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Núria Mas,1–3 Irene Galiana,3 Silvia Hurtado,† Laura Mondragón,1–3 Andrea Bernardos,1–3 Félix Sancenón,1–3 María D Marcos,1–3 Pedro Amorós,4 Nuria Abril-Utrillas,5 Ramón Martínez-Máñez,1–3 José Ramón Murguía1,3 1Centro de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Centro Mixto Universidad Politécnica de Valencia, Universidad de Valencia, Valencia, Spain; 2Departamento de Química, Universidad Politécnica de Valencia, Valencia, Spain; 3CIBER de Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain; 4Institut de Ciència del Materials (ICMUV), Universitat de València, Valencia, Spain; 5Servicio Ginecología y Obstetricia, Hospital de la Plana, Vila-real, Spain†Silvia Hurtado passed away in September 2013 Abstract: pH-sensitive gated mesoporous silica nanoparticles have been synthesized. Increased extracellular pH and internalization into living yeast cells triggered molecular gate aperture and cargo release. Proper performance of the system was demonstrated with nanodevices loaded with fluorescein or with the antifungal agent tebuconazole. Interestingly, nanodevices loaded with tebuconazole significantly enhanced tebuconazole cytotoxicity. As alterations of acidic external pH are a key parameter in the onset of fungal vaginitis, this nanodevice could improve the treatment for vaginal mycoses.Keywords: capped mesoporous nanoparticles, intracellular release, pH-responsive nanoparticles, Saccharomyces cerevisiae, tebuconazole loading

Los cambios de las últimas décadas en torno al estudio de la transición política española han conllevado a la identificación de la mayoría social como impulsora del cambio político. Pese a ello, la izquierda armada ha quedado relegada de buena parte de las investigaciones, los relatos y las crónicas del periodo. El presente artículo pretende revisar de manera crítica algunas de las lecturas hegemónicas de la transición a la vez que aportar algunas claves para avanzar en el estudio de la izquierda armada vinculada a la liberación nacional como agente implicado en el proceso transicional.

Accumulation of senescent cells with age leads to tissue dysfunction and related diseases. Their detection in vivo still constitutes a challenge in aging research. We describe the generation of a fluorogenic probe (sulfonic-Cy7Gal) based on a galactose derivative, to serve as substrate for β-galactosidase, conjugated to a Cy7 fluorophore modified with sulfonic groups to enhance its ability to diffuse. When administered to male or female mice, β-galactosidase cleaves the O-glycosidic bond, releasing the fluorophore that is ultimately excreted by the kidneys and can be measured in urine. The intensity of the recovered fluorophore reliably reflects an experimentally controlled load of cellular senescence and correlates with age-associated anxiety during aging and senolytic treatment. Interestingly, our findings with the probe indicate that the effects of senolysis are temporary if the treatment is discontinued. Our strategy may serve as a basis for developing fluorogenic platforms designed for easy longitudinal monitoring of enzymatic activities in biofluids., (© 2024. The Author(s).)

Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer with a poor prognosis and limited effective therapeutic options. Induction of senescence, arrest of cell proliferation, has been explored as an effective method to limit tumor progression in metastatic breast cancer. However, relapses occur in some patients, possibly as a result of the accumulation of senescent tumor cells in the body after treatment, which promote metastasis. In this study, we explored the combination of senescence induction and the subsequent removal of senescent cells (senolysis) as an alternative approach to improve outcomes in TNBC patients. We demonstrate that a combination treatment, using the senescence-inducer palbociclib and the senolytic agent navitoclax, delays tumor growth and reduces metastases in a mouse xenograft model of aggressive human TNBC (hTNBC). Furthermore, considering the off-target effects and toxicity derived from the use of navitoclax, we propose a strategy aimed at minimizing the associated side effects. We use a galacto-conjugated navitoclax (nav-Gal) as a senolytic prodrug that can preferentially be activated by β-galactosidase overexpressed in senescent cells. Concomitant treatment with palbociclib and nav-Gal in vivo results in the eradication of senescent hTNBC cells with consequent reduction of tumor growth, while reducing the cytotoxicity of navitoclax. Taken together, our results support the efficacy of combination therapy of senescence-induction with senolysis for hTNBC, as well as the development of a targeted approach as an effective and safer therapeutic opportunity., Competing Interests: Declaration of Competing Interest Not applicable., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A detailed understanding of the interactions and the best dose-fractionation scheme of radiation to maximize antitumor immunity have not been fully established. In this study, the effect on the host immune system of a single dose of 20 Gy through intraoperative radiation therapy (IORT) on the surgical bed in low-risk breast cancer patients undergoing conserving breast cancer has been assessed. Peripheral blood samples from 13 patients were collected preoperatively and at 48 h and 3 and 10 weeks after the administration of radiation. We performed a flow cytometry analysis for lymphocyte subpopulations, natural killer cells (NK), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs). We observed that the subpopulation of NK CD56+high CD16+ increased significantly at 3 weeks after IORT (0.30-0.42%, P < 0.001), while no changes were found in immunosuppressive profile, CD4+CD25+Foxp3+Helios+ Treg cells, granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (Mo-MDSCs). A single dose of IORT may be an effective approach to improve antitumor immunity based on the increase in NK cells and the non-stimulation of immunosuppressive cells involved in immune escape. These findings support future combinations of IORT with immunotherapy, if they are confirmed in a large cohort of breast cancer patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

In vivo detection of cellular senescence is accomplished by using mesoporous silica nanoparticles loaded with the NIR-FDA approved Nile blue (NB) dye and capped with a galactohexasaccharide (S3). NB emission at 672 nm is highly quenched inside S3, yet a remarkable emission enhancement is observed upon cap hydrolysis in the presence of β-galactosidase and dye release. The efficacy of the probe to detect cellular senescence is tested in vitro in melanoma SK-Mel-103 and breast cancer 4T1 cells and in vivo in palbociclib-treated BALB/cByJ mice bearing breast cancer tumor., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: We hypothesized that radiation doses delivered with high-dose-rate (HDR) and pulsed-dose-rate (PDR) brachytherapy in patients with cervical cancer could trigger immune stimulation by modulating immune cells in the tumor microenvironment. The objective was to determine CD68, CD163, and PD-L1 expression in biopsies from patients with cervical cancer and to compare the effects of HDR vs. PDR brachytherapy on the expression of these proteins., Methods and Materials: Nineteen consecutive women (mean age, 55.9 years) with histologically proven cervical cancer scheduled for brachytherapy after standard external beam irradiation therapy combined with platinum-based chemotherapy were included in a prospective study. Core tissue biopsies were obtained before radiochemotherapy (biopsy #1), after completion of radiochemotherapy and before brachytherapy (biopsy #2), and 2 weeks after completion of brachytherapy (biopsy #3). HDR or PDR brachytherapy was delivered according to availability of equipment. CD68, CD163, and PD-L1 immunohistochemical expression was estimated using a quantitative method. Conditional logistic regression models were used to assess the relationship between gene expression and time of biopsy for each brachytherapy technique., Results: In relation to CD68 and CD163, statistically significant relationships between gene expression and biopsy tissue samples were not found in any of the brachytherapy techniques, although there was trend toward downexpression of CD68 and CD163 in biopsies #2 and #3 in the HDR brachytherapy cohort only. There was a significant increase in PD-L1 expression in biopsy #3 also in the HDR cohort as compared with the PDR cohort., Conclusions: Decreased CD68 and CD163 expression did not reach statistical significance, but this trend may have clinical translational potential. Overexpression of PD-L1 in tissue biopsies taken at 14 days in the HDR brachytherapy cohort may tentatively suggest that this time period would be an adequate interval for blockade of the PD-1/PD-L1 axis., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Walking and running have fundamentally different biomechanics, which makes developing devices that assist both gaits challenging. We show that a portable exosuit that assists hip extension can reduce the metabolic rate of treadmill walking at 1.5 meters per second by 9.3% and that of running at 2.5 meters per second by 4.0% compared with locomotion without the exosuit. These reduction magnitudes are comparable to the effects of taking off 7.4 and 5.7 kilograms during walking and running, respectively, and are in a range that has shown meaningful athletic performance changes. The exosuit automatically switches between actuation profiles for both gaits, on the basis of estimated potential energy fluctuations of the wearer's center of mass. Single-participant experiments show that it is possible to reduce metabolic rates of different running speeds and uphill walking, further demonstrating the exosuit's versatility., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Amongst all efforts for improving oncological management outcomes, nanoparticles enhanced radiation for breast cancer patient's treatment is a novel approach that has grown interest for research in the last decade. Multiple preclinical data has been published, from all around the globe; however, clinical evidence is still insufficient for implementing the method in routine practice and in disease specific management. Gold nanoparticles (AuNP), which may be among the most studed materials, account for the majority of available data; however, some new materials have also been used in preclinical settings. Without any safety data available at the moment to support an active use, dosimetric in vitro and in vivo information seems to be consistent with a very promising and hopeful panorama for clinical applications. This review evaluates existing dosimetric data in breast cancer tissue, and a probable future impact in treatment choices and patient outcomes, as further investigation is required in a clinical setting.

Senescent cells accumulate in multiple aging-associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal β-galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with galacto-oligosaccharides. We show that gal-encapsulated fluorophores are preferentially released within senescent cells in mice. In a model of chemotherapy-induced senescence, gal-encapsulated cytotoxic drugs target senescent tumor cells and improve tumor xenograft regression in combination with palbociclib. Moreover, in a model of pulmonary fibrosis in mice, gal-encapsulated cytotoxics target senescent cells, reducing collagen deposition and restoring pulmonary function. Finally, gal-encapsulation reduces the toxic side effects of the cytotoxic drugs. Drug delivery into senescent cells opens new diagnostic and therapeutic applications for senescence-associated disorders., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Soft exosuits are a recent approach for assisting human locomotion, which apply assistive torques to the wearer through functional apparel. Over the past few years, there has been growing recognition of the importance of control individualization for such gait assistive devices to maximize benefit to the wearer. In this paper, we present an updated version of autonomous multi-joint soft exosuit, including an online parameter tuning method that customizes control parameters for each individual based on positive ankle augmentation power., Methods: The soft exosuit is designed to assist with plantarflexion, hip flexion, and hip extension while walking. A mobile actuation system is mounted on a military rucksack, and forces generated by the actuation system are transmitted via Bowden cables to the exosuit. The controller performs an iterative force-based position control of the Bowden cables on a step-by-step basis, delivering multi-articular (plantarflexion and hip flexion) assistance during push-off and hip extension assistance in early stance. To individualize the multi-articular assistance, an online parameter tuning method was developed that customizes two control parameters to maximize the positive augmentation power delivered to the ankle. To investigate the metabolic efficacy of the exosuit with wearer-specific parameters, human subject testing was conducted involving walking on a treadmill at 1.50 m s - 1 carrying a 6.8-kg loaded rucksack. Seven participants underwent the tuning process, and the metabolic cost of loaded walking was measured with and without wearing the exosuit using the individualized control parameters., Results: The online parameter tuning method was capable of customizing the control parameters, creating a positive ankle augmentation power map for each individual. The subject-specific control parameters and resultant assistance profile shapes varied across the study participants. The exosuit with the wearer-specific parameters significantly reduced the metabolic cost of load carriage by 14.88 ± 1.09% (P = 5 × 10 - 5 ) compared to walking without wearing the device and by 22.03 ± 2.23% (P = 2 × 10 - 5 ) compared to walking with the device unpowered., Conclusion: The autonomous multi-joint soft exosuit with subject-specific control parameters tuned based on positive ankle augmentation power demonstrated the ability to improve human walking economy. Future studies will further investigate the effect of the augmentation-power-based control parameter tuning on wearer biomechanics and energetics.

Although it is clear that walking over different irregular terrain is associated with altered biomechanics, there is little understanding of how we quickly adapt to unexpected variations in terrain. This study aims to investigate which adaptive strategies humans adopt when performing an unanticipated step on an irregular surface, specifically a small bump. Nine healthy male participants walked at their preferred walking speed along a straight walkway during five conditions: four involving unanticipated bumps of two different heights, and one level walking condition. Muscle activation of eight lower limb muscles and three-dimensional gait analysis were evaluated during these testing conditions. Two distinct adaptive strategies were found, which involved no significant change in total lower limb mechanical work or walking speed. An ankle-based strategy was adopted when stepping on a bump with the forefoot, whereas a hip-based strategy was preferred when stepping with the rearfoot. These strategies were driven by a higher activation of the plantarflexor muscles (6-51%), which generated a higher ankle joint moment during the forefoot conditions and by a higher activation of the quadriceps muscles (36-93%), which produced a higher knee joint moment and hip joint power during the rearfoot conditions. These findings provide insights into how humans quickly react to unexpected events and could be used to inform the design of adaptive controllers for wearable robots intended for use in unstructured environments that can provide optimal assistance to the different lower limb joints., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

A naphthalimide-based two-photon probe (AHGa) for the detection of cell senescence is designed. The probe contains a naphthalimide core, an l-histidine methyl ester linker, and an acetylated galactose bonded to one of the aromatic nitrogen atoms of the l-histidine through a hydrolyzable N-glycosidic bond. Probe AHGa is transformed into AH in senescent cells resulting in an enhanced fluorescent emission intensity. In vivo detection of senescence is validated in mice bearing tumor xenografts treated with senescence-inducing chemotherapy.