Blog Archive

Αλέξανδρος Γ. Σφακιανάκης

Tuesday, September 20, 2022

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

alexandrossfakianakis shared this article with you from Inoreader

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

alexandrossfakianakis shared this article with you from Inoreader

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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Polygenic risk score and peer victimisation independently predict depressive symptoms in adolescence: results from the Quebec Longitudinal Study of Children Development

alexandrossfakianakis shared this article with you from Inoreader

Background

Peer victimisation has been associated with depressive symptoms during adolescence, however not all peer victimised adolescents will exhibit such symptoms. This study tested whether having a genetic predisposition to developing depression increased the risk of experiencing depressive symptoms in peer victimised youth. To date, no study has explored such gene–environment interaction using a polygenic risk score for depression (PRS-depression) in the context of peer victimisation and depressive symptoms in adolescence.

Methods

The sample included 748 participants born in 1997/98 from the Quebec Longitudinal Study of Child Development with genotype data and prospectively collected information on peer victimisation (12–13 years) obtained from both self- and teacher-reports, as well as self-reported depressive symptoms (15–17 years). The PRS-depression was based on the genome-wide association meta-analysis of broad depression by Howard et al. (2019).

Results

Self- and teacher-reported peer victimisation in early adolescence were both associated with depressive symptoms in adolescence (β = 0.34, p < .001; β = 0.14, p = .001 respectively), and this association remained significant when accounting for PRS-depression (β = 0.33, p < .001; β = 0.13, p = .002 respectively). PRS-depression was independently associated with depressive symptoms, but there was no significant PRS-depression by peer victimisation interaction (self-reported and teacher-reported). PRS-depression was correlated with self-reported, but not teacher-reported, peer victimisation.

Conclusions

Our findings suggested that a partial measure of an individual's genetic predisposition to depression, as measured by PRS-depression, and being exposed to peer victimisation (self- and teacher-reported) were independently associated with depressive symptoms in adolescence. Furthermore, PRS-depression did not exacerbate the risk of depressive symptoms among adolescents who had been peer victimised. Lastly, we found evidence of a gene–environment correlation between PRS-depression and self-reported peer victimisation. Future studies are needed to replicate this finding and to further understand the role of genetic predispositions in experiencing depressive symptoms following peer victimisation.

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The impact of extended treatment with artemether-lumefantrine on antimalarial exposure and reinfection risks in Ugandan children with uncomplicated malaria: A randomized controlled trial

alexandrossfakianakis shared this article with you from Inoreader

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ABSTRACT
Background. Artemether-lumefantrine (AL) is the most widely used artemisinin-based combination therapy (ACT) in sub-Saharan Africa and is threatened by the emergence of artemisinin resistance. Dosing is suboptimal in young children. We hypothesized that extending AL duration will improve exposure and reduce reinfection risks.Methods. We conducted a prospective, randomized, open-label pharmacokinetic/pharmacodynamic study of extended durat ion AL (EXALT) in children with malaria in high transmission rural Uganda. Children received 3-day (standard 6-dose) or 5-day (10-dose) AL with sampling for artemether, dihydroartemisinin (DHA), and lumefantrine over 42-day clinical follow-up. Primary outcomes were 1) comparative pharmacokinetic parameters between regimens, and 2) recurrent parasitemia analyzed as intention-to-treat.Results. 177 children ages 16 months to 16 years were randomized, contributing 227 total episodes. Terminal median lumefantrine concentrations were significantly increased in the 5-day versus 3-day regimen on days 7, 14, and 21 (p-values < 0.001). A pre-defined day 7 lumefantrine threshold of 280 ng/mL was strongly predictive of recurrence risk at 28 and 42 days (p < 0.001). Kaplan-Meier estimated 28-day (51% vs 40%) and 42-day risk (75% vs 68%) did not significantly differ between 3-day and 5-day regimens. No significant toxicity was seen with the extended regimen. Conclusions. Extending the duration of AL was safe and significantly enhanced overall drug exposure in young children but did not lead to significant reductions in recurrent parasitemia risk in our high transmission setting. However, day 7 levels were strongly predictive of recurrent parasitemia risk and those in the lowest weight-band were at higher risk of underdosing with the standard 3-day regimen.
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Molecular and regulatory mechanisms of oxidative stress adaptation in Streptococcus mutans

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Dental caries is a chronic progressive disease, which destructs dental hard tissues under the influence of multiple factors, mainly bacteria. Streptococcus mutans (S. mutans) is the main cariogenic bacteria. However, its cariogenic virulence is affected by environmental stress such as oxidative stress, nutrient deficiency and low pH to some extent. Oxidative stress is one of the main stresses that S. mutans faces in oral cavity. But there are a variety of protective molecules to resist oxidative stress in S. mutans, including superoxide dismutase, nicotinamide adenine dinucleotide oxidase, Dps-like peroxide resistance protein, alkyl-hydrogen peroxide reductase, thioredoxin, glutamate-reducing protein system and some metabolic substances. Additionally, some transcriptional regulatory factors (SloR, PerR, Rex, Spx, etc.) and two-component systems are also closely related to oxidative stress adaptation by modulating the expression of protective molecules. This review summarizes the research progress of protective molecules and regulatory mechanisms (mainly transcription factors) of oxidative stress adaptation of S. mutans.

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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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Transfer effects from language processing to visual attention dynamics: The impact of orthographic transparency

alexandrossfakianakis shared this article with you from Inoreader

Abstract

The consistency between letters and sounds varies across languages. These differences have been proposed to be associated with different reading mechanisms (lexical vs. phonological), processing grain sizes (coarse vs. fine) and attentional windows (whole words vs. individual letters). This study aimed to extend this idea to writing to dictation. For that purpose, we evaluated whether the use of different types of processing has a differential impact on local windowing attention: phonological (local) processing in a transparent language (Spanish) and lexical (global) processing of an opaque language (English). Spanish and English monolinguals (Experiment 1) and Spanish–English bilinguals (Experiment 2) performed a writing to dictation task followed by a global–local task. The first key performance showed a critical dissociation between languages: the response times (RTs) from the Spanish writing to dictation task was modulated by word length, whereas the RTs from the English w riting to dictation task was modulated by word frequency and age of acquisition, as evidence that language transparency biases processing towards phonological or lexical strategies. In addition, after a Spanish task, participants more efficiently processed local information, which resulted in both the benefit of global congruent information and the reduced cost of incongruent global information. Additionally, the results showed that bilinguals adapt their attentional processing depending on the orthographic transparency.

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The problem with picking: Permittance, escape and shame in problematic skin picking

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Objectives

Problematic skin picking (SP) is a poorly understood experience characterised by a drive to pick the skin and related psychosocial impact. In the DSM-5, problematic SP is classified as 'excoriation (skin picking) disorder'. The aim of this article is to present a rare qualitative perspective on the lived experience of problematic SP, prioritising participants' voices and sense-making.

Design

An in-depth qualitative study of individuals who self-identified as picking their skin problematically and experienced related distress.

Methods

Seventeen UK-based participants were recruited online and interviewed about their SP. Participants were given choice of interview modality, including instant messenger platforms, telephone, email and Skype, to maximise comfort and improve the accessibility of the study. Transcripts were analysed using thematic analysis.

Results

Three themes offering novel insight into the phenomenology of participants' SP are highlighted and explored: (1) how cognitions and circumstances drove and permitted SP, (2) how participants 'zoned out' while SP and the escape or relief that this attentional experience offered and (3) participants' feelings of shame and distress in how they felt their SP may appear to others.

Conclusions

This study contributes in-depth and novel ideas to the understanding of SP phenomenology and identifies how environmental factors, cognitions, contextual distress and shame may be considerations in therapeutic intervention. It presents the complexity of SP sense-making and demonstrates the need for individual formulation.

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Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study

alexandrossfakianakis shared this article with you from Inoreader
imageObjective: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. Background: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. Methods: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. Results: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P
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