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GM3 is a ganglioside that has been biochemically identified as dominating the cell surface of several human tumours, but is also found on human normal cells at much lower density. Since GM3 is widely distributed in essentially all types of animal cells, there is a conflict with the concepts of tumour-associated antigen, immunogen, and toxicity. We have designed a GM3-based cancer vaccine for the treatment of human breast and melanoma tumours. Prior to the Phase I clinical trial, we carried out a 12-month dose repeated toxicity study in five male Macaca fascicularis monkeys. Four male monkeys were treated with placebo in a similar way. During the study, no differences were observed between control and treated monkeys related to daily clinical observations (other than local damage) including rectal temperature, blood pressure, respiratory and cardiac rates, weight gain, biochemical and hematological parameters (with the exception of transitory pathological changes), and anti-DNA and anti-nuclear antibodies, although treated monkeys consistently developed both IgM- and IgG-specific anti-GM3 antibodies. Sixty per cent of treated monkeys developed moderate local reactions at the injection site, which disappeared without sequels. We concluded that this GM3 cancer vaccine overcame in monkeys the natural tolerance to GM3 ganglioside evidenced by a strong immune response, while the local reactions elicited were transitory without apparent important systemic toxicity effects. [ABSTRACT FROM AUTHOR]

Marta Osorio,1 Elias Gracia,1 Edmundo Reigosa,1 Julio Hernandez,2 Ana de la Torre,2 Giselle Saurez,3 Kirenia Perez,3 Carmen Viada,3 Meylán Cepeda,2 Adriana Carr,3 Yisel Ávila,4 Migdalia Rodríguez,4 Luis E Fernandez31National Institute of Oncology and Radiobiology, Havana, 2Dr Celestino Hernández Oncology Hospital, Villa Clara, 3Center of Molecular Immunology, Havana, 4National Center of Clinical Trials, Havana, CubaAbstract: NeuGc-containing gangliosides have been described in melanoma cells and are an attractive target for cancer immunotherapy because they are minimally or not expressed in normal human tissues. Melanoma patients treated with a vaccine based on N-glycolyl gangliosides have shown benefit in progression free survival and overall survival. We conducted a multicenter Phase I/II clinical trial in patients with metastatic cutaneous melanoma treated with the N-gycolyl GM3/very-small-size proteoliposomes vaccine by the subcutaneous route. Selecting the optimal biological dose of the vaccine was the principal objective based on immunogenicity, efficacy, and safety results. Six dose levels were studied and the treatment schedule consisted of five doses administered every 2 weeks and then monthly until 15 doses had been given. Dose levels evaluated were 150, 300, 600, 900, 1200, and 1500 µg with five patients included in each dose level except the 900 µg dose (n = 10). Immunogenicity was determined by antibody titers generated in patients after vaccination. Antitumor effect was measured by response criteria of evaluation in solid tumors and safety was evaluated by common toxicity criteria of adverse events. The vaccine was safe and immunogenic at all doses levels. The most frequent adverse events related to vaccination were mild to moderate injection site reactions and flu-like symptoms. Vaccination induced specific anti-NeuGcGM3 immunoglobulin M and immunoglobulin G antibody responses in all patients. Disease control (objective response or stable disease) was obtained in 38.46% of patients. Global median overall survival was 20.20 months. Two patients achieved overall survival duration of about 4 and 5 years, respectively. The 900 µg dose resulted in overall survival duration of 19.40 months and was selected as the biological optimal dose.Keywords: melanoma, clinical trial, therapeutic vaccine, ganglioside, N-glycolyl GM3

Por su complejidad, el vocabulario es uno de los contenios de los manuales didácticos para el aprendizaje de idiomas que presenta mayor dificultad para su selección. En este artículo se propone como recurso para lograrlo, seleccionar los vocablos más últiles por centros de interés, es decir, los que tengan un índice de disponibilidad superior a 0.1 y hayan sido mencionados por más del 25% de los informantes nativos.

Abstract Background Although Staphylococcus aureus is considered the main etiological agent of infectious mastitis, recent studies have suggested that coagulase-negative staphylococci (CNS) may also play an important role in such infections. The aims of this work were to isolate staphylococci from milk of women with lactational mastitis, to select and characterize the CNS isolates, and to compare such properties with those displayed by CNS strains isolated from milk of healthy women. Results The milk of 30 women was collected and bacterial growth was noted in 27 of them, of which Staphylococcus epidermidis was isolated from 26 patients and S. aureus from 8. Among the 270 staphylococcal isolates recovered from milk of women with mastitis, 200 were identified as Staphylococcus epidermidis by phenotypic assays, species-specific PCR and PCR sequencing. They were typified by pulsed field gel electrophoresis (PFGE) genotyping. The PFGE profiles of the S. epidermidis strains were compared with those of 105 isolates from milk of healthy women. A representative of the 76 different PFGE profiles was selected to study the incidence of virulence factors and antibiotic resistance. The number of strains that contained the biofilm-related icaD gene and that showed resistance to oxacillin, erythromycin, clindamycin and mupirocin was significantly higher among the strains isolated from mastitic milk. Conclusion S. epidermidis may be a frequent but largely underrated cause of infectious mastitis in lactating women. The resistance to diverse antibiotics and a higher ability to form biofilms found among the strains isolated from milk of women suffering mastitis may explain the chronic and/or recurrent nature of this infectious condition.

Abstract Background Breast milk is an important source of staphylococci and other bacterial groups to the infant gut. The objective of this work was to analyse the bacterial diversity in feces of breast-fed infants and to compare it with that of formula-fed ones. A total of 23 women and their respective infants (16 breast-fed and 7 formula-fed) participated in the study. The 16 women and their infants provided a sample of breast milk and feces, respectively, at days 7, 14, and 35. The samples were plated onto different culture media. Staphylococcal and enterococcal isolates were submitted to genetic profiling and to a characterization scheme, including detection of potential virulence traits and sensitivity to antibiotics. Results The feeding practice had a significant effect on bacterial counts. A total of 1,210 isolates (489 from milk, 531 from breast-fed and 190 from formula-fed infants) were identified. Staphylococcus epidermidis was the predominant species in milk and feces of breast-fed infants while it was less prevalent in those of formula fed-infants. Enterococcus faecalis was the second predominant bacterial species among the fecal samples provided by the breast-fed infants but it was also present in all the samples from the formula-fed ones. The biofilm-related icaD gene and the mecA gene were only detected in a low number of the S. epidermidis strains. Several enterococcal isolates were also characterized and none of them contained the cylA or the vanABDEG antibiotic-resistance genes. All were sensitive to vancomycin. Conclusion The presence of S. epidermidis is a differential trait of the fecal microbiota of breast-fed infants. Globally, the staphyloccal isolates obtained from milk and feces of breast-fed infants contain a low number of virulence determinants and are sensitive to most of the antibiotics tested.

EI propósito de este ensayo es explorar aquellas dimensiones descuidadas de la llamada "revolución microelectrónica".

Sticholysin II (StII), a pore-forming toxin from the marine anemone Stichodactyla helianthus, enhances an antigen-specific cytotoxic T lymphocyte (CTL) response when co-encapsulated in liposomes with a model antigen. This capacity does not depend exclusively on its pore-forming activity and is partially supported by its ability to activate Toll-like receptor 4 (TLR4) in dendritic cells, presumably by interacting with this receptor or by triggering signaling cascades upon binding to lipid membrane. In order to investigate whether the lipid binding capacity of StII is required for immunomodulation, we designed a mutant in which the aromatic amino acids from the interfacial binding site Trp110, Tyr111 and Trp114 were substituted by Ala. In the present work, we demonstrated that StII3A keeps the secondary structure composition and global folding of StII, while it loses its lipid binding and permeabilization abilities. Despite this, StII3A upregulates dendritic cells maturation markers, enhances an antigen-specific effector CD8+ T cells response and confers antitumor protection in a preventive scenario in C57BL/6 mice. Our results indicate that a mechanism independent of its lipid binding ability is involved in the immunomodulatory capacity of StII, pointing to StII3A as a promising candidate to improve the reliability of the Sts-based vaccine platform., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Artisanal and small-scale gold mining (ASGM) is the primary global source of anthropogenic mercury (Hg) emissions. It has impacted the Amazon rainforest in the Peruvian region of Madre de Dios. However, few studies have investigated Hg's distribution in terrestrial ecosystems in this region. We studied Hg's distribution and its predictors in soil and native plant species from artisanal mining sites. Total Hg concentrations were determined in soil samples collected at different depths (0-5 cm and 5-30 cm) and plant samples (roots, shoots, leaves) from 19 native plant species collected in different land cover categories: naked soil (L1), gravel piles (L2), natural regeneration (L3), reforestation (L4), and primary forest (L5) in the mining sites. Hg levels in air were also studied using passive air samplers. The highest Hg concentrations in soil (average 0.276 and 0.210 mg kg -1 dw.) were found in the intact primary forest (L5) at 0-5 cm depth and in the plant rooting zones at 5-30 cm depth, respectively. Moreover, the highest Hg levels in plants (average 0.64 mg kg -1 dw) were found in foliage of intact primary forest (L5). The results suggest that the forest in these sites receives Hg from the atmosphere through leaf deposition and that Hg accumulates in the soil surrounding the roots. The Hg levels found in the plant leaves of the primary forest are the highest ever recorded in this region, exceeding values found in forests impacted by Hg pollution worldwide and raising concerns about the extent of the ASGM impact in this ecosystem. Correlations between Hg concentrations in soil, bioaccumulation in plant roots, and soil physical-chemical characteristics were determined. Linear regression models showed that the soil organic matter content (SOM), pH, and electrical conductivity (EC) predict the Hg distribution and accumulation in soil and bioaccumulation in root plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Understanding the past habitable environments of Mars increases the requirement to recognize and examine modern analogs and to evaluate the mechanisms that may preserve biosignatures in them. The phenomenon that originates and preserves possible microbial biosignatures in mineral phases is of particular interest in astrobiology. On Earth, the precipitation of carbonate matrices can be mediated by bacteria. Besides microbialites and other sedimentary structures, carbonate formations can be observed in certain karstic caves. The present work is focused on the remote laser-induced breakdown spectroscopy (LIBS) characterization of cyanobacteria, exploring the possibilities for identification and discrimination on carbonate substrates. For this purpose, the extremophile cyanobacterium Chroococcidiopsis sp. (collected from the Nerja Cave, Malaga, Spain) was analyzed under laboratory-simulated martian conditions in terms of chemical composition and gas pressure. LIBS results related to acquired molecular emission features allowed bacterial differentiation from the colonized mineral substrate. In addition, the limits of detection were estimated with a laboratory-grown culture of the cyanobacterium Microcystis aureginosa . Our results reveal LIBS's capability to detect biological traces under simulated martian conditions. Additionally, the time-resolved analysis of the biological samples demonstrates the selection of optimal temporal conditions as a critical parameter for the preferential acquisition of molecular species in organic material.

Background: Immune suppression is common in neoplasia and a major driver is tumor-induced myeloid dysfunction. Yet, overcoming such myeloid cell defects remains an untapped strategy to reverse suppression and improve host defense. Exposure of bone marrow progenitors to heightened levels of myeloid growth factors in cancer or following certain systemic treatments promote abnormal myelopoiesis characterized by the production of myeloid-derived suppressor cells (MDSCs) and a deficiency in antigen-presenting cell function. We previously showed that a novel immune modulator, termed 'very small size particle' (VSSP), attenuates MDSC function in tumor-bearing mice, which was accompanied by an increase in dendritic cells (DCs) suggesting that VSSP exhibits myeloid differentiating properties. Therefore, here, we addressed two unresolved aspects of the mechanism of action of this unique immunomodulatory agent: (1) does VSSP alter myelopoiesis in the bone marrow to redirect MDSC differentiation toward a monocyte/macrophage or DC fate? and (2) does VSSP mitigate the frequency and suppressive function of human tumor-induced MDSCs?, Methods: To address the first question, we first used a murine model of granulocyte-colony stimulating factor-driven emergency myelopoiesis following chemotherapy-induced myeloablation, which skews myeloid output toward MDSCs, especially the polymorphonuclear (PMN)-MDSC subset. Following VSSP treatment, progenitors and their myeloid progeny were analyzed by immunophenotyping and MDSC function was evaluated by suppression assays. To strengthen rigor, we validated our findings in tumor-bearing mouse models. To address the second question, we conducted a clinical trial in patients with metastatic renal cell carcinoma, wherein 15 patients were treated with VSSP. Endpoints in this study included safety and impact on PMN-MDSC frequency and function., Results: We demonstrated that VSSP diminished PMN-MDSCs by shunting granulocyte-monocyte progenitor differentiation toward monocytes/macrophages and DCs with heightened expression of the myeloid-dependent transcription factors interferon regulatory factor-8 and PU.1. This skewing was at the expense of expansion of granulocytic progenitors and rendered the remaining MDSCs less suppressive. Importantly, these effects were also demonstrated in a clinical setting wherein VSSP monotherapy significantly reduced circulating PMN-MDSCs, and their suppressive function., Conclusions: Altogether, these data revealed VSSP as a novel regulator of myeloid biology that mitigates MDSCs in cancer patients and reinstates a more normal myeloid phenotype that potentially favors immune activation over immune suppression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Induction of CD8 + T cell responses against tumor cells and intracellular pathogens is an important goal of modern vaccinology. One approach of translational interest is the use of liposomes encapsulating pore-forming proteins (PFPs), such as Listeriolysin O (LLO), which has shown efficacy at priming strong and sustained CD8 + T cell responses. Recently, we have demonstrated that Sticholysin II (StII), a PFP from the sea anemone Stichodactyla helianthus, co-encapsulated into liposomes with ovalbumin (OVA) was able to stimulate, antigen presenting cells, antigen-specific CD8 + T cells and anti-tumor activity in mice. In the present study, we aimed to compare StII and LLO in terms of their abilities to stimulate dendritic cells and to induce major histocompatibility complex (MHC) class I restricted T cell responses against OVA. Interestingly, StII exhibited similar abilities to LLO in vitro of inducing dendritic cells maturation, as measured by increased expression of CD40, CD80, CD86 and MHC-class II molecules, and of stimulating OVA cross-presentation to a CD8 + T cell line. Remarkably, using an ex vivo Enzyme-Linked ImmunoSpot Assay (ELISPOT) to monitor gamma interferon (INF-γ) producing effector memory CD8 + T cells, liposomal formulations containing either StII or LLO induced comparable frequencies of OVA-specific INF-γ producing CD8 + T cells in mice that were sustained in time. However, StII-containing liposomes stimulated antigen-specific memory CD8 + T cells with a higher potential to secrete IFN-γ than liposomes encapsulating LLO. This StII immunostimulatory property further supports its use for the rational design of T cell vaccines against cancers and intracellular pathogens. In summary, this study indicates that StII has immunostimulatory properties similar to LLO, despite being evolutionarily distant PFPs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)