Virus-like particle-mediated delivery of structure-selected neoantigens demonstrates immunogenicity and antitumoral activity in mice.

BACKGROUND: Neoantigens are patient- and tumor-specific peptides that arise from somatic mutations. They stand as promising targets for personalized therapeutic cancer vaccines. The identification process for neoantigens has evolved with the use of next-generation sequencing technologies and bioinformatic tools in tumor genomics. However, in-silico strategies for selecting immunogenic neoantigens still have very low accuracy rates, since they mainly focus on predicting peptide binding to Major Histocompatibility Complex (MHC) molecules, which is key but not the sole determinant for immunogenicity. Moreover, the therapeutic potential of neoantigen-based vaccines may be enhanced using an optimal delivery platform that elicits robust de novo immune responses. METHODS: We developed a novel neoantigen selection pipeline based on existing software combined with a novel prediction method, the Neoantigen Optimization Algorithm (NOAH), which takes into account structural features of the peptide/MHC-I interaction, as well as the interaction between the peptide/MHC-I complex and the TCR, in its prediction strategy. Moreover, to maximize neoantigens' therapeutic potential, neoantigen-based vaccines should be manufactured in an optimal delivery platform that elicits robust de novo immune responses and bypasses central and peripheral tolerance. RESULTS: We generated a highly immunogenic vaccine platform based on engineered HIV-1 Gag-based Virus-Like Particles (VLPs) expressing a high copy number of each in silico selected neoantigen. We tested different neoantigen-loaded VLPs (neoVLPs) in a B16-F10 melanoma mouse model to evaluate their capability to generate new immunogenic specificities. NeoVLPs were used in in vivo immunogenicity and tumor challenge experiments. CONCLUSIONS: Our results indicate the relevance of incorporating other immunogenic determinants beyond the binding of neoantigens to MHC-I. Thus, neoVLPs loaded with neoantigens enhancing the interaction with the TCR can promote the generation of de novo antitumor-specific immune responses, resulting in a delay in tumor growth. Vaccination with the neoVLP platform is a robust alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy.

Neuropsychological profiles in first-episodes psychosis and their relationship with clinical, metacognition and social cognition variables.

An increasing interest in the assessment of neuropsychological performance variability in people with first-episode psychosis (FEP) has emerged. However, its association with clinical and functional outcomes requires further study. Furthermore, FEP neuropsychological subgroups have not been characterized by clinical insight or metacognition and social cognition domains. The aim of this exploratory study was to identify specific groups of patients with FEP based on neuropsychological variables and to compare their sociodemographic, clinical, metacognition and social cognition profiles. A sample of 149 FEP was recruited from adult mental health services. Neuropsychological performance was assessed by a neuropsychological battery (WAIS-III; TMT; WSCT; Stroop Test; TAVEC). The assessment also included sociodemographic characteristics, clinical, functional, metacognition and social cognition variables. Two distinct neuropsychological profiles emerged: one neuropsychological impaired cluster (N = 56) and one relatively intact cluster (N = 93). Significant differences were found between both profiles in terms of sociodemographic characteristics (age and level of education) (p = 0.001), clinical symptoms (negative, positive, disorganized, excitement and anxiety) (p = 0.041-0.001), clinical insight (p = 0.038-0.017), global functioning (p = 0.014), as well as in social cognition domains (emotional processing and theory of mind) (p = 0.001; p = 0.002). No significant differences were found in metacognitive variables (cognitive insight and 'jumping to conclusions' bias). Relationship between neurocognitive impairment, social cognition and metacognition deficits are discussed. Early identifying of neuropsychological profiles in FEP, characterized by significant differences in clinical and social cognition variables, could provide insight into the prognosis and guide the implementation of tailored early-intervention.

The influence of gender in cognitive insight and cognitive bias in people with first-episode psychosis: an uncontrolled exploratory analysis.

PURPOSE: Previous studies have investigated the role of gender in clinical symptoms, social functioning, and neuropsychological performance in people with first-episode psychosis (FEP). However, the evidence of gender differences for metacognition in subjects with FEP is still limited and controversial. The aim of the present study was to explore gender differences in cognitive insight and cognitive biases in this population. METHODS: Cross-sectional study was carried out in a sample of 104 patients with FEP (35 females and 69 males) recruited from mental health services. Symptoms were assessed with the Positive and Negative Syndrome Scale, cognitive insight with the Beck Cognitive Insight Scale, and cognitive bias by the Cognitive Biases Questionnaire for Psychosis. The assessment also included clinical and sociodemographic characteristics. RESULTS: After controlling for potential confounders (level of education, marital status, and duration of psychotic illness) analysis of covariance revealed that males presented greater self-reflectiveness (p = 0.004) when compared to females. However, no significant differences were found in self-certainty and composite index of the cognitive insight scale, as in the cognitive biases assessed. CONCLUSIONS: Gender was an independent influence factor for self-reflectiveness, being better for males. Self-reflectiveness, if shown to be relatively lacking in women, could contribute to the design of more gender-sensitive and effective psychotherapeutic treatments, as being able to self-reflect predicts to better treatment response in psychosis.

Production and Immunogenicity of FeLV Gag-Based VLPs Exposing a Stabilized FeLV Envelope Glycoprotein.

The envelope glycoprotein (Env) of retroviruses, such as the Feline leukemia virus (FeLV), is the main target of neutralizing humoral response, and therefore, a promising vaccine candidate, despite its reported poor immunogenicity. The incorporation of mutations that stabilize analogous proteins from other viruses in their prefusion conformation (e.g., HIV Env, SARS-CoV-2 S, or RSV F glycoproteins) has improved their capability to induce neutralizing protective immune responses. Therefore, we have stabilized the FeLV Env protein following a strategy based on the incorporation of a disulfide bond and an Ile/Pro mutation (SOSIP) previously used to generate soluble HIV Env trimers. We have characterized this SOSIP-FeLV Env in its soluble form and as a transmembrane protein present at high density on the surface of FeLV Gag-based VLPs. Furthermore, we have tested its immunogenicity in DNA-immunization assays in C57BL/6 mice. Low anti-FeLV Env responses were detected in SOSIP-FeLV soluble protein-immunized animals; however, unexpectedly no responses were detected in the animals immunized with SOSIP-FeLV Gag-based VLPs. In contrast, high humoral response against FeLV Gag was observed in the animals immunized with control Gag VLPs lacking SOSIP-FeLV Env, while this response was significantly impaired when the VLPs incorporated SOSIP-FeLV Env. Our data suggest that FeLV Env can be stabilized as a soluble protein and can be expressed in high-density VLPs. However, when formulated as a DNA vaccine, SOSIP-FeLV Env remains poorly immunogenic, a limitation that must be overcome to develop an effective FeLV vaccine.

Predictors of clinical insight in first-episode psychosis: Different patterns in men and women.

BACKGROUND: We aimed to explore gender-related differences in the associations of insight impairment with clinical symptoms, metacognition, and social cognition in psychosis. METHODS: Regression analysis of several clinical insight dimensions was conducted on the data from 116 men and 56 women with first-episode psychosis. Various clinical symptoms and measures of metacognition and social cognition were entered as predictors. RESULTS: In both men and women, delusions emerged as a strong predictor of all insight dimensions, and verbal hallucinations as a strong predictor of symptom relabelling. In men, certain negative symptoms as well as self-certainty, lack of self-reflectiveness, impaired theory of mind, attributional biases, and a jumping-to-conclusions bias were additional predictors of poor insight, while good insight was associated with depression, anxiety, avolition, blunted affect, and impaired emotional recognition. In women, poor insight was associated with a self-serving/externalising bias, impaired emotional recognition, and attention disorders. CONCLUSIONS: Poor insight in first-episode psychosis is strongly linked to deficits in metacognition and social cognition, with marked differences between men and women with respect to the specific skills involved in the impairment. Meanwhile, good insight is linked to a variety of affective manifestations in men. These findings suggest new avenues for more targeted cognitive interventions to improve clinical insight in psychosis.

Cognitive insight in first-episode psychosis: Exploring the complex relationship between executive functions and social cognition.

Social cognition (SC) and executive function (EF) have been described as important variables for social functioning and recovery of patients with psychosis. However, the relationship between SC and EF in first-episode psychosis (FEP) deserves further investigation, especially focusing on gender differences. AIMS: To investigate the relationship between EF and different domains of SC in FEP patients and to explore gender differences in the relationship between these domains. METHODS: A cross-sectional study of 191 patients with new-onset psychosis recruited from two multicenter clinical trials. A comprehensive cognitive battery was used to assess SC (Hinting Task, Face Test and IPSAQ) and EF (TMT, WSCT, Stroop Test and digit span - WAIS-III). Pearson correlations and linear regression models were performed. RESULTS: A correlation between Theory of Mind (ToM), Emotional Recognition (ER) and EF was found using the complete sample. Separating the sample by gender showed different association profiles between these variables in women and men. CONCLUSIONS: A relationship between different domains of SC and EF is found. Moreover, women and men presented distinct association profiles between EF and SC. These results should be considered in order to improve the treatment of FEP patients and designing personalized interventions by gender.

Family Metacognitive Training (MCT-F): Adapting MCT to Mothers with Psychosis and Their Adolescent Children.

Over half of women with psychosis are mothers. Research suggests that mothers with psychosis face unique challenges affecting both their mental health prognosis and their relationship with their children. Moreover, those children have a higher risk of developing a mental disorder. Notwithstanding, interventions specifically tailored to these families remain largely uncovered. Metacognitive Training (MCT) has demonstrated its efficacy in improving cognitive insight, symptom management, and social cognition in people with psychosis. However, there is no evidence of the efficacy of MCT in a family setting (MCT-F). This study describes the first adaptation of MCT for mothers with psychosis and their adolescent children in an online group setting. The phases (assessment, decision, adaptation, production, topical experts' integration) of the ADAPT-ITT model were systematically applied through a participatory approach (n = 22), including a first-person perspective and involving qualitative (e.g., topical expert literature review and consensus groups, interviews, thematic analyses) and quantitative methods. While MCT's core components were retained, participants guided adaptations both in content and delivery. The findings suggest the importance of community engagement and sharing decision-making processes to demonstrate the acceptability and feasibility of the adapted intervention. Employing a structured approach such as the ADAPT-ITT model ensures readiness of the new training for efficacy trials.

Immunization with V987H-stabilized Spike glycoprotein protects K18-hACE2 mice and golden Syrian hamsters upon SARS-CoV-2 infection.

Safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are crucial to fight against the coronavirus disease 2019 pandemic. Most vaccines are based on a mutated version of the Spike glycoprotein [K986P/V987P (S-2P)] with improved stability, yield and immunogenicity. However, S-2P is still produced at low levels. Here, we describe the V987H mutation that increases by two-fold the production of the recombinant Spike and the exposure of the receptor binding domain (RBD). S-V987H immunogenicity is similar to S-2P in mice and golden Syrian hamsters (GSH), and superior to a monomeric RBD. S-V987H immunization confer full protection against severe disease in K18-hACE2 mice and GSH upon SARS-CoV-2 challenge (D614G or B.1.351 variants). Furthermore, S-V987H immunized K18-hACE2 mice show a faster tissue viral clearance than RBD- or S-2P-vaccinated animals challenged with D614G, B.1.351 or Omicron BQ1.1 variants. Thus, S-V987H protein might be considered for future SARS-CoV-2 vaccines development.

Effectiveness of family metacognitive training in mothers with psychosis and their adolescent children: a multicenter study protocol.

Background: More than half of women with psychosis take care of their children despite the difficulties caused by the disease. Additionally, these kids have a higher risk of developing a mental health disorder. However, no interventions have been developed to meet these needs. Metacognitive Training (MCT) is a psychological intervention that has demonstrated its efficacy in improving cognitive insight, symptom management and social cognition in people with first-episode psychosis (FEP). Additionally, MCT has shown better results in women than men with FEP. This study aims to adapt and evaluate the efficacy of MCT-F in mothers and adolescent children in an online group context with the main purpose of improving family relationships, cognitive awareness and symptoms in women with psychosis and increase their children's knowledge of the disease and their functioning. As secondary objectives, it also aims to evaluate improvements in metacognition, social cognition, symptoms, protective factors and self-perception of stigma. Materials and methods: A quasi-experimental design with participants acting as their own control will be carried out. Forty-eight mothers with psychosis and their adolescent children (between 12 and 20 years old) recruited from a total of 11 adult mental health care centers will receive MCT-F. Participants will be evaluated 11 weeks before the intervention (T1), at baseline (T2), and post-intervention (T3) with a cognitive insight scale, as a primary outcome. Measures of metacognitive and social cognition, symptoms, cognitive functioning, family and social functioning, protective factors (self-esteem, resilience, and coping strategies) and self-perceived stigma will be addressed as secondary outcomes. Assessment will also address trauma and attachment in mothers and, lastly, the feasibility and acceptability of MCT-F in both participant groups. Discussion: This will be the first investigation of the efficacy, acceptability, and viability of the implementation of MCT-F. The results of this study may have clinical implications, contributing to improving mothers' with psychosis and adolescents' functioning and better understanding of the disease, in addition to the possible protective and preventive effect in adolescents, who are known to be at higher risk of developing severe mental disorders.Clinical trial registration:https://clinicaltrials.gov/, identifier [NCT05358457].

Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant.

Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations increases the production and immunogenicity of the recombinant S trimer, suggesting that these two parameters are related. Nevertheless, S-2P still shows some molecular instability and it is produced with low yield. Here we described a novel set of mutations identified by molecular modeling and located in the S2 region of the S-2P that increase its production up to five-fold. Besides their immunogenicity, the efficacy of two representative S-2P-based mutants, S-29 and S-21, protecting from a heterologous SARS-CoV-2 Beta variant challenge was assayed in K18-hACE2 mice (an animal model of severe SARS-CoV-2 disease) and golden Syrian hamsters (GSH) (a moderate disease model). S-21 induced higher level of WH1 and Delta variants neutralizing antibodies than S-2P in K18-hACE2 mice three days after challenge. Viral load in nasal turbinate and oropharyngeal samples were reduced in S-21 and S-29 vaccinated mice. Despite that, only the S-29 protein protected 100% of K18-hACE2 mice from severe disease. When GSH were analyzed, all immunized animals were protected from disease development irrespectively of the immunogen they received. Therefore, the higher yield of S-29, as well as its improved immunogenicity and efficacy protecting from the highly pathogenic SARS-CoV-2 Beta variant, pinpoint the S-29 mutant as an alternative to the S-2P protein for future SARS-CoV-2 vaccine development.

Gender differences in incipient psychosis

Background and Objectives: To describe gender differences in a group of patients with first-episode psychotic in different aspects: socio-demographic features, characteristics of the phases prior to disease onset (premorbid and prodromic periods), clinical manifestation of psychotic symptoms and possible corresponding cognitive alterations after disease onset, using the age at onset of first psychotic episode as a control variable. Methods: Longitudinal study of 53 consecutive cases with a first psychotic episode. Inclusion criteria: two or more psychotic symptoms; age between 7 to 65 years old; first consultation to the medical center of study; less than 6 months since the first contact to the medical service; and less than a year of symptoms’ evolution. The methodologic assessment includes: a socio-demographic questionnaire and an extensive battery of tests to asses premorbid/prodromic, clinical and cognitive characteristics. We perform mean differences tests to analyze continuous variables (non-parametric U-Mann-Whitney and t-Student test) and chi-square test for categorical variables (SPSS 16.0).Results: In the group of patients under 18 years, men showed higher scores in adjustment premorbid (U = 54.0, p = 0.050), more neurological soft signs (U = 31.0 p = 0.003), more negative psychotic symptoms (U = 48.5, p = 0.051) and worse insight (U = 30.0, p = 0.003)than women (after 8 weeks of psychotic episode onset).Conclusions: We found gender differences in most of the variables analyzed when age at onset was controlled. These differences should be taken into account to learn more about the different types of onset of the disease, its prevention and possible improvements in therapeutic approach. Our findings suggest that younger men with an earlier onset of psychotic episode have more alterations in the stages prior to the onset of the disease supporting the neurodevelopmental hypothesis for gender differences (AU)

Edad de inicio del primer episodio psicótico: ¿hay diferencias clínicas entre varones y mujeres? / Age of onset of a first psychotic episode: are there any clinical differences between men and women?

Introducción: En la última década, los estudios sobre primeros episodios psicóticos han alcanzado relevancia. En nuestro estudio se analizan las diferencias por sexo en la edad de inicio, así como las diferencias en el tipo y la gravedad de los síntomas psicóticos en función de la edad de inicio, en varones y mujeres con un primer episodio psicótico. Material y método: Estudio transversal de 24 casos consecutivos con un primer episodio psicótico. Criterios de inclusión: dos o más síntomas psicóticos; edad comprendida entre 7 y 65 años; primera consulta en el centro de estudio; menos de 6 meses desde el primer contacto con los servicios. Los instrumentos utilizados fueron un cuestionario clínico y sociodemográfico, la PANSS y la ICG-ESQ. Para el análisis de los datos se ha utilizado la prueba de U Mann-Whitney para datos no paramétricos, del SPSS. Resultados: En nuestra muestra, el 66,7% eran varones y el 41,7% tenía una edad < 18 años. No se observan diferencias por sexo significativas en la edad de inicio del episodio (p = 0,580). Se obtienen resultados significativos en la dimensión excitativa (p = 0,015) y tendencias en la dimensión positiva de la PANSS (p = 0,079) en los varones adultos respecto a los adolescentes. Además encontramos diferencias significativas en adultos frente a adolescentes en los ítems de la PANSS negativa: retraimiento emocional (p = 0,021) y contacto pobre (p = 0,036); sin embargo, sólo encontramos tendencia a la significación en la dimensión negativa de la PANSS (p = 0,080) en varones adolescentes respecto a adultos. Conclusiones: Se evidencia un patrón de inicio del episodio psicótico en varones adolescentes con predominio de sintomatología negativa. Este patrón de inicio con síntomas negativos se suma a las evidencias encontradas en otros estudios a lo largo de los años que apoyan la hipótesis del neurodesarrollo (AU)

Introduction: In the past decade, studies of first psychotic episodes have become increasingly important. In the present study, we analyzed gender differences in age of onset, as well as differences in the type and severity of psychotic symptoms according to age of onset, in men and women with a first psychotic episode. Material and method: We performed a cross-sectional study of 24 consecutive patients with a first psychotic episode. Inclusion criteria consisted of two or more psychotic symptoms, age from 7 to 65 years, first visit to a center participating in the study, and a less than 6-month time lapse since the first contact with services. The instruments used were a clinical and sociodemographic questionnaire, the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Schizophrenia (CGI-SCH) scale. Data were analyzed using the Mann-Whitney U-test for non-parametric data with the SPSS statistical package. Results: In our sample, 66.7% of the sample were male and 41.7% were < 18 years old. No significant gender differences in age at onset of a first psychotic episode were observed (p = 0.580). Significant differences were obtained in the excitative dimension (p = 0.015) and a tendency was found in the positive dimension of the PANSS (p = 0.079) between adult males and adolescents. Significant differences were also found between adult males and adolescents in the negative PANSS items: emotional withdrawal (p = 0.021) and poor rapport (p = 0.036); however only a tendency towards significance was found in the negative dimension of the PANSS (p = 0.080) between adolescent males and adults. Conclusions: A pattern of onset of first psychotic episodes emerged in male adolescents with a predominance of negative symptoms. This pattern of onset with negative symptoms can be added to the evidence found in other studies over the years supporting the neurodevelopment hypothesis (AU)