12 different university hospitals (January 2018-2022). All patients met criteria for proven, probable or possible IFI according to EORTC-MSG. Results: A total of 238 IFIs were treated with isavuconazole during the study period. Combination therapy was administered in 27.7% of cases. The primary IFI was aspergillosis (217, 91.2%). Other IFIs treated with isavuconazole were candidemia (n = 10), mucormycosis (n = 8), histoplasmosis (n = 2), cryptococcosis (n = 2), and others (n = 4). Median time of isavuconazole treatment was 29 days. Only 5.9% (n = 14) of cases developed toxicity, mainly hepatic-related (10 patients, 4.2%). Nine patients (3.8%) had treatment withdrawn. Successful clinical response at 12 weeks was documented in 50.5% of patients. Conclusion: Isavuconazole is an adequate treatment for non-neutropenic patients with IFIs. Toxicity rates were low and its effectiveness was comparable to other antifungal therapies previously reported. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/

The impact of the addition of iodoform on the physicochemical properties of an epoxy-based endodontic sealer

Due to the low radiopacity of Sealer 26, iodoform is frequently empirically added to this sealer. Thus, the interference of this procedure with the physicochemical properties of Sealer 26 must be evaluated. OBJECTIVE: This study evaluated the influence of the addition of iodoform on setting time, flow, solubility, pH, and calcium release of an epoxy-based sealer. MATERIAL AND METHODS: The control group was pure Sealer 26, and the experimental groups were Sealer 26 added with 1.1 g, 0.55 g or 0.275 g of iodoform. Setting time evaluation was performed in accordance with the ASTM C266-03 speciflcation. The analysis of flow and solubility was in accordance with the ISO 6876-2001 speciflcation. For the evaluation of pH and calcium ion release, polyethylene tubes were filled with the materials and immersed in flasks with 10 ml of deionized water. After 24 h, 7, 14, 21, 28, and 45 days pH was measured. In 45 days, the calcium released was evaluated with an atomic absorption spectrophotometer. RESULTS: The addition of iodoform increased setting time in comparison with pure sealer (P<0.05). As for flow, solubility, and calcium release, the mixtures presented results similar to pure sealer (p>0.05). In the 24 h period, the mixture with 1.1 g and 0.55 g of iodoform showed lower pH than pure sealer and than sealer added with 0.275 g of iodoform (P<0.05). CONCLUSIONS: The iodoform added to Sealer 26 interferes with its setting time and solubility properties. Further studies are needed to address the clinical signiflcance of this interference

The Level of DING Proteins Is Increased in HIV-Infected Patients: In Vitro and In Vivo Studies

DING proteins constitute an interesting family, owing to their intriguing and important activities. However, after a decade of research, little is known about these proteins. In humans, at least five different DING proteins have been identified, which were implicated in important biological processes and diseases, including HIV. Indeed, recent data from different research groups have highlighted the anti-HIV activity of some DING representatives. These proteins share the ability to inhibit the transcriptional step of HIV-1, a key step of the viral cycle that is not yet targeted by the current therapies. Since such proteins have been isolated from humans, we undertook a comprehensive study that focuses on the relationship between these proteins and HIV-infection in an infectious context. Hence, we developed a home-made ELISA for the quantification of the concentration of DING proteins in human serum. Using this method, we were able to determine the concentration of DING proteins in healthy and HIV-infected patients. Interestingly, we observed a significant increase of the concentration of DING proteins in non treated and treated HIV-infected patients compared to controls. In addition, cell cultures infected with HIV also show an increased expression of DING proteins, ruling out the possible role of antiretroviral treatment in the increase of the expression of DING proteins. In conclusion, results from this study show that the organism reacts to HIV-infection by an overexpression of DING proteins

Influence of the interaction between nodal fibroblast and breast cancer cells on gene expression

Our aim was to evaluate the interaction between breast cancer cells and nodal fibroblasts, by means of their gene expression profile. Fibroblast primary cultures were established from negative and positive lymph nodes from breast cancer patients and a similar gene expression pattern was identified, following cell culture. Fibroblasts and breast cancer cells (MDA-MB231, MDA-MB435, and MCF7) were cultured alone or co-cultured separated by a porous membrane (which allows passage of soluble factors) for comparison. Each breast cancer lineage exerted a particular effect on fibroblasts viability and transcriptional profile. However, fibroblasts from positive and negative nodes had a parallel transcriptional behavior when co-cultured with a specific breast cancer cell line. The effects of nodal fibroblasts on breast cancer cells were also investigated. MDA MB-231 cells viability and migration were enhanced by the presence of fibroblasts and accordingly, MDA-MB435 and MCF7 cells viability followed a similar pattern. MDA-MB231 gene expression profile, as evaluated by cDNA microarray, was influenced by the fibroblasts presence, and HNMT, COMT, FN3K, and SOD2 were confirmed downregulated in MDA-MB231 co-cultured cells with fibroblasts from both negative and positive nodes, in a new series of RT-PCR assays. In summary, transcriptional changes induced in breast cancer cells by fibroblasts from positive as well as negative nodes are very much alike in a specific lineage. However, fibroblasts effects are distinct in each one of the breast cancer lineages, suggesting that the inter-relationships between stromal and malignant cells are dependent on the intrinsic subtype of the tumor