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About 5 to 15% of all colorectal cancers harbor mismatch repair deficient/microsatellite instability–high status (dMMR/MSI-H) that associates with high tumor mutation burden and increased immunogenicity. As a result, and in contrast to other colorectal cancer phenotypes, a significant subset of dMMR/MSI-H cancer patients strongly benefit from immunotherapy. Yet, a large proportion of these tumors remain unresponsive to any immuno-modulating treatment. For this reason, current efforts are focused on the characterization of resistance mechanisms and the identification of predictive biomarkers to guide therapeutic decision-making. Here, we provide an overview on the new advances related to the diagnosis and definition of dMMR/MSI-H status and focus on the distinct clinical, functional, and molecular cues that associate with dMMR/MSI-H colorectal cancer. We review the development of novel predictive factors of response or resistance to immunotherapy and their potential application in the clinical setting. Finally, we discuss current and emerging strategies applied to the treatment of localized and metastatic dMMR/MSI-H colorectal tumors in the neoadjuvant and adjuvant setting.

Background Canine leishmaniosis (CanL), caused by Leishmania infantum , is an important vector-borne parasitic disease in dogs with implications for human health. Despite advancements, managing CanL remains challenging due to its complexity, especially in chronic, relapsing cases. Mathematical modeling has emerged as a powerful tool in various medical fields, but its application in understanding CanL relapses remains unexplored. Methods This retrospective study aimed to investigate risk factors associated with disease relapse in a cohort of dogs naturally infected with L. infantum . Data from 291 repeated measures of 54 dogs meeting the inclusion criteria were included. Two logistic mixed-effects models were created to identify clinicopathological variables associated with an increased risk of clinical relapses requiring a leishmanicidal treatment in CanL. A backward elimination approach was employed, starting with a full model comprising all potential predictors. Variables were iteratively eliminated on the basis of their impact on the model, considering both statistical significance and model complexity. All analyses were conducted using R software, primarily employing the lme4 package, and applying a significance level of 5% ( P  < 0.05). Results This study identified clinicopathological variables associated with an increased risk of relapses requiring a leishmanicidal treatment. Model 1 revealed that for each 0.1 increase in the albumin/globulin ratio (A/G) ratio, the odds of requiring treatment decreased by 45%. Conversely, for each unit increase in the total clinical score (CS), the odds of requiring treatment increase by 22–30%. Indirect immunofluorescence antibody test (IFAT) was not a significant risk factor in model 1. Model 2, incorporating individual albumin and globulins values, showed that dogs with high IFAT titers, hyper beta-globulinemia, hypoalbuminemia, anemia, and high CS were at increased risk of relapse. Both models demonstrated a good fit and explained a substantial amount of variability in treatment decisions. Conclusions Dogs exhibiting higher CS, dysproteinemia, anemia, and high IFAT titers are at increased risk of requiring leishmanicidal treatment upon clinical relapse in CanL. Regular monitoring and assessment of risk factors prove essential for early detection of relapses and effective intervention in CanL cases. The contrasting findings between the two models highlight the complexity of aspects influencing treatment decisions in this disease and the importance of tailored management strategies to improve outcomes for affected dogs. Graphical Abstract

Leishmania infantum , the etiological agent of canine leishmaniosis (CanL) in Europe, was responsible of the largest outbreak of human leishmaniosis in Spain. The parasite infects and survives within myeloid lineage cells, causing a potentially fatal disease if left untreated. The only treatment option relies on chemotherapy, although immunotherapy strategies are being considered as novel approaches to prevent progression of the disease. To this aim, a deeper characterization of the molecular mechanisms behind the immunopathogenesis of leishmaniosis is necessary. Thus, we evaluated, for the first time, the host immune response during L. infantum infection through transcriptome sequencing of the popliteal lymph nodes aspirates of dogs with CanL. Differential expression and weighted gene co-expression network analyses were performed, resulting in the identification of 5,461 differentially expressed genes (DEGs) and four key modules in sick dogs, compared to controls. As expected, defense response was the highest enriched biological process in the DEGs, with six genes related to immune response against pathogens ( CHI3L1, SLPI, ACOD1, CCL5, MPO, BPI ) included among the ten most expressed genes; and two of the key co-expression modules were associated with regulation of immune response, which also positively correlated with clinical stage and blood monocyte concentration. In particular, sick dogs displayed significant changes in the expression of Th1, Th2, Th17 and Tr1 cytokines (e. g. TNF-α, IFN-γ, IL-21, IL-17, IL-15), markers of T cell and NK cell exhaustion (e. g. LAG3, CD244, Blimp-1, JUN ), and B cell, monocyte and macrophage disrupted functionality (e. g. CD40LG, MAPK4, IL-1R, NLRP3, BCMA ). In addition, we found an overexpression of XBP1 and some other genes involved in endoplasmic reticulum stress and the IRE1 branch of the unfolded protein response, as well as one co-expression module associated with these processes, which could be induced by L. infantum to prevent host cell apoptosis and modulate inflammation-induced lymphangiogenesis at lymph nodes. Moreover, 21 lncRNAs were differentially expressed in sick dogs, and one key co-expression module was associated with chromatin organization, suggesting that epigenetic mechanisms could also contribute to dampening host immune response during natural L. infantum infection in the lymph nodes of dogs suffering from clinical leishmaniosis.

The natural products industry is gaining increasing interest, not only due to modern lifestyles becoming more aware of environmental and sustainability issues but also because of the loss of efficacy and undesirable side effects of synthetic ingredients. This pioneering study provides a comprehensive comparison between extracts obtained from wild and commercial samples of Fucus vesiculosus Linnaeus, highlighting their multifaceted benefits in cosmetic applications. The antiaging potential of acetone (70 and 90%) and ethanol 60% extracts from wild and commercial samples of F. vesiculosus, focusing on their application in cosmetics, was explored. The extracts were chemically characterized, their carotenoid profiles being established by HPLC, and the total phenolic content and phlorotannins by spectrophotometry. The extracts were evaluated for their antioxidant potential against the physiologic free radicals superoxide anion radical (O2•−) and nitric oxide (•NO), for their ability to inhibit the enzymes hyaluronidase and tyrosinase, and for their anti-inflammatory potential in the macrophage cell model RAW 264.7. The acetone 70% extract of wild F. vesiculosus was the richest in fucoxanthin, which accounted for more than 67% of the total pigments identified, followed by the acetone 90% extract of the same sample, where both fucoxanthin and pheophytin-a represented 40% of the total pigments. The same behavior was observed for phenolic compounds, with the ethanol 60% presenting the lowest values. A chemical correlation could be established between the chemical composition and the biological activities, with acetone extracts from the wild F. vesiculosus, richer in fucoxanthin and phlorotannins, standing out as natural ingredients with anti-aging potential. Acetone 90% can be highlighted as the most effective extraction solvent, their extracts presenting the highest radicals scavenging capacity, ability to inhibit tyrosinase to a greater extent than the commercial ingredient kojic acid, and potential to slow down the inflammatory process.

The extraction of antioxidant compounds from brown macroalgae is of growing industrial interest; however, the weak correlation often observed between polyphenol content and antioxidant activity challenges the conventional strategy of optimizing only extraction yield. This study introduces, for the first time in brown macroalgae, a functionality-driven optimization approach in which ultrasound-assisted extraction (UAE) conditions are optimized based on antioxidant activity as the primary response variable, rather than compound concentration. A green UAE process was developed and optimized for four edible brown algae ( , , , and ), considering algae amount, solvent type and concentration, extraction time, ultrasound power, and temperature. The optimized extracts achieved 69.17-94.68% DPPH inhibition, together with high antioxidant capacity supported by ORAC (18.63-491.30 μmol TE g DW) and FRAP (1.24-87.65 µmol Fe g DW) values, identifying and as the most promising species. Chromatographic analyses confirmed the presence of phlorotannins and carotenoid pigments such as fucoxanthin as the main contributors to antioxidant activity. Overall, this work validates a functionality-driven UAE optimization strategy for efficiently maximizing antioxidant activity in brown algal extracts.

Background Canine leishmaniosis (CanL), caused by Leishmania infantum , can be subclinical or present as a systemic, chronic, and potentially fatal disease. Treatment response in sick dogs is influenced by many factors associated with the host, the vector, and the environment. This study aimed to identify risk factors for poor prognosis in CanL, focusing on demographic, epidemiological, and clinical/clinocopathological variables. Methods A retrospective analysis was conducted on a cohort of 300 dogs with CanL diagnosed between 2000 and 2022. Two logistic regression models were built to identify variables associated with an increased risk of relapses requiring repeated leishmanicidal treatments or of mortality due to CanL. A database with several variables was used to perform the study. These included demographic (age, sex, breed, and body weight), epidemiological (living conditions, travel history, and preventative measures), and clinical variables (clinical signs reported by the pet owner and physical examination findings, antibody titers, and LeishVet clinical stage), treatment history (first-line treatment, drug combinations), and outcome, among others. All analyses were conducted using R software and applying a significance level of 5% ( P  < 0.05). Results Young dogs and those displaying weakness and ocular signs were more likely to develop relapses and require multiple leishmanicidal treatments, while weight loss was associated with a decreased risk. Additionally, dogs treated with miltefosine in combination with allopurinol as first-line treatment had a fivefold higher risk of needing multiple leishmanicidal treatments than those receiving meglumine antimoniate and allopurinol. Medium- to large-sized dogs had a fourfold higher mortality risk than small dogs, while this risk was almost 25 times higher in dogs in LeishVet stage IV compared with those in stage I. Mortality risk was also significantly higher in dogs displaying weakness, gastrointestinal signs, and lymphadenomegaly. Conversely, treatment with domperidone was associated with an 88% reduction in mortality risk. Conclusions Our study highlights important risk factors for poor prognosis in CanL that should be carefully considered by clinicians and researchers when managing sick dogs, particularly regarding therapy decision-making. Graphical Abstract

This article deals with the implementation of British blacklists in Spain, leading to a case study not widely seen before in the international historiography of the First World War. It shows how British intervention in the southern and eastern Spanish markets set a de facto model for the operation of the embargo system. Under the strong stimulus of economic nationalism, the British actions regarding the commercial vetoes were tested against Spanish local interests during the short war (1914–15). The initiative was supposedly fuelled by a sense of revenge against pre-war Germany's commercial progress as well as the desire to control a very appetizing market share, for the British and French alike. In a climate of inter-Allied commercial rivalry, this study focuses on the key role played by members of the consular service. It explains the spurious motivations that in many cases underlay the practical implementation of the blockade from below, and analyses how partisan procedures which lacked homogenized and clarified criteria for collecting and applying commercial intelligence challenged British strategies and the inter-Allied united front in Spain until well into 1917.

This investigation aimed to synthesize poly( d , l -lactide) (PLA)-based fibrous scaffolds containing natural essential oils (i.e., linalool and citral) and determine their antimicrobial properties and cytocompatibility as a clinically viable cell-friendly disinfection strategy for regenerative endodontics. PLA-based fibrous scaffolds were fabricated via electrospinning with different concentrations of linalool and citral. The micromorphology and average diameter of the fibers was investigated through scanning electron microscopy (SEM). The chemical composition of the scaffolds was inferred by Fourier-transform infrared spectroscopy (FTIR). Antimicrobial efficacy against Enterococcus faecalis and Actinomyces naeslundii was also evaluated by agar diffusion and colony-forming units (CFU) assays. The scaffolds’ cytocompatibility was determined using dental pulp stem cells (DPSCs). Statistical analyses were performed and the significance level was set at α  = 5%. Linalool and citral’s incorporation in the PLA fibrous scaffolds was confirmed in the FTIR spectra. SEM images indicate no morphological changes upon inclusion of the essential oils, except the reduced diameter of 40% linalool-laden fibers ( p  < 0.05). Importantly, significant antimicrobial properties were reported for citral-containing scaffolds for CFU/mL counts ( p  < 0.05), while only 20% and 40% linalool-laden scaffolds reduced CFU/mL ( p  < 0.05). Meanwhile, the inhibition halos were verified in a concentration-dependent manner for all monoterpenes-laden scaffolds. Citral- and linalool-laden PLA-based fibrous scaffolds showed acceptable cytocompatibility. The incorporation of natural monoterpenes did not alter the scaffolds’ fibrous morphology, promoted antimicrobial action against endodontic pathogens, and preserved DPSCs viability. Linalool- and citral-laden electrospun scaffolds hold promise as naturally derived antimicrobial therapeutics for applications in regenerative endodontics.

Fucus vesiculosus is a brown seaweed known for its strong antioxidant properties, mainly attributed to its high polyphenolic content. This study aimed to evaluate the antioxidant protective effect of an optimised F. vesiculosus extract in an experimental model of intestinal ischemia/reperfusion (I/R) injury, considering the intestine as particularly vulnerable to this pathology. Seventy-two male Wistar albino rats were randomly divided into twelve groups: Sham, I/R groups (3 and 24 h reperfusion), I/R plus vehicle groups (three application times, 3 h reperfusion), and I/R plus F. vesiculosus extract groups (three application times, 3 and 24 h reperfusion). Intestinal injury was assessed through biochemical markers (malondialdehyde [MDA], superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], and mieloperoxidase [MPO]), inflammatory cytokines (interleukin 1 β [IL-1β] and interleukin [IL-10]), and histological analysis. Results demonstrated that treatment with F. vesiculosus significantly reduced oxidative stress and inflammation caused by I/R injury (p < 0.05), restoring analysed parameters (MDA, SOD, CAT, IL-10) to levels comparable to the Sham group. Histological examination confirmed the preservation of intestinal mucosal integrity following F. vesiculosus administration. These findings suggest that the antioxidant extract from F. vesiculosus effectively protects against intestinal I/R injury, highlighting its potential for clinical use in preventing and managing this pathological condition, particularly in surgical contexts.