Metal substrate catalysis in the confined space for platinum drug delivery

[EN] Catalysis-based approaches for the activation of anticancer agents hold considerable promise. These principally rely on the use of metal catalysts capable of deprotecting inactive precursors of organic drugs or transforming key biomolecules available in the cellular environment. Nevertheless, the efficiency of most of the schemes described so far is rather low, limiting the benefits of catalytic amplification as strategy for controlling the therapeutic effects of anticancer compounds. In the work presented here, we show that flavin reactivity within a hydrogel matrix provides a viable solution for the efficient catalytic activation and delivery of cisplatin, a worldwide clinically-approved inorganic chemotherapy agent. This is achieved by ionically adsorbing a flavin catalyst and a Pt(iv) prodrug as substrate into porous amino-functionalized agarose beads. The hydrogel chassis supplies high local concentrations of electron donating groups/molecules in the surrounding of the catalyst, ultimately boosting substrate conversion rates (TOF >200 min(-1)) and enabling controlled liberation of the drug by light or chemical stimuli. Overall, this approach can afford platforms for the efficient delivery of platinum drugs as demonstrated herein by using a transdermal diffusion model simulating the human skin.We acknowledge financial support from the Spanish State Research Agency (grants CTQ2016-80844-R, PID2019-109111RBI00, RTI2018-094398-B-I00, BIO2014-61838-EXP) and the Basque Government (Eusko Jaurlaritza, grant PIBA_2021_1_0034). S. V. L. thanks the Mexican Council of Science and Technology (CONACyT) for the postdoctoral fellowship she received (ref. CVU-267390). C. S. C. thanks Gipuzkoa Foru Aldundia (Gipuzkoa Fellows program; grant number 2019-FELL-000018-01/62/2019) for.nancial support. L. S. thanks the Spanish MultiMetDrugs network (RED2018-102471-T) for fruitful discussion. FLG thanks the Spanish Biocatalysis network (RED2018-102403T) and the European Research Council (ERC-Co-2018 818089). This work was performed under the Maria de Maeztu and Severo Ochoa Centres of Excellence Programme run by the Spanish State Research Agency, Grant No. MDM-2017-0720 (CIC biomaGUNE) and CEX2018-000867-S (DIPC)

GABAergic deficits in absence of LPA1 receptor, associated anxiety-like and coping behaviors, and amelioration by interneuron precursor transplants into the dorsal hippocampus

Defects in GABAergic function can cause anxiety- and depression-like behaviors among other neuropsychiatric disorders. Therapeutic strategies using the transplantation of GABAergic interneuron progenitors derived from the medial ganglionic eminence (MGE) into the adult hippocampus reversed the symptomatology in multiple rodent models of interneuron-related pathologies. In turn, the lysophosphatidic acid receptor LPA1 has been reported to be essential for hippocampal function. Converging evidence suggests that deficits in LPA1 receptor signaling represent a core feature underlying comparable hippocampal dysfunction and behaviors manifested in common neuropsychiatric conditions. Here, we first analyzed the GABAergic interneurons in the hippocampus of wild-type and maLPA1-null mice, lacking the LPA1 receptor. Our data revealed a reduction in the number of neurons expressing GABA, calcium-binding proteins, and neuropeptides such as somatostatin and neuropeptide Y in the hippocampus of maLPA1-null mice. Then, we used interneuron precursor transplants to test links between hippocampal GABAergic interneuron deficit, cell-based therapy, and LPA1 receptor-dependent psychiatric disease-like phenotypes. For this purpose, we transplanted MGE-derived interneuron precursors into the adult hippocampus of maLPA1-null mice, to test their effects on GABAergic deficit and behavioral symptoms associated with the absence of the LPA1 receptor. Transplant studies in maLPA1-null mice showed that grafted cells were able to restore the hippocampal host environment, decrease the anxiety-like behaviors and neutralize passive coping, with no abnormal effects on motor activity. Furthermore, grafted MGE-derived cells maintained their normal differentiation program. These findings reinforce the use of cell-based strategies for brain disorders and suggest that the LPA1 receptor represents a potential target for interneuron-related neuropsychiatric disorders

Supporting central nervous system neuroprotection and remyelination by specific TLR4 antagonism

ApTOLL is an aptamer specifically designed to antagonize toll-like receptor 4 (TLR4), which is involved in the innate immunity that promotes inflammatory responses in several diseases, including multiple sclerosis (MS). MS is a chronic, immune, demyelinating and neurodegenerative disease of the central nervous system that represents the second most important cause of neurological disability in young adults. The drugs currently available to treat this disease are immunomodulators and, to date, there are no therapeutic remyelinating drugs available to manage MS. In this study, we show that TLR4 is located in post-mortem cortical lesions of MS patients and as a result, we evaluated the effect of its inhibition by ApTOLL in two different animal models of MS, that of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. ApTOLL administration ameliorated the clinical symptomatology of the affected mice, which was associated with better preservation and restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals. This revealed not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL which was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs). In summary, the molecular nature of ApTOLL and its mechanism of action strongly supports its further study and use in novel strategies to treat MS and eventually, other demyelinating diseases.This work was supported by grant IND2018/BMD-9751 (Programa de Doctorados Industriales, Comunidad de Madrid, Spain), SAF2016-77575-R (Spanish Ministerio de Economía, Industria y Competitividad-MINECO), and the contract for technological support ApTLR2019-PC-MS-001 (AptaTargets, S.L., Spain) to FdC. BF-G is currently hired by Aptatargets S.L., PG-M is hired under PEJ-2020-AI/BMD-18541 de la Comunidad de Madrid, Spain (associated with the youth guarantee fund to FdC), SN had a predoctoral contract from the UCLM and was hired under SAF2012-40023, SAF2016- 77575-R, RD12-0032/0012 and RD16-0015/0019 (Spanish Ministerio de Economía, Industria y Competitividad-MINECO) and IND2018/BMD-9751, YL has been contracted under ReTics and SAF (to FdC). We thank David Segarra and Mª Eugenia Zarabozo (AptaTargets S.L.) for their constant technological support, Laude Garmendia for her indispensable constant help at the animal facility (Instituto Cajal-CSIC), including the extra effort during Covid-19 pandemics, Profs María Ángeles Moro (Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid and Universidad Complutense de Madrid, Spain) and Ignacio Lizasoaín (Universidad Complutense de Madrid, Spain) for lending us the TLR4 knockout mice, and the former GNDe member Dr. Carolina MeleroJerez (currently working at JazzPharma, Spain) for the initial training of BF-G on EAE animal model and different techniques at the laboratory. Human samples were supplied by the UK Multiple Sclerosis Tissue Bank, funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland (registered charity 207495).N

Ética profesional en educación superior : finalidades, estrategias y desafíos de la formación

Todo proyecto educativo que no responde a su época se expone a problemas de legitimidad y al duro escrutinio y sanción de los usuarios. Las instituciones de educación superior no son la excepción de esta premisa clásica, incluso más validada por eldinamismos, la versatilidad y ojo crítico en el mundo contemporáneo. La ética se ha convertido en el baremo principal para someter a juicio a las instituciones y a las personas que ahí actuan, como a las finalidades que se pretenden en sus acciones. En esta perspectiva, debe examinarse la función de las instituciones de educación superior.Este libro es el esfuerzo colectivo por acercarnos a esa problemática, en especial a las finalidades, estrategias y relaciones en juego para cumplir la tarea de la formación y sus nexos inevitables con la ética profesional

Impact of Biological Agents on Postsurgical Complications in Inflammatory Bowel Disease : A Multicentre Study of Geteccu

Background: The impact of biologics on the risk of postoperative complications (PC) in inflammatory bowel disease (IBD) is still an ongoing debate. This lack of evidence is more relevant for ustekinumab and vedolizumab. Aims: To evaluate the impact of biologics on the risk of PC. Methods: A retrospective study was performed in 37 centres. Patients treated with biologics within 12 weeks before surgery were considered "exposed". The impact of the exposure on the risk of 30-day PC and the risk of infections was assessed by logistic regression and propensity score-matched analysis. Results: A total of 1535 surgeries were performed on 1370 patients. Of them, 711 surgeries were conducted in the exposed cohort (584 anti-TNF, 58 vedolizumab and 69 ustekinumab). In the multivariate analysis, male gender (OR: 1.5; 95% CI: 1.2-2.0), urgent surgery (OR: 1.6; 95% CI: 1.2-2.2), laparotomy approach (OR: 1.5; 95% CI: 1.1-1.9) and severe anaemia (OR: 1.8; 95% CI: 1.3-2.6) had higher risk of PC, while academic hospitals had significantly lower risk. Exposure to biologics (either anti-TNF, vedolizumab or ustekinumab) did not increase the risk of PC (OR: 1.2; 95% CI: 0.97-1.58), although it could be a risk factor for postoperative infections (OR 1.5; 95% CI: 1.03-2.27). Conclusions: Preoperative administration of biologics does not seem to be a risk factor for overall PC, although it may be so for postoperative infections

Trends in the epidemiology of catheter-related bloodstream infections; towards a paradigm shift, Spain, 2007 to 2019

Altres ajuts: Departament de Salut. Generalitat de Catalunya ("Pla estratègic de recerca i innovació en salut (PERIS) 2019-2021"); Ministerio de Asuntos Económicos y Transformación Digital; Red Española de Investigación en Patología Infecciosa (REIPI).Background: Catheter-related bloodstream infections (CRBSI) are frequent healthcare-associated infections and an important cause of death. Aim: To analyse changes in CRBSI epidemiology observed by the Infection Control Catalan Programme (VINCat). Methods: A cohort study including all hospital-acquired CRBSI episodes diagnosed at 55 hospitals (2007-2019) in Catalonia, Spain, was prospectively conducted. CRBSI incidence rates were adjusted per 1,000patientdays. To assess the CRBSI rate trend per year, negative binomial models were used, with the number of events as the dependent variable, and the year as the main independent variable. From each model, the annual rate of CRBSI diagnosed per 1,000patientdays and the incidence rate ratio (IRR) with its 95% confidence intervals (CI) were reported. Results: During the study, 9,290 CRBSI episodes were diagnosed (mean annual incidence rate:0.20episodes/1,000patientdays). Patients' median age was 64.1years; 36.6% (3,403/9,290) were female. In total, 73.7% (n=6,845) of CRBSI occurred in non-intensive care unit (ICU) wards, 62.7% (n=5,822) were related to central venous catheter (CVC), 24.1% (n=2,236) to peripheral venous catheters (PVC) and 13.3% (n=1,232) to peripherally-inserted central venous catheters (PICVC). Incidence rate fell over the study period (IRR:0.94;95%CI:0.93-0.96), especially in the ICU (IRR:0.88;95%CI:0.87-0.89). As a whole, while episodes of CVC CRBSI fell significantly (IRR:0.88;95%CI:0.87-0.91), peripherally-inserted catheter CRBSI (PVC and PICVC) rose, especially in medical wards (IRR PICVC:1.08;95%CI:1.05-1.11; IRR PVC: 1.03; 95% 1.00-1.05). Conclusions: Over the study, CRBSIs associated with CVC and diagnosed in ICUs decreased while episodes in conventional wards involving peripherally-inserted catheters increased. Hospitals should implement preventive measures in conventional wards

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

Phytoplankton across Tropical and Subtropical Regions of the Atlantic, Indian and Pacific Oceans

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