Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination

: The introduction of anti-SARS-CoV-2 vaccines in late 2020 substantially changed the pandemic picture, inducing effective protection in the population. However, individual variability was observed with different levels of cellular response and neutralizing antibodies. We report data on the impact of age, gender, and 16 single nucleotide polymorphisms (SNPs) of cytokine genes on the anti-SARS-CoV-2 IgG titers measured 31 and 105 days after administration of the second dose of BNT162b2 vaccine to 122 healthy subjects from the health care staff of the Palermo University Hospital, Italy. The higher titers at 31 days were measured in the younger subjects and in subjects bearing T-positive genotypes of IL-1R1 rs2234650 or the GG homozygous genotype of IL-6 rs1800795 SNP. T-positive genotypes are also significantly more common in subjects with higher titers at day 105. In addition, in this group of subjects, the frequency of the CT genotype of IL-4 rs2243250 is higher among those vaccinated with higher titers. Moreover, these SNPs and TNFA rs1800629 are differently distributed in a group of subjects that were found infected by SARS-CoV-2 at day 105 of evaluation. Finally, subjects that were found to be infected by SARS-CoV-2 at day 105 were significantly older than the uninfected subjects. Taken together, these data seem to suggest that age and polymorphisms of key cytokines, which regulate inflammation and humoral immune response, might influence the magnitude of the antibody response to vaccination with BNT162B2, prompting speculation about the possible benefit of a genetic background-based assessment of a personalized approach to the anti-COVID vaccination schedule

The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value

Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases which contribute to cellular iron homeostasis by favouring its export. Down-regulation of HEPH expression, possibly by stimulating cell proliferation due to an increase in iron availability, has shown to correlate with poor survival in breast cancer. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tension present, however, HEPH distribution in lung cancer and its influence on prognosis have not been investigated yet. In this study we explored the prognostic value of HEPH and its expression pattern in the most prevalent histotypes of lung cancers, namely lung adenocarcinoma and lung squamous cell carcinoma. In silico analyses, based on UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter bioinformatics, revealed a significant correlation between higher levels of HEPH expression and favorable prognosis, in both cancer histotypes. Moreover, TIMER web platform showed a statistically significant association between HEPH expression and cell elements belonging to the tumor microenvironment identified as endothelial cells and a subpopulation of cancer-associated fibroblasts, further confirmed by double immunohistochemical labeling with cell type specific markers. Taken together, these data shed a light on the complex mechanisms of local iron handling lung cancer can exploit to support tumorigenesis

Redox Modulations, Antioxidants, and Neuropsychiatric Disorders

Although antioxidants, redox modulations, and neuropsychiatric disorders have been widely studied for many years, the field would benefit from an integrative and corroborative review. Our primary objective is to delineate the biological significance of compounds that modulate our redox status (i.e., reactive species and antioxidants) as well as outline their current role in brain health and the impact of redox modulations on the severity of illnesses. Therefore, this review will not enter into the debate regarding the perceived medical legitimacy of antioxidants but rather seek to clarify their abilities and limitations. With this in mind, antioxidants may be interpreted as natural products with significant pharmacological actions in the body. A renewed understanding of these often overlooked compounds will allow us to critically appraise the current literature and provide an informed, novel perspective on an important healthcare issue. In this review, we will introduce the complex topics of redox modulations and their role in the development of select neuropsychiatric disorders

Molecular characterisation of congenital myasthenic syndromes in Southern Brazil

Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c. 70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c. 70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000

Molecular characterisation of congenital myasthenic syndromes in Southern Brazil

Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c. 70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c. 70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000

Comparison of intrascalar location of straight vs perimodiolar electrode array by flat-panel computerized tomography

Introduction, One of the fields of technological advancement in cochlear implants (CI) pursued by all manufacturers is the development of less traumatic electrodes that can conform to the anatomy of the cochlea, and possibly enhance the outcomes. Recently, a slim precurved perimodiolar electrode with an insertion guidance sleeve has been designed in order to facilitate the insertion and to avoid the inter-scalar dislodgement that frequently occurs at the first basal turn. Aim of this study was to evaluate the intracochlear position of different Nucleus electrode arrays in aduld and pediatric CI recipients by means of flat-panel volume computerized tomography (FPCT). Methods, Fifty-six CI recipients (37 females, 19 males), 1 to 80 years of age, operated by the same surgeon with the same technique, were included. All underwent FPCT with a C-arm angiographic system including a digital flat panel detector 30 x 40 cm, with a source-to-image-receptor distance of 120cm. The imaging assessment was performed the day after surgery in all cases. Sequential and simultaneous CI were included and a total of 68 ears have been analyzed. The primary objective was to identify the scalar location of the array (completely in scala tympani vs. partially dislodged in scala vestibuli) and the site of dislocation. Secondarily, we measured the medial-lateral position within the scala, the insertion depth (mm and angles). The FPCT findings were also contrasted with the type of cochleostomy (round window (RW), extended RW, promontorial) and with the residual hearing preservation. Results, Fifty-nine ears were implanted with a perimodiolar electrode, either Nucleus CI532 (n=45) or a CI412 / CI512 Contour Advance (n=14), while 9 received a straight one (Nucleus CI422/CI522). A RW approach was performed more frequently (41 out of 45 = 91.1 %) with CI532 than with the other arrays (10 out of 23 = 43.5%). Inferior and/or anterior cochleostomy were never performed. The CI532 showed the most consistent and reliable intrascalar position, close to the modiolus and in the scala tympani. Scala vestibuli dislodgement was observed in (14.3%) of the Contour Advance electrodes and in (6.7%) of the CI532. Pre-operative residual hearing was preserved within 10 dB HL in 62% of the cases. Conclusions: the CI532 electrode array achieved the most consistent and reliable perimodiolar location by FPCT; in our small series it appeared to be dislodged in the scala tympani in the minority of cases

Pathological implications of Th1/Th2 cytokine genetic variants in Beh\ue7et's disease: Data from a pilot study in a Sicilian population

Cytokines act as pleiotropic polypeptides able to regulate inflammatory/immune responses and to provide important signals in physiological and pathological processes. Several cytokines (Th1, Th2, and Th17) seem to be involved in the pathophysiology of Beh\ue7et's disease, a chronic immune-mediated disease characterized by oral and genital lesions and ocular inflammation. Its individual susceptibility seems to be modulated by genetic variants in genes codifying these cytokines. Th1 and Th17 seem to be involved in the disease's active phases, and Th2 seems to affect the development or severity of the disease; however, contrasting data are reported. In this study, some genetic variants of the Th1/Th2 cytokine genes were investigated in Sicilian patients and age- and gender-matched controls. Three very significant associations with Beh\ue7et's disease were detected, and combined genotypes associated with increased disease risk were identified. Results obtained point to the key role of Th1/Th2 cytokine genetic variants in disease susceptibility

Genetic and epigenetic factors of takotsubo syndrome: A systematic review

Takotsubo syndrome (TTS), recognized as stress’s cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations

Robust Local Stabilization of Discrete-Time Systems with Time-Varying State Delay and Saturating Actuators

The robust local stabilization of uncertain discrete-time systems with time-varying state delayed and subject to saturating actuators is investigated in this work. A convex optimization method is proposed to compute robust state feedback control law such that the uncertain closed-loop is locally asymptotically stable if the initial condition belongs to an estimate of the region of attraction for the origin. The proposed procedure allows computing estimates of the region of attraction through the intersection of ellipsoidal sets in an augmented space, reducing the conservatism of the estimates found in the literature. Also, the conditions can handle the amount of delay variation between two consecutive samples, which is new in the literature for the discrete-time case. Although the given synthesis conditions are delay dependent, the proposed control law is delay independent, yielding to easier real time implementations. A convex procedure is proposed to maximize the size of the set of safe initial conditions. Numerical examples are provided to illustrate the effectiveness of our approach and also to compare it with other conditions in the literature.Fil: Silva, J. V. V.. Centro Federal de Educação Tecnológica de Minas Gerais; BrasilFil: Silva, L. F. P.. Centro Federal de Educação Tecnológica de Minas Gerais; BrasilFil: Rubio Scola, Ignacio Eduardo Jesus. Cefetmg/ufjs;Fil: Leite, V. J. S.. Cefetmg/ufjs