Αρχειοθήκη ιστολογίου

Τρίτη 20 Σεπτεμβρίου 2022

CRISPR/Cas9‐HPV‐liposome enhances antitumor immunity and treatment of HPV infection associated cervical cancer

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ABSTRACT

Increasing evidence shows that human papillomavirus (HPV) E6/E7 deletion in cervical cancer cells may be related to immunosuppressive tumour microenvironment and adverse reactions or resistance to immune checkpoint blockade. Here, we demonstrate that liposome delivery of CRISPR/cas9 can effectively knock out HPV, which in turn induces autophagy and triggers cell death-related immune activation by releasing damage-related molecular patterns. The results of in vivo experiments showed that HPV-targeting gRNA–liposomes could promote CD8+ T cell infiltration in tumour tissues; enhance the expression of pro-inflammatory cytokines, such as interleukin-12, tumour necrosis factor-α and interferon-γ and reduce regulatory T cells and myeloid suppressor cells. The combination of HPV-targeting gRNA–liposomes with immune checkpoint inhibitors and anti-programmed death-1 antibodies produced highly effective antitumour effects. In addition, combination therapy induced immune memory in the cervical cancer model.

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Single‐cell transcriptome atlas reveals protective characteristics of COVID‐19 mRNA vaccine

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Abstract

mRNA vaccines are promising alternatives to conventional vaccines in many aspects. We previously developed a lipopolyplex (LPP)-based mRNA vaccine (SW0123) that demonstrated robust immunogenicity and strong protective capacity against SARS-CoV-2 infection in mice and rhesus macaques. However, the immune profiles and mechanisms of pulmonary protection induced by SW0123 remain unclear. Through high-resolution single-cell analysis, we found that SW0123 vaccination effectively suppressed SARS-CoV-2-induced inflammatory responses by inhibiting the recruitment of pro-inflammatory macrophages and increasing the frequency of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). In addition, the apoptotic process in both lung epithelial and endothelial cells was significantly inhibited, which was proposed to be one major mechanism contributing to vaccine-induced lung protection. Cell-cell interaction in the lung compartment was also altered by vaccination. These data collectively unravel the mechanisms by which the SW0123 protects against lung damage caused by SARS-CoV-2 infection.

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Tracheostomy dependence following “organ preservation” (chemo)radiation protocol for laryngeal and hypopharyngeal cancers

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Abstract

Background

Patients receiving primary (chemo)radiotherapy for laryngeal or hypopharyngeal cancer risk developing severe laryngeal dysfunction and becoming tracheostomy dependent, detracting from the benefits of organ preservation. We aim to describe the airway outcomes for this cohort and identify risk factors for developing tracheostomy dependence.

Methods

Patients with laryngeal or hypopharyngeal cancer who were recommended for and underwent primary (chemo)radiotherapy over a 6-year period were identified from a tertiary hospital Head and Neck cancer database. Patient, tumor, and treatment details were collected and analyzed.

Results

Of 166 patients, 18.7% (N = 31) required tracheostomy insertion. Advanced tumor classification was the only significant predictor (p < 0.00001). Successful decannulation was observed in 12.9% (N = 4). Decannulation was observably less successful with advanced tumors, bilateral vocal cord immobility, tracheostomies inserted under emergency conditions.

Conclusion

We quantified tracheostomy insertion rates and dependence in patients undergoing "organ-preserving" (chemo)radiotherapy, to assist in the pre-treatment counseling of patients opting for this approach.

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Prevalence and functional impact of social (pragmatic) communication disorders

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Background

The aim of this study was to evaluate the Children's Communication Checklist-2 (CCC-2) for measuring social-pragmatic communication deficits and to ascertain their prevalence and functional impact in a community sample.

Methods

We used parent and teacher responses to the CCC-2 to approximate inclusion (poor social-pragmatic skills) and exclusion (poor structural language skills or autistic symptomatology) criteria for social (pragmatic) communication disorder (SPCD). We tested the prevalence of social-pragmatic deficits in a population-based sample of children (n = 386) aged 5–6 years old using CCC-2 algorithms. We also investigated the academic and behavioural profiles of children with broadly defined limitations in social-pragmatic competence on the CCC-2.

Results

Regardless of the diagnostic algorithm used, the resulting prevalence rates for social-pragmatic deficits indicated that very few children had isolated social-communication difficulties (0–1.3%). However, a larger proportion of children (range: 6.1–10.5%) had social-pragmatic skills outside the expected range alongside structural language difficulties and/or autism spectrum symptoms, and this profile was associated with a range of adverse academic and behavioural outcomes.

Conclusions

A considerable proportion of children in the early years of primary school has social-pragmatic deficits that interfere with behaviour and scholastic activity; however, these rarely occur in isolation. Exclusionary criteria that include structural language may lead to underidentification of individuals with social-pragmatic deficits that may benefit from tailored support and intervention.

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Developmental pathways linking early behavioral inhibition to later anxiety

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Behavioral Inhibition is a temperament identified in the first years of life that enhances the risk for development of anxiety during late childhood and adolescence. Amongst children characterized with this temperament, only around 40 percent go on to develop anxiety disorders, meaning that more than half of these children do not. Over the past 20 years, research has documented within-child and socio-contextual factors that support differing developmental pathways. This review provides a historical perspective on the research documenting the origins of this temperament, its biological correlates, and the factors that enhance or mitigate risk for development of anxiety. We review as well, research findings from two longitudinal cohorts that have identified moderators of behavioral inhibition in understanding pathways to anxiety. Research on these moderators has led us to develop the Detection and Dual Control (DDC) framework to understand differing developm ental trajectories among behaviorally inhibited children. In this review, we use this framework to explain why and how specific cognitive and socio-contextual factors influence differential pathways to anxiety versus resilience.

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Facial reactions to emotional films in young children with conduct problems and varying levels of callous‐unemotional traits

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Background

Elevated levels of callous-unemotional (CU) traits have proven useful for identifying a distinct subgroup of children whose conduct problems (CP) are early emerging, severe, persistent, and underpinned by aberrant emotional processing. The early childhood emotional experiences and expressions of CP subtypes are poorly understood, despite their importance to understanding the problematic attachments and atypical social affiliation experienced by children with elevated CU traits. The current study aimed to test for differences in facial emotional reactions to mood-inducing film clips in children with CP and varying levels of CU traits.

Method

We compared facial emotional reactions during a developmentally appropriate mood induction task in a mixed-sex sample of clinic-referred preschool children (M age = 3.64 years, SD = 0.63, 66.9% male) classified as CP with elevated levels of CU traits (CP + CU; n = 25) versus low CU traits (CP-only; n = 47), and typically developing children (TD; n = 28).

Results

Relative to TD children, children with clinical CP showed less congruent and more incongruent facial emotional expressions to sad and happy film clips, controlling for child sex, age, and ethnicity.

Conclusions

Consistent with older samples, young children with CP show atypical facial emotional expressions in response to positive and negative emotional stimuli. Findings have implications for developmental models of childhood antisocial behavior and can inform the development of targeted interventions.

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Opening a DOOR for pivotal studies: an example for complicated urinary tract infections

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Associations of Immunogenicity and Reactogenicity After SARS-CoV-2 mRNA-1273 Vaccine in COVE and TeenCOVE Trials

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Abstract
Background
The reactogenicity and immunogenicity of Coronavirus 2019 (COVID-19) vaccines is well-studied. Little is known regarding the relationship between immunogenicity and reactogenicity of COVID-19 vaccines.
Methods
This study assessed the association between immunogenicity and reactogenicity after two mRNA-1273 (100 µg) injections in 1671 total adolescent and adult participants (≥12 years) from the primary immunogenicity sets of the blinded per iods of the Coronavirus Efficacy (COVE) and TeenCOVE trials. Associations between immunogenicity through day 57 and solicited ARs after the first and second injections of mRNA-1273 were evaluated among participants with and without solicited ARs using linear mixed-effects models.
Results
The mRNA-1273 reactogenicity in this combined analysis set was similar to that reported for these trials. The vaccine elicited high neutralizing antibody (nAb) geometric mean titers (GMTs) in evaluable participants. GMTs at day 57 were significantly higher in participants who experienced solicited systemic ARs after the second injection (1227.2 [1164.4-1293.5]) than those who did not (980.1 [886.8-1083.2], p = 0.001) and were associated with fever, chills, headache, fatigue, myalgia, and arthralgia. Significant associations with local ARs were not found.
Conclusions
These data show an association of systemic ARs with increased nAb titers following a second mRNA-1273 injection. While these data indicate systemic ARs are associated with increased antibody titers, high nAb titers were observed in participants after both injections, consistent with the immunogenicity and efficacy in these trials. These results add to the body of evidence regarding the relationship of immunogenicity and reactogenicity and can contribute toward the design of future mRNA vaccines.
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Transition Metals and Enterococcus faecalis: Homeostasis, Virulence and Perspectives

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Enterococcus faecalis, a Gram-positive bacterium is known to be a key player in several chronic infections as well as nosocomial, heart valve, urinary tract, surgical wound and dental root canal infections. The capability to sense different transition metal levels and tune its response accordingly endows it with the potential to thrive and cause infections in several host niches. Over the past decade, our knowledge of how transition metals play a critical role in maintaining homeostasis of E. faecalis has improved significantly. The aim of this review is to elucidate the roles of metals such as iron, manganese, zinc and copper in the physiology, metabolism, and pathogenicity of E. faecalis. These essential micronutrients contribute to energy production, redox stress response, expression of virulence determinants, and cooperation in polymicrobial communities. The review also highlights metal homeostasis systems in E. faecalis, which respond to fluctuatio ns in extracellular metal levels, and regulate the intracellular metal content. Regulation of intracellular metallome secures the tolerance of E. faecalis to oxidative stress and host-mediated metal sequestration strategies. Therapeutic interventions which deprive E. faecalis of its essential metal requirements or disrupt its homeostatic control have been proposed to combat E. faecalis infections.

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Institutional cisnormativity and educational injustice: Trans children's experiences in primary and early secondary education in the UK

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

Transgender children are known to face a wide range of barriers, difficulties and injustices at school. Few studies have focused on the educational experiences of trans pupils who socially transition at or before primary school, with no such studies in the UK.

Aims

To learn about the at-school experiences of transgender children who socially transitioned at or before primary school in the UK, listening to children's and parental accounts of navigating cisnormativity in UK primary and early secondary education.

Sample

The primary sample included 30 parents whose children had socially transitioned under the age of 11 in the UK. This sample was complemented with data directly from 10 of these trans children. The primary sample was accessed through six trans positive parenting groups in the UK, supplemented through snowball sampling.

Methods

Semi-structured interviews produced a rich and detailed qualitative data set, that was analysed through inductive thematic analysis.

Results

Three major themes are presented, highlighting experiences of (i) institutional cisnormativity in UK schools, (ii) a failure to protect trans children and (iii) evidence of educational injustice. The results demonstrate how institutional cisnormativity leaves trans pupils in unsafe educational environments, contributing to school drop-out and trauma.

Conclusions

Cisnormative attitudes normalize injustice, making it acceptable for trans children to lose access to education, or to experience trauma in school. Educators, schools and school leaders need to take action to protect trans children in our schools.

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