Depósito Académico
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Results
- A small virus to deliver small antibodies: new targeted therapies based on AAV delivery of nanobodies(MDPI AG, 2021) Silva-Pilipich, N.R. (Noelia Romina); Smerdou, C. (Cristian); Vanrell, L. (Lucía)Nanobodies are camelid-derived single-domain antibodies that present some advantages versus conventional antibodies, such as a smaller size, and higher tissue penetrability, stability, and hydrophilicity. Although nanobodies can be delivered as proteins, in vivo expression from adeno-associated viral (AAV) vectors represents an attractive strategy. This is due to the fact that AAV vectors, that can provide long-term expression of recombinant genes, have shown an excellent safety profile, and can accommodate genes for one or several nanobodies. In fact, several studies showed that AAV vectors can provide sustained nanobody expression both locally or systemically in preclinical models of human diseases. Some of the pathologies addressed with this technology include cancer, neurological, cardiovascular, infectious, and genetic diseases. Depending on the indication, AAV-delivered nanobodies can be expressed extracellularly or inside cells. Intracellular nanobodies or "intrabodies" carry out their function by interacting with cell proteins involved in disease and have also been designed to help elucidate cellular mechanisms by interfering with normal cell processes. Finally, nanobodies can also be used to retarget AAV vectors, when tethered to viral capsid proteins. This review covers applications in which AAV vectors have been used to deliver nanobodies, with a focus on their therapeutic use.
- Health-related quality of life in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation: results from the randomized phase III ALCYONE trial(BioMed Central, 2021) Knop, S. (Stefan); Mateos, M.V. (María Victoria); Dimopoulos, M.A. (Meletios A.); Suzuki, K. (Kenshi); Jakubowiak, A. (Andrzej); Doyen, C. (Chantal); Lucio, P. (Paulo); Nagy, Z. (Zsolt); Usenko, G. (Ganna); Pour, L. (Ludek); Cook, M. (Mark); Grosicki, S. (Sebastian); Crepaldi, A. (Andre); Liberati, A.M. (Anna Marina); Campbell, P. (Philip); Shelekhova, T. (Tatiana); Yoon, S. (Sung-Soo); Losava, G. (Genadi); Fujisaki, T. (Tomoaki); Garg, M. (Mamta); Wang, J. (Jianping); Wroblewski, S. (Susan); Kudva, A. (Anupa); Gries, K.S. (Katharine S.); Fastenau, J. (John); San-Miguel, J.F. (Jesús F.); Cavo, M. (Michele)Background: In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. Methods: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. Results: Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. Conclusions: Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP.
- Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis(MDPI, 2021) Buñuales, M. (María); Ballesteros-Briones, M.C. (María Cristina); Gonzalez-Aparicio, M. (Manuela); Hervas-Stubbs, S. (Sandra); Eva Martisova ; Mancheño, U. (Uxua); Ricobaraza, A. (Ana); Lumbreras, S. (Sara); Smerdou, C. (Cristian); Hernandez-Alcoceba, R. (Rubén)Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.
- Idiotype vaccines produced with a non‑cytopathic alphavirus self‑amplifying RNA vector induce antitumor responses in a murine model of B‑cell lymphoma(Nature portfolio, 2021) Casales, E. (Erkuden); Martisova, E. (Eva); Villanueva, H. (Helena); Lopez-Diaz-de-Cerio, A. (Ascensión); Inoges, S. (Susana); Silva-Pilipich, N.R. (Noelia Romina); Ballesteros-Briones, M.C. (María Cristina); Aranda, A. (Alejandro); Bezunartea, J. (Jaione); Bendandi, M. (Maurizio); Pastor, F. (Fernando); Smerdou, C. (Cristian)A promising therapy for patients with B-cell lymphoma is based on vaccination with idiotype monoclonal antibodies (mAbs). Since idiotypes are different in each tumor, a personalized vaccine has to be produced for each patient. Expression of immunoglobulins with appropriate post-translational modifications for human use often requires the use of stable mammalian cells that can be scaled-up to reach the desired level of production. We have used a noncytopathic self-amplifying RNA vector derived from Semliki Forest virus (ncSFV) to generate BHK cell lines expressing murine follicular lymphoma-derived idiotype A20 mAb. ncSFV/BHK cell lines expressed approximately 2 mg/L/24 h of A20 mAb with proper quaternary structure and a glycosylation pattern similar to that of A20 mAb produced by hybridoma cells. A20 mAb purified from the supernatant of a ncSFV cell line, or from the hybridoma, was conjugated to keyhole limpet hemocyanin and used to immunize Balb/c mice by administration of four weekly doses of 25 µg of mAb. Both idiotype mAbs were able to induce a similar antitumor protection and longer survival compared to non-immunized mice. These results indicate that the ncSFV RNA vector could represent a quick and efficient system to produce patient-specific idiotypes with potential application as lymphoma vaccines.
- Effect of Nb and Mo additions in the microstructure/tensile property relationship in high strength quenched and quenched and tempered boron steels(MDPI, 2020) Zurutuza, I. (Irati); Isasti, N. (Nerea); Detemple, E. (Eric); Schwinn, V. (Volker); Mohrbacher, H. (Hardy); Uranga, P. (Pello)Recently, advanced thermomechanical hot rolling schedules followed by direct quenching are being developed in order to avoid reheating and quenching treatment after hot rolling to eliminate an energy and cost consuming step. The use of boron as an alloying element is a widely known practice in high strength medium carbon steels to increase the strength due its potential for delaying phase transformation and improving hardenability. In addition, a significant synergetic effect on hardenability could be reached combining B with microalloying elements (adding Nb, Mo or NbMo). With the purpose of exploring the effect of microalloying elements and thermomechanical rolling schedule, laboratory thermomechanical simulations reproducing plate mill conditions were performed using ultra high strength steels micro-alloyed with Nb, Mo, and Nb-Mo. To that end, plane compression tests were performed, consisting of an initial preconditioning step, followed by several roughing and finishing deformation passes and a final quenching step. After fast cooling to room temperature, a tempering treatment was applied. In the present paper, the complex interaction between the martensitic microstructure, the tempering treatment, the addition of microalloying elements, and the resulting tensile properties was evaluated. For that purpose, an exhaustive EBSD quantification was carried out in both quenched as well as quenched and tempered states for all the steel grades and the contribution of different strengthening mechanisms on yield strength was analyzed. Highest tensile properties are achieved combining Nb and Mo, for both quenched (Q) and quenched and tempered states (Q&T), reaching yield strength values of 1107 MPa and 977 MPa, respectively. Higher tempering resistance was measured for the Mo-bearing steels, making the CMnNbMoB steel the one with the lowest softening after tempering. For CMnB grade, the yield strength reduction after tempering of about 413 MPa was measured, while for NbMo micro-alloyed steel, yield strength softening is considerably reduced to 130 MPa.
- Toughness property control by Nb and Mo additions in high-strength quenched and tempered boron steels(MDPI, 2021) Zurutuza, I. (Irati); Isasti, N. (Nerea); Detemple, E. (Eric); Schwinn, V. (Volker); Mohrbacher, H. (Hardy); Uranga, P. (Pello)The synergetic effect on hardenability by combining boron with other microalloying elements (such as Nb, Mo and Nb + Mo) is widely known for high-strength medium carbon steels produced by direct quenching and subsequent tempering treatment. The improvement of mechanical properties could be reached through optimization of different mechanisms, such as solid solution hardening, unit size refinement, strain hardening, fine precipitation hardening and the effect of carbon in solid solution. The current study proposes a procedure for evaluating the contribution of different microstructural aspects on Charpy impact toughness. First, the effect that austenite conditioning has on low-temperature transformation unit sizes and microstructural homogeneity was analysed for the different microalloying element combinations. A detailed crystallographic characterization of the tempered martensite was carried out using electron backscattered diffraction (EBSD) in order to quantify the effect of unit size refinement and dislocation density. The impact of heterogeneity and presence of carbides was also evaluated. The existing equations for impact transition temperature (ITT50%) predictions were extended from ferrite-pearlite and bainitic microstructures to tempered martensite microstructures. The results show that microstructural refinement is most beneficial to strength and toughness while unit size heterogeneity has a particularly negative effect on ductileto-brittle transition behaviour. By properly balancing alloy concept and processing, steel having a yield strength above 900 MPa and low impact transition temperature could be obtained by direct quenching and tempering.
- Urinary tartaric acid, a biomarker of wine intake, correlates with lower total and LDL cholesterol(MDPI Publishing, 2021) Domínguez-López, I. (Inés); Parilli-Moser, I. (Isabella); Arancibia-Riveros, C. (Camila); Tresserra-Rimbau, A. (Anna); Martinez-Gonzalez, M.A. (Miguel Ángel); Ortega-Azorin, C. (Carolina); Salas-Salvado, J. (Jordi); Castañer, O. (Olga); Lapetra, J. (José); Aros, F. (Fernando); Fiol, M. (Miquel); Serra-Majem, L. (Lluís); Pinto, X. (Xavier); Gomez-Gracia, E. (Enrique); Ros, E. (Emilio); Lamuela-Raventos, R.M. (Rosa Maria); Estruch, R. (Ramón)Postmenopausal women are at higher risk of developing cardiovascular diseases due to changes in lipid profile and body fat, among others. The aim of this study was to evaluate the association of urinary tartaric acid, a biomarker of wine consumption, with anthropometric (weight, waist circumference, body mass index (BMI), and waist-to-height ratio), blood pressure, and biochemical variables (blood glucose and lipid profile) that may be affected during the menopausal transition. This sub-study of the PREDIMED (Prevención con Dieta Mediterránea) trial included a sample of 230 women aged 60-80 years with high cardiovascular risk at baseline. Urine samples were diluted and filtered, and tartaric acid was analyzed by liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Correlations between tartaric acid and the study variables were adjusted for age, education level, smoking status, physical activity, BMI, cholesterol-lowering, antihypertensive, and insulin treatment, total energy intake, and consumption of fruits, vegetables, and raisins. A strong association was observed between wine consumption and urinary tartaric acid (0.01 μg/mg (95% confidence interval (CI): 0.01, 0.01), p-value < 0.001). Total and low-density lipoprotein (LDL) cholesterol were inversely correlated with urinary tartaric acid (-3.13 μg/mg (-5.54, -0.71), p-value = 0.016 and -3.03 μg/mg (-5.62, -0.42), p-value = 0.027, respectively), whereas other biochemical and anthropometric variables were unrelated. The results suggest that wine consumption may have a positive effect on cardiovascular health in postmenopausal women, underpinning its nutraceutical properties.
- Exposure-response and population pharmacokinetic analyses of a novel subcutaneous formulation of daratumumab administered to multiple myeloma patients(Hall Associates, 2021) Melody-Luo, M. (Man); Usmani, S.Z. (Saad Z.); Mateos, M.V. (María Victoria); Nahi, H. (Hareth); Chari, A. (Ajai); San-Miguel, J.F. (Jesús F.); Touzeau, C. (Cyrille); Suzuki, K. (Kenshi); Kaiser, M. (Martin); Carson, R. (Robin); Heuck, C. (Christoph); Qi, M. (Ming); Zhou, H. (H.); Sun, Y.N. (Yu-Nien); Parasrampuria, D.A. (Dolly A.)We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough ) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.
- Preclinical evaluation of the safety and immunological action of allogeneic ADSC-collagen scaffolds in the treatment of chronic ischemic cardiomyopathy(MDPI, 2021) Lopez-Diaz-de-Cerio, A. (Ascensión); Pérez-Estenaga, I. (Iñigo); Inoges, S. (Susana); Abizanda-Sarasa, G. (Gloria); Gavira, J.J. (Juan José); Larequi-Ardanaz, E. (Eduardo); Andreu, E.J. (Enrique José); Rodriguez, S. (Saray); Gil, A.G. (Ana Gloria); Crisostomo, V. (Verónica); Sanchez-Margallo, F.M. (Francisco Miguel); Bermejo-Busto, J. (Javier); Jauregui, B. (Blanca); Quintana, L. (Lluis); Fernandez-Aviles, F. (Francisco); Pelacho, B. (Beatriz); Prosper-Cardoso, F. (Felipe)The use of allogeneic adipose-derived mesenchymal stromal cells (alloADSCs) represents an attractive approach for treating myocardial infarction (MI). Furthermore, adding a natural support improves alloADSCs engraftment and survival in heart tissues, leading to a greater therapeutic effect. We aimed to examine the safety and immunological reaction induced by epicardial implantation of a clinical-grade collagen scaffold (CS) seeded with alloADSCs for its future application in humans. Thus, cellularized scaffolds were myocardially or subcutaneously implanted in immunosuppressed rodent models. The toxicological parameters were not significantly altered, and tumor formation was not found over the short or long term. Furthermore, biodistribution analyses in the infarcted immunocompetent rats displayed cell engraftment in the myocardium but no migration to other organs. The immunogenicity of alloADSC-CS was also evaluated in a preclinical porcine model of chronic MI; no significant humoral or cellular alloreactive responses were found. Moreover, CS cellularized with human ADSCs cocultured with human allogeneic immune cells produced no alloreactive response. Interestingly, alloADSC-CS significantly inhibited lymphocyte responses, confirming its immunomodulatory action. Thus, alloADSC-CS is likely safe and does not elicit any alloreactive immunological response in the host. Moreover, it exerts an immunomodulatory action, which supports its translation to a clinical setting.
- Machine learning-based approach highlights the use of a genomic variant profile for precision medicine in ovarian failure(MDPI AG, 2021) Henarejos-Castillo, I. (Ismael); Aleman, A. (Alejandro); Martinez-Montoro, B. (Begoña); Gracia, F.J. (Francisco Javier); Sebastian-Leon, P. (Patricia); Romeu, M. (Monica); Remohi, J. (Jose); Patiño-García, A. (Ana); Royo, P. (Pedro); Alkorta-Aranburu, G. (Gorka); Díaz, P. (Patricia)Ovarian failure (OF) is a common cause of infertility usually diagnosed as idiopathic, with genetic causes accounting for 10-25% of cases. Whole-exome sequencing (WES) may enable identifying contributing genes and variant profiles to stratify the population into subtypes of OF. This study sought to identify a blood-based gene variant profile using accumulation of rare variants to promote precision medicine in fertility preservation programs. A case-control (n = 118, n = 32, respectively) WES study was performed in which only non-synonymous rare variants <5% minor allele frequency (MAF; in the IGSR) and coverage ≥ 100× were considered. A profile of 66 variants of uncertain significance was used for training an unsupervised machine learning model to separate cases from controls (97.2% sensitivity, 99.2% specificity) and stratify the population into two subtypes of OF (A and B) (93.31% sensitivity, 96.67% specificity). Model testing within the IGSR female population predicted 0.5% of women as subtype A and 2.4% as subtype B. This is the first study linking OF to the accumulation of rare variants and generates a new potential taxonomy supporting application of this approach for precision medicine in fertility preservation.