Multi-step regulation of microRNA expression and secretion into small extracellular vesicles by insulin.

Tissues release microRNAs (miRNAs) in small extracellular vesicles (sEVs) including exosomes, which can regulate gene expression in distal cells, thus acting as modulators of local and systemic metabolism. Here, we show that insulin regulates miRNA secretion into sEVs from 3T3-L1 adipocytes and that this process is differentially regulated from cellular expression. Thus, of the 53 miRNAs upregulated and 66 miRNAs downregulated by insulin in 3T3-L1 sEVs, only 12 were regulated in parallel in cells. Insulin regulated this process in part by phosphorylating hnRNPA1, causing it to bind to AU-rich motifs in miRNAs, mediating their secretion into sEVs. Importantly, 43% of insulin-regulated sEV-miRNAs are implicated in obesity and insulin resistance. These include let-7 and miR-103, which we show regulate insulin signaling in AML12 hepatocytes. Together, these findings demonstrate an important layer to insulin's regulation of adipose biology and provide a mechanism of tissue crosstalk in obesity and other hyperinsulinemic states.

Immune checkpoint inhibitor-induced cardiotoxicity in patients with lung cancer: a systematic review and meta-analysis.

BACKGROUND: The use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer may precipitate cardiotoxic events. We aimed to perform a meta-analysis to evaluate the cardiotoxicity associated with ICIs in patients with lung cancer. METHODS: A literature search was conducted across four electronic databases (Cochrane CENTRAL, MEDLINE, OVID EMBASE and Google Scholar) from inception through 31st May 2023. Randomized controlled trials (RCTs) assessing the impact of ICIs on cardiac outcomes in lung cancer patients were considered for inclusion. Risk ratios (RR) with 95% confidence intervals (CIs) were pooled and analysis was performed using a random-effects model. The Grading of Recommendations Assessment, Development and Evaluation approach was followed to assess confidence in the estimates of effect (i.e., the quality of evidence). RESULTS: A total of 30 studies including 16,331 patients, were included in the analysis. Pooled results showed that single ICI (RR: 2.15; 95% CI: 1.13-4.12; p = 0.02; I2 = 0%) or a combination of single ICI plus chemotherapy (RR: 1.38 [1.05-1.82]; p = 0.02) significantly increased the risk of cardiac adverse events when compared with chemotherapy alone. No significant difference was noted when a dual ICI (RR: 0.48 [0.13-1.80]; p = 0.27) was compared with single ICI. In addition, there was no significant association between the use of ICIs and incidence of cardiac failure (RR: 1.11 [0.48-2.58]; p = 0.80), or arrhythmia (RR: 1.87; [0.69-5.08]; p = 0.22). CONCLUSION: Compared with chemotherapy alone, use of a single ICI or a combination of single ICI plus chemotherapy significantly increased the risk of cardiotoxicity. However, employing dual immunotherapy did not result in a significant increase in the risk of cardiotoxicity when compared to the use of a single ICI.

An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress.

Cellular response to redox imbalance is crucial for organismal health. microRNAs are implicated in stress responses. ALG-1, the C. elegans ortholog of human AGO2, plays an essential role in microRNA processing and function. Here we investigated the mechanisms governing ALG-1 expression in C. elegans and the players controlling lifespan and stress resistance downstream of ALG-1. We show that upregulation of ALG-1 is a shared feature in conditions linked to increased longevity (e.g., germline-deficient glp-1 mutants). ALG-1 knockdown reduces lifespan and oxidative stress resistance, while overexpression enhances survival against pro-oxidant agents but not heat or reductive stress. R02D3.7 represses alg-1 expression, impacting oxidative stress resistance at least in part via ALG-1. microRNAs upregulated in glp-1 mutants (miR-87-3p, miR-230-3p, and miR-235-3p) can target genes in the protein disulfide isomerase pathway and protect against oxidative stress. This study unveils a tightly regulated network involving transcription factors and microRNAs which controls organisms' ability to withstand oxidative stress.

Involvement of the GABAA Receptor in the Antidepressant-Like Effects Produced by Low and High Doses of the Flavonoid Chrysin in the Rat: A Longitudinal Study.

BACKGROUND: The flavonoid chrysin produces rapid and long-lasting anxiolytic- and antidepressant-like effects in rats. However, it is not known whether low and high doses of chrysin produce differential anti-immobility effects through the Gamma-Aminobutyric Acid sub-type A (GABAA) receptor. The goal of this work was therefore to compare low and high doses of chrysin for their effects on depression-like behavior in a longitudinal study. Moreover, chrysin was compared with the serotonergic fluoxetine and Gamma-Aminobutyric Acid (GABA)ergic allopregnanolone, and its involvement with the GABAA receptor after chronic treatment was also investigated. METHODS: Male Wistar rats were assigned to five groups (n = 8 each): vehicle, 1 mg/kg chrysin, 5 mg/kg chrysin, 1 mg/kg fluoxetine, and 1 mg/kg allopregnanolone. In the first experiment, treatments were injected daily and the effects on locomotor activity and the forced swim test were evaluated at 0, 1, 14, and 28 days of treatment, and 48 h after the final treatment. In the second experiment, similar groups were treated for 28 days with injection of 1 mg/kg picrotoxin to investigate the role of the GABAA receptor. Depending on the experimental design, one- and two-way analysis of variance (ANOVA) tests were used for statistical analysis, with p < 0.05 set as the criteria for significance. RESULTS: In both experiments, the treatments did not alter locomotor activity. However, low and high doses of chrysin, allopregnanolone, and fluoxetine gradually produced antidepressant-like effects in the forced swim test, and maintained this effect for 48 h post-treatment, except with low dose chrysin. Picrotoxin blocked the antidepressant-like effects produced by low dose chrysin, but did not affect those produced by high dose chrysin, allopregnanolone, or fluoxetine. CONCLUSIONS: The differential antidepressant-like effects caused by low and high doses of chrysin are time-dependent. Low dose chrysin produces a rapid antidepressant-like effect, whereas high dose chrysin produces a delayed but sustained the effect, even 48 h after withdrawal. The effect with high dose chrysin was similar to that observed with allopregnanolone and fluoxetine. The mechanism for the antidepressant-like effect of low chrysin appears to be GABAergic, whereas the effect of high dose chrysin may involve other neurotransmission and neuromodulation systems related to the serotonergic system.

Early improvement of global longitudinal strain after iron deficiency correction in heart failure with reduced ejection fraction.

BACKGROUND: Iron deficiency correction with ferric carboxymaltose improves symptoms and reduces rehospitalization in patients with reduced left ventricular ejection fraction. The mechanisms underlying these improvements are poorly understood. This study aimed to determine changes in left ventricular contractility after iron treatment as reflected in global longitudinal strain. METHODS: Prospective single-center study including 43 adults with reduced ejection fraction, non-anemic iron deficiency, and functional class II-III heart failure despite optimal medical treatment. Global longitudinal strain through speckle-tracking echocardiography was measured at baseline and 4 weeks after ferric carboxymaltose. RESULTS: A significant improvement in global longitudinal strain was detected (from -12.3% ± 4.0% at baseline to -15.6% ± 4.1%, p < .001); ferritin and transferrin saturation index had increased, but ejection fraction presented no significant changes (baseline 35.7% ± 4.6%, follow-up 37.2% ± 6.6%, p = .073). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, the correction of iron deficiency with ferric carboxymaltose is associated with an early improvement in global longitudinal strain, possibly suggesting a direct effect of iron correction on myocardial contractility.

Coping in the Face of Violence - a Qualitative Study on the Impacts of Stressful Life Events on the Mental Health of Older Adults in Colombia.

BACKGROUND: Many older adults in Colombia have lived through violent and stressful life events, particularly in areas of poverty. The aim of this qualitative study was to understand the impact of stressful life events on the mental health and wellbeing of older Colombians living in areas of relative poverty. METHODS: Older adults (aged 60+) living in the Turbo region in Colombia were interviewed face-to-face between August and December 2021. Transcripts were coded in Spanish and English by at least two researchers, using inductive thematic analysis. RESULTS: Twenty-six older adults participated in the study. Four overarching themes were generated: Living in violent and dangerous communities; Disturbing gender violence and gender roles; Lack of mental health awareness; Coping mechanisms. Older adults experienced a long narrative of stressful life events. Younger generations appeared to disrespect older members of Society. Without any mental health support, older adults coped by accepting the extreme situations or seeking solace in their faith. CONCLUSIONS: The health system and Government need to build up trust and generate an awareness of mental health, as older Colombians will not approach psychological support otherwise. Intergenerational community-based interventions may provide a first avenue of mental health support.

Effects of Non-Ablative Solid-State Vaginal Laser (SSVL) for the Treatment of Vulvovaginal Atrophy in Breast Cancer Survivors after Adjuvant Aromatase Inhibitor Therapy: Preliminary Results.

BACKGROUND: One of the side effects of anti-estrogen treatments in breast cancer survivors (BCSs), especially with aromatase inhibitor (AI) treatment, is the frequent appearance of vulvo-vaginal atrophy (VVA). We aim to evaluate the efficacy, safety and feasibility of a new type of non-ablative Solid-State Vaginal Laser (SSVL) treatment in BCSs with VVA. METHODS: A total of 30 BCSs with a history of AI use and symptoms of VVA were treated with a non-ablative SSVL (LASEmaR 1500™-EUFOTON)in this non-randomized pilot study. The effects of the laser have been evaluated at baseline, 10 wk and 24 wk using a visual analogue scale (VAS), the Vaginal Health Index (VHI), the Vulvar Health Index (VuHI), the Female Sexual Function Index (FSFI), the EORTC QLQ-BR23, the Vaginal Maturation Index (VMI) and vaginal pH. RESULTS: At 10-week follow-up vs. baseline there were no statistically significant differences in FSFI, lubrication and EORTC QLQ-BR23. In all the subjective (dyspareunia, VHI, VuHI, FSFI, QLQ) and objective parameters (VMI and pH) there was a statistically significant improvement at the 6-month follow-up. Satisfaction was very high (4.7 out of 5), with 95.7% of patients being satisfied, more than or very satisfied. CONCLUSIONS: Preliminary results of SSVL treatment of VVA and dyspareunia in BCSs after AI treatment suggest clinical improvement, without relevant side effects and with a high degree of satisfaction.

Complete genome sequences of Gordonia rubripertincta phages OtterstedtS21 and Patos.

We report the genomes of two viruses with siphovirus morphology, OtterstedtS21 and Patos, from Albany, New York, using Gordonia rubripertincta. The genomes of OtterstedtS21 and Patos are ~68 kbp long with 58% GC content. Both phages group with cluster DV based on gene content similarity to phages in the Actinobacteriophage database.

Effect of a Multi-Ingredient Coriolus-versicolor-Based Vaginal Gel in Women with HPV-Dependent Cervical Lesions: The Papilobs Real-Life Prospective Study.

Human papillomavirus (HPV) is responsible for virtually all cervical cancers in women. HPV infection and persistency may lead to different-grade squamous intraepithelial lesions that can result in high-grade lesions and cancer. The objective was to prospectively evaluate the results of using a Coriolus-versicolor-based vaginal gel (Papilocare®) on HPV-dependent low-grade cervical lesion repair in a real-life scenario. HPV-positive women ≥ 25 years with ASCUS/LSIL cervical cytology results and concordant colposcopy images were included, receiving the vaginal gel one cannula/day for 21 days (first month) + one cannula/alternate days (five months). A 6-month second treatment cycle was prescribed when needed. Repair of the cervical low-grade lesions through cytology and colposcopy, HPV clearance, and level of satisfaction, and tolerability were evaluated. In total, 192 and 201 patients accounted for the total and safety analyses, respectively, and 77.1% repaired cervical lesions at 6 or 12 months (76.0% for high-risk HPV). Additionally, 71.6% achieved HPV clearance throughout the study's duration (70.6% for high-risk HPV). Satisfaction level was rated 7.9 and 7.5 out of 10 at 6 and 12 months, respectively. Only three mild-moderate product-related adverse events were reported, and all of them were resolved by the end of the study. In our study, we observed higher regression rates of low-grade cervical lesions in women treated with Papilocare® vaginal gel than spontaneous regression rates reported in the literature.

A New Method for Gain Calculation in Quantified Visuo-vestibular Interaction Test.

OBJECTIVE: To develop a new method to quantify visually-enhanced vestibulo-ocular reflex (VVOR) gain, in patients with vestibular function loss, that is mathematically suitable given the nature of the test, and determine the reliability of the method by comparing results with those of the gold standard, the video head impulse test (vHIT). MATERIALS AND METHODS: We developed a new method for VVOR gain quantification and conducted a cross-sectional study in patients diagnosed with vestibular function loss and controls, all participants undergoing both a VVOR test and a vHIT. We measured VVOR gain with three different methods: area under the curve (AUC), slope regression, and a Fourier method (VVORAUC , VVORSP , and VVORFR , respectively); and compared these gain values with vHIT gain calculated using the AUC method. RESULTS: Overall, 111 patients were included: 29 healthy subjects and 82 patients with vestibular function loss. Intraclass correlation coefficients (ICC(1,1)) between gain from the gold standard and each of the VVOR gain methods were: 0.68 (CI: 0.61-0.75) for VVORAUC , 0.66 (CI: 0.58-0.73) for VVORSP and 0.71 (CI: 0.64-0.77) for VVORFR . No interference was found between VVOR gain calculation methods and potentially influential variables considered (p ≥ 0.98). CONCLUSION: The new method for quantifying VVOR gain showed good concordance with the vHIT method. LEVEL OF EVIDENCE: 2: Individual cross-sectional studies with consistently applied reference standard and blinding (Diagnosis) Laryngoscope, 133:3554-3563, 2023.

Evidence-based Management of Left Main Coronary Artery Disease.

Left main coronary artery disease (LMCAD) is associated with high morbidity and mortality due to the large myocardial mass at risk. Although medical treatment may be an option in selected low-risk patients, revascularisation is recommended to improve survival in the majority of patients presenting with a significant left main stenosis. In the past decade, multiple randomised clinical trials and meta-analyses have compared coronary artery bypass grafting surgery (CABG) versus percutaneous coronary intervention (PCI), finding controversial results. The strategy for LMCAD revascularisation is still challenging. Coronary anatomy complexity, clinical features and patient preferences are key elements to be considered by the heart team. The current guidelines define CABG as standard therapy, but the continuous improvements in PCI techniques, the use of intracoronary imaging and functional assessment make PCI a feasible alternative in selected patients, particularly in those with comorbidities and contraindications to CABG. This review analyses the most important studies comparing CABG versus PCI in patients with LMCAD.

A Videogame as a Tool for Clinical Screening of Possible Vulnerability to Impulsivity and Attention Disturbances in Children.

An attention disturbance is a problem that affects many school-aged children. The assessment in children is usually report-based, and as a result, controversy surrounds the diagnosis. To solve this issue, the aim of this study was to develop a new tool to detect possible attention-related problems and impulsive behavior in 4- and 5-year-old children. This tool was developed as an Android app and could be used to provide an early indicator of possible future development problems. A sample of 103 children (48 girls and 55 boys) was randomly selected from primary schools and assessed by Pinky-Piggy, a videogame application based on a classical paradigm in experimental psychology. Data from this app were compared with a Child Neuropsychological Maturity Questionnaire. The subjects displayed different patterns of response to play a very simple game called Pinky-Piggy. The application discriminated between high-responders and low responders. The results showed a relationship between these two profiles and the levels of attention and neurodevelopment in each group. The tool could identify different types of profiles and demonstrated its potential to evaluate endophenotypes to predict attentional problems related to impulsive behavior. Additionally, it required less time and fewer tests to identify possible at-risk populations, thus assisting in clinical diagnosis.

SARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner.

Visceral adiposity is a risk factor for severe COVID-19, and a link between adipose tissue infection and disease progression has been proposed. Here we demonstrate that SARS-CoV-2 infects human adipose tissue and undergoes productive infection in fat cells. However, susceptibility to infection and the cellular response depends on the anatomical origin of the cells and the viral lineage. Visceral fat cells express more ACE2 and are more susceptible to SARS-CoV-2 infection than their subcutaneous counterparts. SARS-CoV-2 infection leads to inhibition of lipolysis in subcutaneous fat cells, while in visceral fat cells, it results in higher expression of pro-inflammatory cytokines. Viral load and cellular response are attenuated when visceral fat cells are infected with the SARS-CoV-2 gamma variant. A similar degree of cell death occurs 4-days after SARS-CoV-2 infection, regardless of the cell origin or viral lineage. Hence, SARS-CoV-2 infects human fat cells, replicating and altering cell function and viability in a depot- and viral lineage-dependent fashion.

Participation of the Serotonergic System and Brain-Derived Neurotrophic Factor in the Antidepressant-like Effect of Flavonoids.

Depressive disorders are among the most disabling diseases experienced around the world, and their incidence has significantly increased over the last few decades due to multiple environmental, social, and biological factors. The search for new pharmacological alternatives to treat depression is a global priority. In preclinical research, molecules obtained from plants, such as flavonoids, have shown promising antidepressant-like properties through several mechanisms of action that have not been fully elucidated, including crossing of the blood brain barrier (BBB). This review will focus on discussing the main findings related to the participation of the serotonergic system and brain-derived neurotrophic factor (BDNF) on the antidepressant-like effect of some flavonoids reported by behavioral, neurochemical, and molecular studies. In this sense, evidence shows that depressive individuals have low levels of serotonin and BDNF, while flavonoids can reverse it. Finally, the elucidation of the mechanism used by flavonoids to modulate serotonin and BDNF will contribute to our understanding of the neurobiological bases underlying the antidepressant-like effects produced by these natural compounds.

Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Dental anomalies in cleft lip and palate: A case-control comparison of total and outside the cleft prevalence.

This study's objective was to compare the total and outside the cleft prevalence of dental anomalies (DA) between patients with cleft lip and palate (CLP) and a control group. This retrospective cross-sectional study was done under a case-control design. The case group consisted of 192 non-syndromic patients with complete CLP, while the control group included 411 patients. All subjects had orthopantomography, intra, and extraoral photographs. The prevalence of dental agenesis, supernumerary teeth, impacted teeth, dental transposition, and microdontia were compared using a chi-squared test (P < .05). Next, a second test was made, but only the anomalies outside the cleft were considered for this study. Total prevalence was 89.1% for cases, and 20.9% for controls (P < .01). The prevalence of each DA was significantly higher for the case group. In the analysis of DAs outside the cleft, the total prevalence was still significantly associated (P < .01); however, only dental agenesis was statistically significant (P < .01). Further analysis found that a high rate of upper premolar absence (P < .01) could explain this event. Patients with CLP have a higher prevalence of DAs compared to controls. After considering only the DAs outside the cleft, the total prevalence remains significantly higher. However, this phenomenon is explained mainly by the elevated prevalence of upper premolars' agenesis. This study's results suggest that environmental factors are behind the high prevalence of DAs in subjects with CLP.

A Predictive Model of Bilateral Sensorineural Hearing Loss in Meniere Disease Using Clinical Data.

OBJECTIVES: Meniere disease (MD) is defined by a clinical syndrome of recurrent attacks of spontaneous vertigo associated with tinnitus, aural fullness, and sensorineural hearing loss (SNHL). Most patients have unilateral SNHL, but some of them will develop contralateral SNHL during the course of the disease. Several studies have reported a frequency of 2 to 73% SNHL in the second ear, according to the duration of disease and the period of follow-up. We hypothesize that unilateral and bilateral MD are different conditions, the first would initially involve the apical turn of the cochlea, while bilateral MD would affect the entire length of the cochlea. The aim of the study is to search for clinical predictors of bilateral SNHL in MD to build a predictive model of bilateral involvement. DESIGN: A retrospective, longitudinal study including two cohorts with a total of 400 patients with definite MD was carried out. The inception cohort consisted of 150 patients with MD and the validation cohort included 250 cases. All of the cases were diagnosed of unilateral MD according to their hearing loss thresholds. The following variables were assessed as predictors of bilateral SNHL for the two cohorts: sex, age of onset, familiar history of MD, migraine and high-frequency hearing loss (HFHL, defined if hearing threshold >20 dB in two or more consecutive frequencies from 2 to 8 KHz). A descriptive analysis was carried out according to the presence of HFHL in the first audiogram for the main variables. By using multiple logistic regression, we built-up several predictive models for the inception cohort and validated it with the replication cohort and merged dataset. RESULTS: Twenty-three (19.3%) and 78 (41%) of patients with HFHL developed contralateral SNHL during the follow-up, in the inception and validation cohorts, respectively. In the inception cohort, the best predictive model included HFHL in the first audiogram (OR = 6.985, p = 0.063) and the absence of migraine (OR = 0.215, p = 0.144) as clinical predictors for bilateral SNHL [area under the curve (AUC) = 0.641, p = 0.002]. The model was validated in the second cohort (AUC = 0.621, p < 0.001). Finally, we merged both datasets to improve the precision of the model including HFHL in the first audiogram (OR = 3.168, p = 0.001), migraine (OR = 0.482, p = 0.036) and age of onset >35 years old (OR = 2.422, p = 0.006) as clinical predictors (AUC = 0.639, p < 0.001). CONCLUSIONS: A predictive model including the age of onset, HFHL in the first audiogram and migraine can help to assess the risk of bilateral SNHL in MD. This model may have significant implications for clinical management of patients with MD.

Estrous cycle modulates the anxiogenic effects of caffeine in the elevated plus maze and light/dark box in female rats.

Caffeine is a commonly used stimulant of the central nervous system that reduces fatigue, increases alertness, and exerts positive effects on emotion through actions on various brain structures. High doses of caffeine can cause headaches, heart palpitations, hyperactivity, and anxiety symptoms. Consequently, reducing the consumption of stimulant substances, such as sugar and caffeine, is proposed to ameliorate symptoms of premenstrual syndrome in women. The administration of steroid hormones has been suggested to modulate the effects of caffeine, but unknown is whether endogenous hormone variations during the estrous cycle modulate the pharmacological effects of caffeine. The present study evaluated the effects of caffeine (10, 20, and 40 mg/kg) during metestrus-diestrus and proestrus-estrus of the ovarian cycle in rats on anxiety-like behavior using the elevated plus maze and light/dark box. During metestrus-diestrus, all doses of caffeine increased anxiety-like behavior, indicated by the main variables in both behavioral tests (i.e., higher Anxiety Index and lower percent time spent on the open arms in the elevated plus maze and less time spent in the light compartment in the light/dark box). During proestrus-estrus, only 20 and 40 mg/kg caffeine increased these parameters of anxiety-like behavior, albeit only slightly. In conclusion, caffeine increased anxiety-like behaviors in metestrus-diestrus, with an attenuation of these effects of lower doses of caffeine in proestrus-estrus. These effects that were observed in metestrus-diestrus and proestrus-estrus may be associated with low and high concentrations of steroid hormones, respectively, that naturally occur during these phases of the ovarian cycle.

Extracellular miRNAs in redox signaling: Health, disease and potential therapies.

Extracellular microRNAs (miRNAs) have emerged as important mediators of cell-to-cell communication and intertissue crosstalk. MiRNAs are produced by virtually all types of eukaryotic cells and can be selectively packaged and released to the extracellular medium, where they may reach distal cells to regulate gene expression cell non-autonomously. By doing so, miRNAs participate in integrative physiology. Oxidative stress affects miRNA expression, while miRNAs control redox signaling. Disruption in miRNA expression, processing or release to the extracellular compartment are associated with aging and a number of chronic diseases, such as obesity, type 2 diabetes, neurodegenerative diseases and cancer, all of them being conditions related to oxidative stress. Here we discuss the interplay between redox balance and miRNA function and secretion as a determinant of health and disease states, reviewing the findings that support this notion and highlighting novel and yet understudied venues of research in the field.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

BACKGROUND: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age. METHODS: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study. RESULTS: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study. CONCLUSIONS: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220.