SN‐38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN‐38, however, also leads to serious side effects. To reduce ...systemic toxicity by controlling where and when SN‐38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium‐mediated activation. Blocking the phenolic OH of SN‐38 with a 2,6‐bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44‐fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd‐activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics—sequentially or simultaneously—by the same bioorthogonal catalyst to increase anticancer activity.
Palladium‐functionalized microdevices were used to uncage newly developed prodrug that releases SN‐38 (irinotecan′s active metabolite) in combination with previously known anticancer prodrug of 5FU.
Mentalization or reflective functioning (RF) is the capacity to interpret oneself or the others in terms of internal mental states. Its failures have been linked to several mental disorders and ...interventions improving RF have a therapeutic effect. Mentalizing capacity of the parents influences the children's attachment. The Reflective Functioning Questionnaire (RFQ-8) is a widely used tool for the assessment of RF. No instrument is available to assess general RF in Spanish-speaking samples. The aim of this study is to develop a Spanish version of the RFQ-8 and to evaluate its reliability and validity in the general population and in individuals with personality disorders.
602 non-clinical and 41 personality disordered participants completed a Spanish translation of the RFQ and a battery of self-reported questionnaires assessing several RF related constructs (alexithymia, perspective taking, identity diffusion and mindfulness), psychopathology (general and specific) and interpersonal problems. Temporal stability was tested in a non-clinical sub-sample of 113 participants.
Exploratory and confirmatory factor analyses suggested a one-factor structure in the Spanish version of the RFQ-8. RFQ-8 understood as a single scale was tested, with low scorings reflecting genuine mentalizing, and high scorings uncertainty. The questionnaire showed good internal consistence in both samples and moderate temporal stability in non-clinical sample. RFQ correlated significantly with identity diffusion, alexithymia, and general psychopathology in both samples; and with mindfulness, perspective taking, and interpersonal problems in clinical sample. Mean values of the scale were significantly higher in the clinical group.
This study provides evidence that the Spanish version of the RFQ-8, understood as a single scale, has an adequate reliability and validity assessing failures in reflective functioning (i.e., hypomentalization) in general population and personality disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The promising potential of bioorthogonal catalysis in biomedicine is inspiring incremental efforts to design strategies that regulate drug activity in living systems. To achieve this, it is not only ...essential to develop customized inactive prodrugs and biocompatible metal catalysts but also the right physical environment for them to interact and enable drug production under spatial and/or temporal control. Toward this goal, here, we report the first inactive precursor of the potent broad-spectrum anticancer drug paclitaxel (a.k.a. Taxol) that is stable in cell culture and labile to Pd catalysts. This new prodrug is effectively uncaged in cancer cell culture by Pd nanosheets captured within agarose and alginate hydrogels, providing a biodegradable catalytic framework to achieve controlled release of one of the most important chemotherapy drugs in medical practice. The compatibility of bioorthogonal catalysis and physical hydrogels opens up new opportunities to administer and modulate the mobility of transition metal catalysts in living environs.
5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. ...Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.
Rationale, aims and objectives
Pressure ulcers (PUs) are a common and serious complication in critically ill patients. The aim of this study was to evaluate the relationship between the development ...of a PU and hospital mortality in patients requiring mechanical ventilation (MV) in an intensive care unit (ICU).
Methods
A prospective cohort study was performed over two years in patients requiring MV for ≥ 24 hours in a medical‐surgical ICU. Primary outcome measure was hospital mortality and main independent variable was the development of a PU grade ≥ II. Hazard ratios (HRs) were calculated using a Cox model with time‐dependent covariates.
Results
Out of 563 patients in the study, 110 (19.5%) developed a PU. Overall hospital mortality was 48.7%. In the adjusted multivariate model, PU onset was a significant independent predictor of mortality (adjusted HR, 1.28; 95% confidence interval, 1.003–1.65; P = 0.047). The model also included the Acute Physiology and Chronic Health Evaluation II score, total Sequential Organ Failure Assessment on day 3, hepatic cirrhosis and medical admission.
Conclusion
Within the limitations of a single‐centre approach, PU development appears to be associated with an increase in mortality among patients requiring MV for 24 hours or longer.
This study examined the associations between eating or skipping breakfast and the quality of breakfast eaten on health-related quality of life (HRQOL), perceived stress and depression in 527 Spanish ...adolescents. Results showed differences in stress and two domains of HRQOL; Moods and Emotions and Parent Relations and Home Life between adolescent breakfast skippers and eaters, those having breakfast showing higher levels of stress and poor HRQOL. When breakfast quality was analyzed in breakfast eaters, adolescents who ate a good quality breakfast showed better HRQOL and lower levels of stress and depression than those who ate a poor or very poor quality breakfast. Further, breakfast skippers showed better HRQOL and lower levels of stress and depression than breakfast eaters who ate a poor or very poor quality breakfast. These findings indicate the importance of eating a good quality breakfast, rather than just having or not having breakfast. The conclusions of the present study are especially relevant for clinicians and nutritional educators, given the significant impact of breakfast quality on health-related quality of life, stress and depression observed in the adolescents studied.
Bioorthogonal metallocatalysis has opened up a xenobiotic route to perform nonenzymatic catalytic transformations in living settings. Despite their promising features, most metals are deactivated ...inside cells by a myriad of reactive biomolecules, including biogenic thiols, thereby limiting the catalytic functioning of these abiotic reagents. Here we report the development of cytocompatible alloyed AuPd nanoparticles with the capacity to elicit bioorthogonal depropargylations with high efficiency in biological media. We also show that the intracellular catalytic performance of these nanoalloys is significantly enhanced by protecting them following two different encapsulation methods. Encapsulation in mesoporous silica nanorods resulted in augmented catalyst reactivity, whereas the use of a biodegradable PLGA matrix increased nanoalloy delivery across the cell membrane. The functional potential of encapsulated AuPd was demonstrated by releasing the potent chemotherapy drug paclitaxel inside cancer cells. Nanoalloy encapsulation provides a novel methodology to develop nanoreactors capable of mediating new-to-life reactions in cells.
Summary
Background
There are few data on corticosteroids (CS)‐sparing strategies for checkpoint inhibitor (ICI)‐induced liver injury (ChILI).
Aim
We aimed to assess the performance of a 2‐step ...algorithm for severe ChILI, based on ICI temporary discontinuation (step‐1) and, if lack of biochemical improvement, CS based on the degree of necroinflammation at biopsy (step‐2).
Methods
Prospective study that included all subjects with grade 3/4 ChILI. Peripheral extended immunophenotyping was performed. Indication for CS: severe necroinflammation; mild or moderate necroinflammation with later biochemical worsening.
Results
From 111 subjects with increased transaminases (January 2020 to August 2023), 44 were diagnosed with grade 3 (N = 35) or grade 4 (N = 9) ChILI. Main reason for exclusion was alternative diagnosis. Lung cancer (13) and melanoma (12) were the most common malignancies. ICI: 23(52.3%) anti‐PD1, 8(18.2%) anti‐PD‐L1, 3(6.8%) anti‐CTLA‐4, 10(22.7%) combined ICI. Liver injury pattern: hepatocellular (23,52.3%) mixed (12,27.3%) and cholestatic (9,20.5%). 14(32%) presented bilirubin >1.2 mg/dL. Overall, 30(68.2%) patients did not require CS: 22(50.0%) due to ICI discontinuation (step‐1) and 8/22 (36.4%) based on the degree of necroinflammation (step‐2). Biopsy mainly impacted on grade 3 ChILI, sparing CS in 8 out of 15 (53.3%) non‐improvement patients after ICI discontinuation. CD8+ HLA‐DR expression (p = 0.028), central memory (p = 0.046) were lower in CS‐free managed subjects, but effector‐memory cells (p = 0.002) were higher. Time to transaminases normalisation was shorter in those CS‐free managed (overall: p < 0.001, grade 3: p < 0.001). Considering our results, a strategy based on ICI discontinuation and biopsy for grade 3 ChILI is proposed.
Conclusions
An algorithm based on temporary immunotherapy discontinuation and biopsy allows CS avoidance in two thirds of cases of severe ChILI.
A 2‐step algorithm based on immunotherapy temporary discontinuation and liver biopsy allowed a corticosteroid‐free management in two thirds of cases of severe checkpoint inhibitor‐induced liver injury.
Selected multi-proxy and accurately dated marine and terrestrial records covering the past 2000 years in the Iberian Peninsula (IP) facilitated a comprehensive regional paleoclimate reconstruction ...for the Medieval Climate Anomaly (MCA: 900–1300 AD). The sequences enabled an integrated approach to land–sea comparisons and, despite local differences and some minor chronological inconsistencies, presented clear evidence that the MCA was a dry period in the Mediterranean IP. It was a period characterized by decreased lake levels, more xerophytic and heliophytic vegetation, a low frequency of floods, major Saharan eolian fluxes, and less fluvial input to marine basins. In contrast, reconstruction based on sequences from the Atlantic Ocean side of the peninsula indicated increased humidity. The data highlight the unique characteristics of the MCA relative to earlier (the Dark Ages, DA: ca 500–900 years AD) and subsequent (the Little Ice Age, LIA: 1300–1850 years AD) colder periods. The reconstruction supports the hypothesis of Trouet et al. (2009), that a persistent positive mode of the North Atlantic Oscillation (NAO) dominated the MCA.
► Integration of selected multi-proxy and well-dated paleoclimate records from Iberia. ► Selected records evidence that the MCA was a dry period in Mediterranean Iberia. ► A persistent positive mode of the NAO was dominant during the MCA.
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