Lung Cancer Proteogenomics: Shaping the Future of Clinical Investigation.

BACKGROUND: Lung cancer is associated with a high incidence of mortality worldwide. Molecular mechanisms governing the disease have been explored by genomic studies; however, several aspects remain elusive. The integration of genomic profiling with in-depth proteomic profiling has introduced a new dimension to lung cancer research, termed proteogenomics. The aim of this review article was to investigate proteogenomic approaches in lung cancer, focusing on how elucidation of proteogenomic features can evoke tangible clinical outcomes. METHODS: A strict methodological approach was adopted for study selection and key article features included molecular attributes, tumor biomarkers, and major hallmarks involved in oncogenesis. RESULTS: As a consensus, in all studies it becomes evident that proteogenomics is anticipated to fill significant knowledge gaps and assist in the discovery of novel treatment options. Genomic profiling unravels patient driver mutations, and exploration of downstream effects uncovers great variability in transcript and protein correlation. Also, emphasis is placed on defining proteogenomic traits of tumors of major histological classes, generating a diverse portrait of predictive markers and druggable targets. CONCLUSIONS: An up-to-date synthesis of landmark lung cancer proteogenomic studies is herein provided, underpinning the importance of proteogenomics in the landscape of personalized medicine for combating lung cancer.

Egg White and Yolk Protein Atlas: New Protein Insights of a Global Landmark Food.

(1) Background: The chicken egg is an animal product of great agronomic interest. The egg white and yolk constitute high-quality protein sources for humans with high digestibility and well-balanced amino acid profiles. Despite the egg white and yolk protein's undisputed value, research to unravel their full proteome content and its properties is still ongoing. We aimed to exhaustively analyze the proteome of egg white and yolk by applying intrinsic proteomics and bioinformatics approaches in order to unravel the full protein potential of this landmark food. (2) Methods: A total of 45 freshly laid, unfertilized, chicken eggs were subjected to nanoLC-MS/MS Orbitrap analysis following a peptide pre-fractionation step. A comprehensive bioinformatics processing step was undertaken towards elucidating potential activities and roles of identified molecules. In parallel, the literature was mined concerning all reported egg white and yolk protein identifications. (3) Results: Our analysis revealed 371 and 428 new proteins, reported for the first time to be present in the egg white and yolk, respectively. From the bioactivity standpoint, egg white and yolk proteins showed high enrichment for antioxidant and anti-inflammatory processes, while exerting high relevance for the apoptosis and focal adhesion pathways. (4) Conclusions: Egg white and yolk proteins exert diverse and multifaceted properties. A total of 799 proteins were reported for the first time as being part of the egg and yolk. Our novel protein data enriched those already published in the literature and the first ever chicken egg white and yolk Protein Atlas, comprising 1392 protein entries, was generated. This dataset will provide a cornerstone reference for future studies involving egg proteins.

mRNA in the Context of Protein Replacement Therapy.

Protein replacement therapy is an umbrella term used for medical treatments that aim to substitute or replenish specific protein deficiencies that result either from the protein being absent or non-functional due to mutations in affected patients. Traditionally, such an approach requires a well characterized but arduous and expensive protein production procedure that employs in vitro expression and translation of the pharmaceutical protein in host cells, followed by extensive purification steps. In the wake of the SARS-CoV-2 pandemic, mRNA-based pharmaceuticals were recruited to achieve rapid in vivo production of antigens, proving that the in vivo translation of exogenously administered mRNA is nowadays a viable therapeutic option. In addition, the urgency of the situation and worldwide demand for mRNA-based medicine has led to an evolution in relevant technologies, such as in vitro transcription and nanolipid carriers. In this review, we present preclinical and clinical applications of mRNA as a tool for protein replacement therapy, alongside with information pertaining to the manufacture of modified mRNA through in vitro transcription, carriers employed for its intracellular delivery and critical quality attributes pertaining to the finished product.

Effects of GABAergic Agents on Multiple Sclerosis. A Narrative Review of In-vivo Models.

BACKGROUND: Multiple sclerosis (MS) is a lifelong deteriorating disease characterized by multiple heterogeneous symptoms. Being an autoimmune disease of the central nervous system, mainly affecting the myelin sheath of the nerves ordinarily results in neurological symptoms. GABA has numerous effects on the immune cells, altering cytokine production, cell migration and proliferation. Immune cells express GABA receptors making GABA an inflammation modulator. Therefore, GABAergic- associated agents could provide a compatible add-on therapy for MS patients alleviating their symptoms and providing better quality years. OBJECTIVE: This review aims to highlight and provide evidence of the potential benefits of a secondary treatment option in MS patients, aiming to better manage this disease. METHODS: We conducted a literature search through PubMed, Scopus and Google Scholar for GABA agonists, antagonists and modulators used in the in vivo model of experimental autoimmune encephalomyelitis (EAE), taking into consideration certain inclusion and exclusion criteria. RESULTS: In vivo studies for GABA-a and GABA-b agonists and modulators showed regulation of the autoimmune response in EAE mice. Increased preservation of myelinated sensitive fibers and diminished axonal damage in the CNS was also demonstrated. Further, decreased mononuclear inflammatory infiltration, pro-inflammatory cytokines reduction and reduced levels of Reactive oxygen species (ROS) were also reported. Biological results included decreased peak disease severity, duration, clinical scores and EAE incidence in the treatment groups. CONCLUSION: GABA agonists and modulators efficiently challenged different aspects of disease pathophysiology in vivo models of EAE. The studies showed a significant relevance of neuroprotection via modulation of the autoimmune response in EAE rats, indicating that they should be considered proper therapeutic candidates for clinical use, while also further clinical studies could empower their administration in clinical practice.

Serum Proteome Signatures of Anti-SARS-CoV-2 Vaccinated Healthcare Workers in Greece Associated with Their Prior Infection Status.

Over the course of the pandemic, proteomics, being in the frontline of anti-COVID-19 research, has massively contributed to the investigation of molecular pathogenic properties of the virus. However, data on the proteome on anti-SARS-CoV-2 vaccinated individuals remain scarce. This study aimed to identify the serum proteome characteristics of anti-SARS-CoV-2 vaccinated individuals who had previously contracted the virus and comparatively assess them against those of virus-naïve vaccine recipients. Blood samples of n = 252 individuals, out of whom n = 35 had been previously infected, were collected in the "G. Gennimatas" General Hospital of Thessaloniki, from 4 January 2021 to 31 August 2021. All participants received the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). A label-free quantitative proteomics LC-MS/MS approach was undertaken, and the identified proteins were analyzed using the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes) databases as well as processed by bioinformatics tools. Titers of total RBD-specific IgGs against SARS-CoV-2 were also determined using the SARS-CoV-2 IgG II Quant assay. A total of 47 proteins were significantly differentially expressed, the majority of which were down-regulated in sera of previously infected patients compared to virus-naïve controls. Several pathways were affected supporting the crucial role of the humoral immune response in the protection against SARS-CoV-2 infection provided by COVID-19 vaccination. Overall, our comprehensive proteome profiling analysis contributes novel knowledge of the mechanisms of immune response induced by anti-SARS-CoV-2 vaccination and identified protein signatures reflecting the immune status of vaccine recipients.

The Greek translation and validation of the electronic version of the Meno-D rating scale for post-menopausal depression.

Menopausal transition and post-menopause constitute windows of increased vulnerability to depression. Recently, the Meno-D was introduced, a novel 12-item, with five distinct subscales. The aim of our study was to translate and validate the electronic version of the Meno-D among Greek post-menopausal women. Translation and back-translation were performed by an expert group, while face validity was assessed by five experts. Along with the Beck Depression Inventory-II, the Meno-D scale was distributed online to 502 post-menopausal women. A confirmatory factor analysis was performed to investigate construct validity and both convergent and discriminant validity were evaluated. The data analysis was performed using Statistical Package for Social Sciences and AMOS. The 5-factor model of Meno-D achieved adequate levels of goodness-of-fit indices, scoring lower values in discriminant validity examined with heterotrait-monotrait ratio and composite reliability. The significant correlation with the Beck Depression Inventory-ΙΙ revealed for all subscales was indicative of good convergent validity. An exploratory factor analysis was additionally performed, suggesting a 12-item tool comprising two subscales: (i) psychological and (ii) biological and achieving good levels of fit. Our data confirmed that the electronic version of Meno-D is a valid tool that can be used for screening and evaluation of depression in Greek post-menopausal women.

Atypical antipsychotics in multiple sclerosis: A review of their in vivo immunomodulatory effects.

INTRODUCTION: The high efficacy of atypical antipsychotics (AAP) in treating diverse psychiatric disorders has been partly attributed to their capacity to curb neuroinflammation, a shared aspect of these diseases. These immunomodulatory properties of AAP have lately been explored in the context of multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS. METHODS: This study aimed to review in vivo studies reporting on the therapeutic effects of AAP both in EAE, the main animal model of MS and in cuprizone-induced demyelination. For that matter we conducted a literature search and a screening process that eventually yielded 8 eligible studies. RESULTS: All studies agreed on the efficiency of AAP to dramatically reduce EAE severity and delay its onset, while suppressing the production of numerous inflammatory cytokines. Clozapine showcased similar yet more intense effects than risperidone, quetiapine and olanzapine, significantly attenuating CD4 T cell infiltration and myeloid cell activation, while upregulating Tregs. Clozapine also downregulated chemokines responsible for the migration of immune cells in the CNS and caused dopamine receptor levels in the brain of EAE mice to rise. DISCUSSION: Taken together, these findings unanimously attest to the anti-inflammatory and immunomodulatory properties of AAP, suggesting that their therapeutic potential expands beyond their current neuropsychiatric applications. Despite the salutary effects of AAP in MS reported in vivo, a clinical trial of clozapine on MS patients failed to confirm preclinical findings due to low acceptability of AAP and early participant withdrawal. CONCLUSION: Although preclinical evidence unquestionably supports the multifaceted beneficial properties of AAP in MS, further investigation is required to elucidate the pharmacodynamic profile of these agents and allow for their proper clinical testing on MS patients.

Prevalence of post-menopausal depression and associated factors: A web-based cross-sectional study in Greece.

OBJECTIVES: The impact of depression on post-menopausal women is an important public health issue but remains largely unknown. The purpose of this study was to identify the prevalence of post-menopausal depression in Greece and outline the profile of the women it affects. STUDY DESIGN: A sample of post-menopausal women completed an anonymous, self-administered, web-based survey which included the Beck Depression Inventory-ΙΙ (BDI-II) and questions regarding socio-demographic data. MAIN OUTCOME MEASURES: The dependent variable of interest was a BDI-II score ≥ 20 (the cut-off for moderate depression according to the BDI). RESULTS: Overall, 502 post-menopausal women participated in the study. The median BDI-II score was 13 (range 0-50); 136 (27.1%) of the women scored ≥ 20 and were considered screen-positive for depression. According to the multivariate logistic regression model, age< 55 years (OR: 1.621; 95% CI: 1.036-2.535), not working (OR: 1.580; 95% CI: 1.013-2.465), smoking (OR: 1.656; 95% CI: 1.081-2.536) and history of depression (OR: 1.650; 95% CI: 1.045-2.604) were independently associated with post-menopausal depression. Subgroup analyses revealed that current smokers (OR: 2.514; 95% CI: 1.485-4.256) had higher odds of moderate depression, while obesity (OR: 2.455; 95% CI: 1.206-4.996), absence of healthcare insurance (OR: 4.413; 95% CI: 1.970-9.887) and a history of depression (OR: 2.253; 95% CI: 1.212-4.190) were identified as independent risk factors for severe post-menopausal depression. CONCLUSIONS: More than one out of four post-menopausal women were screen-positive for symptoms indicative of depression, while a personal history of depression, age < 55 years, smoking and current working status were independent predictors of its emergence.

Immunogenicity of the BNT162b2 mRNA Covid-19 vaccine in elderly people over 85 years of age in Greece: the GREVAXIMO study.

BACKGROUND: Elderly people aged over 85 years were among the first groups to receive the BNT162b2 mRNA Covid-19 vaccine in Greece according to the national priority assignment policy. AIM: The aim of this study was to provide useful insight into the antibody generation taking place post-immunization in elderly individuals aged over 85. METHODS: In the first phase of our study, antibody levels were monitored in a total of 400 participants, while our final sample consisted of 297 subjects. Humoral immune responses were recorded in 69.75% (95% CI 65.25-74.25) of vaccinees post-first dose and in 98.99% (95% CI 97.85-100) post-second dose. RESULTS: Overall, a remarkable 40-fold change in IgG levels was observed between the two doses. Subjects displaying low antibody levels after the first dose had significantly higher IgG fold changes than vaccinees whose initial antibody levels were high. CONCLUSION: Taken together, our findings highlighted the high fold change (41.18) recorded in the titers of neutralizing antibodies after the second dose suggesting the need for its timely administration to elderly individuals.

Immunogenicity after the first dose of the BNT162b2 mRNA Covid-19 vaccine: real-world evidence from Greek healthcare workers.

Real-world data regarding the effectiveness, safety and immunogenicity of the Pfizer-BioNTech BNT162b2 mRNA vaccine are accumulating in the literature, suggesting that this vaccine generates high titres of S1-binding IgG antibodies that exhibit potent virus neutralization capacity. This is the first phase IV immunogenicity study to recruit a large number of Greek healthcare workers (n=425) including 63 previously-infected subjects. We measured titres of neutralizing IgGs against the receptor-binding domain of the S1 subunit of the spike protein of SARS-CoV-2 14 days post-immunization with the first dose, employing the SARS-CoV-2 IgG II Quant assay. A total of 92.24 % of our study cohort received a positive assay outcome and titres varied with age. Post-hoc analysis revealed that although titres did not significantly differ among participants aged 20-49 years, a significant decline was marked in the age group of 50-59 years, which was further accentuated in subjects aged over 60. Antibody titres escalated significantly among the previously-infected, indicating the potential booster effect of the first dose in that group.

Second dose of the BNT162b2 mRNA vaccine: Value of timely administration but questionable necessity among the seropositive.

This study monitored titers of neutralizing IgG against the receptor-binding domain of the SARS-CoV-2 S1 subunit 14 days post-injection of each dose of the BNT162b2 mRNA Covid-19 vaccine in 401 Greek healthcare workers aged 20-67. After the first dose, titers varied upon age and history of infection, being lower in the 50+ age group and significantly higher among the seropositive. After the second dose, immunogenicity was significantly boosted in the age 50+ and SARS-CoV-2-naïve individuals, indicating the effectuality of its timely administration, yet questioning its value among the seropositive.

Antidepressants on Multiple Sclerosis: A Review of In Vitro and In Vivo Models.

Background: Increased prevalence of depression has been observed among patients with multiple sclerosis (MS) and correlated with the elevated levels of proinflammatory cytokines and the overall deregulation of monoaminergic neurotransmitters that these patients exhibit. Antidepressants have proved effective not only in treating depression comorbid to MS, but also in alleviating numerous MS symptoms and even minimizing stress-related relapses. Therefore, these agents could prospectively prove beneficial as a complementary MS therapy. Objective: This review aims at illustrating the underlying mechanisms involved in the beneficial clinical effects of antidepressants observed in MS patients. Methods: Through a literature search we screened and comparatively assessed papers on the effects of antidepressant use both in vitro and in vivo MS models, taking into account a number of inclusion and exclusion criteria. Results: In vitro studies indicated that antidepressants promote neural and glial cell viability and differentiation, reduce proinflammatory cytokines and exert neuroprotective activity by eliminating axonal loss. In vivo studies confirmed that antidepressants delayed disease onset and alleviated symptoms in Experimental Autoimmune Encephalomyelitis (EAE), the most prevalent animal model of MS. Further, antidepressant agents suppressed inflammation and restrained demyelination by decreasing immune cell infiltration of the CNS. Conclusion: Antidepressants were efficient in tackling numerous aspects of disease pathophysiology both in vitro and in vivo models. Given that several antidepressants have already proved effective in clinical trials on MS patients, the inclusion of such agents in the therapeutic arsenal of MS should be seriously considered, following an individualized approach to minimize the adverse events of antidepressants in MS patients.

The Effects of PDE Inhibitors on Multiple Sclerosis: a Review of in vitro and in vivo Models.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory and immune-mediated disease, whose current therapeutic means are mostly effective in the relapsing-remitting form of MS, where inflammation is still prominent, but fall short of preventing long term impairment. However, apart from inflammationmediated demyelination, autoimmune mechanisms play a major role in MS pathophysiology, constituting a promising pharmacological target. Phosphodiesterase (PDE) inhibitors have been approved for clinical use in psoriasis and have undergone trials suggesting their neuroprotective effects, rendering them eligible as an option for accessory MS therapy. OBJECTIVE: In this review, we discuss the potential role of PDE inhibitors as a complementary MS therapy. METHODS: We conducted a literature search through which we screened and comparatively assessed papers on the effects of PDE inhibitor use, both in vitro and in animal models of MS, taking into account a number of inclusion and exclusion criteria. RESULTS: In vitro studies indicated that PDE inhibitors promote remyelination and axonal sustenance, while curbing inflammatory cell infiltration, hindering oligodendrocyte and neuronal loss and suppressing cytokine production. In vivo studies underlined that these agents alleviate symptoms and reduce disease scores in MS animal models. CONCLUSION: PDE inhibitors proved to be effective in addressing various aspects of MS pathogenesis both in vitro and in vivo models. Given the latest clinical trials proving that the PDE4 inhibitor Ibudilast exerts neuroprotective effects in patients with progressive MS, research on this field should be intensified and selective PDE4 inhibitors with enhanced safety features should be seriously considered as prospective complementary MS therapy.