Overexpression of miR-22-3p and miR-29c-3p in CFU-Hill colonies is related to senescence process among children with low birth weight.

BACKGROUND: The current study mainly focused on provide further insights into the association of the miR-22-3p and miR-29c-3p expression in CFU-Hill colonies with birth weight and senescence process in children. METHODS: This cross-sectional study evaluated 61 children (32 boys, 29 girls). The CFU-Hill colonies number was evaluated in vitro by cell culture technique and senescence was detected by ß-galactosidase (SA-ß-Gal) assay. Expression of miR-22-3p and miR-29c-3p isolated from CFU-Hill colonies were detected using quantitative real-time polymerase chain reaction. RESULTS: Birth weight was correlated with both CFU-Hill colonies and %SA-ß-Gal positive staining. Multivariate linear regression analysis revealed that the senescence was a predictor of the lower CFU-Hill colonies number, while only the birth weight was a predictor of senescence of CFU-Hill colonies. Overexpression of miR-22-3p and miR-29c-3p was observed in CFU-Hill colonies isolated from children with low birth weight (LBW). Interestingly, we found a significant correlation between %SA-ß-Gal cells staining positive for both miR-22-3p and miR-29c-3p. CONCLUSION: The LBW is associated with decreased CFU-Hill colonies number and high senescence of these cells. The overexpression of miR-22-3p and miR-29c-3p may be partially responsible for this alteration due to regulation of several pathways related to the senescence process. IMPACT: The study establishes a significant correlation between birth weight and the number of CFU-Hill colonies, suggesting that birth weight could be a predictive biomarker for vascular health in children. Data indicates that cellular senescence is a predictor of reduced CFU-Hill colony numbers. This suggests that the aging process of these cells could be an important factor in understanding the vascular health issues in children with low birth weight. The overexpression of miR-22-3p and miR-29c-3p in children with low birth weight and their correlation with increased cellular senescence highlight these microRNAs as possible molecular mechanisms influencing the aging of CFU-Hill colonies.

Oral contraceptives in adolescents: a retrospective population-based study on blood pressure and metabolic dysregulation.

PURPOSE: This study aimed to explore the relationship between oral contraceptive use and blood pressure values and in a national cohort of women adolescents and to investigate the level of coexistence of the high blood pressure levels, dyslipidemia or insulin resistance. METHODS: This is a retrospective cohort study that evaluated data form 14,299 adolescents aged 14 to 17 years. Crude and race-and age-adjusted analyses were performed using Poisson regression to estimate the prevalence ratios. Data clustering analysis was performed using machine learning approaches supported by an unsupervised neural network of self-organizing maps. RESULTS: We found that 14.5% (n = 2076) of the women adolescents use oral contraceptives. Moreover, an increased prevalence of high blood pressure, dyslipidemia, and insulin resistance (all P < 0.001) was observed among adolescents who use oral contraceptives as compared to those who do not. Our analysis also showed that 2.3% of adolescents using oral contraceptives had both high blood pressure levels and dyslipidemia, whereas 3.2% had high blood pressure levels combined with insulin resistance (all P < 0.001). The algorithmic investigative approach demonstrated that total cholesterol, LDLc, HDLc, insulin, and HOMA-IR were the most predicted variables to assist classificatory association in the context of oral contraceptive use among women adolescents with high blood pressure. CONCLUSIONS: These findings suggest that oral contraceptives were associated with an increased prevalence of high blood pressure, dyslipidemia, and insulin resistance among women adolescents. Although the indication of this therapy is adequate to avoid unintended pregnancies, their use must be based on rigorous individual evaluation and under constant control of the cardiometabolic risk factors.

Emotional and relational problems of adolescents with and without a migrant background in Europe: a systematic review.

Mental health of migrant adolescents is a topic that has been widely studied in the past decades. Emotional and behavioural problems are amongst the most explored areas; however, little attention has been paid to the relational sphere, which represents another key aspect of mental health and is paramount during adolescence. This systematic review analysed the available evidence on emotional and relational problems comparing adolescents with and without a migrant background in Europe between 2010 and 2021. The search was conducted in four databases using a common search strategy composed of terms addressing adolescence, migrant population, and emotional and relational problems. Three rounds of screening produced 36 eligible studies. Factors affecting both types of problems were identified and categorised using thematic synthesis, dividing them into factors affecting both types of problems jointly or separately and analysing them according to three systemic levels affecting the adolescents' lives (intrapersonal, interpersonal and external). Critical analysis of the results pointed to mixed findings, with a mild tendency in migrant-background adolescents to portray more emotional problems than their native peers and a stronger tendency for relational problems in the same direction. Several limitations were identified and, along with the conclusions, point to suggestions for future research focusing on studying relational problems as a key component of mental health and its link to emotional problems. Further suggestions entail designing studies that target adolescents with different migrant-background profiles and cultural origins to establish differences between them and identify additional factors affecting emotional and relational problems during the pre-migration and transit phases of the migratory journey to help prevent the onset of these problems.

Bacteremia caused by Veillonella parvula: Two case reports and a review of the literature.

Veillonella parvula is a non-motile Gram-negative coccus that forms part of the normal microbiota in several body sites and which has been rarely isolated as cause of infections in human population, particularly in bacteremias. Here we give the overview of characteristics of genus Veillonella and the summary of its role in infections, particularly in bacteremia. We additionally report two patients with bacteremia due to V. parvula. Two sets of blood cultures of each patient yielded a pure culture of an anaerobic microorganism identified as V. parvula by MALDI-TOF MS, and confirmed by 16S rRNA gene sequencing. The two patients were male and one of them had risk factors for anaerobic bacteremia. The isolates were susceptible to most antibiotics and the outcome was successful in both patients. Bacteremia due to V. parvula is still rare. MALDI-TOF MS appear to be an excellent tool for the correct identification of these species.

Insufficient Answer During the Public Health Emergency: A Lesson from the Persistence of Food Insecurity in Low-Income Communities.

Cohort study in deprived communities to investigate the persistence of food insecurity (FI) during the COVID-19 was conducted. Sample were derived from a list of mobile phone numbers provided by community leaders and local nonprofit organizations. Temporal trends and prevalence ratios of FI persistence, categorized as "never," "occasional FI," "consistent FI," were calculated. A total of 302 households completed three assessments, the majority nonwhite women. During the follow-up, families covered by social assistance increased; however, their income decreased (p < 0.05). 33% were "consistent," and 46% "occasional" FI. Permanent difficulties accessing gas canisters, hygiene products, and hand sanitizers were observed.

KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. Considering the increasing interest of discovering novel NRF2 activators due to its clinical application, initial efforts were devoted to the development of electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through covalent modifications on cysteine residues. However, off-target effects of these drugs prompted the development of an innovative strategy, the search of KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative activators are proposed to target NRF2 in a more selective way, leading to potentially improved drugs with the application for a variety of diseases that are currently under investigation. In this review, we summarize known KEAP1-NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.

CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.

Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co-culture assays with motor neurons and reprogrammed patient skin-derived astrocytes (iAs) to evaluate the effects of (SP-4-2)-[[2,2'-(1,2-dimethyl-1,2-ethanediylidene)bis[N-methylhydrazinecarbothioamidato-κN2 ,κS]](2-)]-copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co-culture with healthy motor neurons. Using this assay, we identified responding and non-responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM-responders, a metabolic phenotype not observed in non-responders. Pre-treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient-specific cellular and molecular profiles could help improve clinical trial design in the future.

Bacteremia due to Clostridium innocuum: Analysis of four cases and literature review.

Clostridium innocuum is a Gram-positive anaerobic spore-forming bacillus that has been identified as part of the normal intestinal microbiota. This bacterium has been rarely associated with human infections, and only few severe infections have been reported until now. In this work, we report on four patients with bacteremia due to C. innocuum, which were well identified by MALDI-TOF MS. Moreover, a review of the previous published cases of bacteremia due to this anaerobic bacterium has been performed.

Interaction between the transmembrane domains of neurotrophin receptors p75 and TrkA mediates their reciprocal activation.

The neurotrophin receptors p75 and tyrosine protein kinase receptor A (TrkA) play important roles in the development and survival of the nervous system. Biochemical data suggest that p75 and TrkA reciprocally regulate the activities of each other. For instance, p75 is able to regulate the response of TrkA to lower concentrations of nerve growth factor (NGF), and TrkA promotes shedding of the extracellular domain of p75 by α-secretases in a ligand-dependent manner. The current model suggests that p75 and TrkA are regulated by means of a direct physical interaction; however, the nature of such interaction has been elusive thus far. Here, using NMR in micelles, multiscale molecular dynamics, FRET, and functional studies, we identified and characterized the direct interaction between TrkA and p75 through their respective transmembrane domains (TMDs). Molecular dynamics of p75-TMD mutants suggests that although the interaction between TrkA and p75 TMDs is maintained upon mutation, a specific protein interface is required to facilitate TrkA active homodimerization in the presence of NGF. The same mutations in the TMD protein interface of p75 reduced the activation of TrkA by NGF as well as reducing cell differentiation. In summary, we provide a structural model of the p75-TrkA receptor complex necessary for neuronal development stabilized by TMD interactions.

Olive-tree polyphenols and urban mining. A greener alternative for the recovery of valuable metals from scrap printed circuit boards.

Recycling printed circuit boards (PCBs) is becoming a source of precious metals and an alternative to conventional mining. This phenomenon is now known as "urban mining." In this work, a polyphenols-rich plant extract has been obtained from olive-tree leaves, and its ability to contribute to reducing four metals, namely, Ag, Cu, Cr, and Sn, that are present in scrap PCBs has been studied. Three reductants (NaBH4, Fe°, and the olive-tree leaves extract) have been used to recover these valuable metals. An attempt has been made to minimize the concentration of the first two, replacing them with a natural, cheaper, and less toxic reductant. To achieve this goal, a computer-assisted factorial, composed, centered, orthogonal, and rotatable statistical design of experiments (FCCORD) has been used to build the experimental matrix to be carried out in the laboratory and, next, for the statistical treatment of the results. The results show that it is possible to achieve only a partial recovery of the four metals (silver, copper, chromium, and tin) from PCBs leachates by using sodium borohydride, iron, and the extract separately. In other words, none of these three reductants alone can completely remove any of the four metals in the leachate. Nevertheless, using the statistical design of experiments, the total recovery of the four metals has been achieved by combining the three reductants in the appropriate concentrations. Hence, polyphenols-rich plant extracts in general and olive-tree leaves extract in particular can be regarded as promising coadjuvants in the rising field of urban mining.

Low birth weight and its relation to physical fitness parameters in children: Its negative effect on muscle strength and cardiorespiratory endurance.

BACKGROUND: There is increasing evidence that low birth weight has a negative effect on physical fitness, muscle strength, and cardiorespiratory endurance, although the findings are inconsistent. OBJECTIVES: This study aimed to evaluate whether birth weight acts as a prenatal determinant of physical fitness parameters and to determine the role of environmental or biological variables on this effect. METHODS: One hundred and sixty-seven children aged 6-14 years were included in this study. The anthropometric data, physical activity index, standing long jump, flexibility, handgrip strength, and cardiorespiratory fitness were evaluated. RESULTS: A positive correlation was found between birth weight and cardiorespiratory fitness (r = .349; p < .001), right handgrip strength (r = .337; p < .001), and left handgrip strength (r = .320; p < .001), suggesting that children with low birth weight had the worst performance in both cardiorespiratory endurance and grip strength tests. These findings remained significant after adjustment for prematurity, sex, age, physical activity index, and body mass index (BMI). Stepwise multiple regression analyses revealed a significant interaction of high birth weight, older age, and low BMI in predicting better cardiorespiratory endurance (R2  = .308). When handgrip strength was tested as the dependent variable, we found that high birth weight, male sex, and older age emerged as important determinants for both sides. CONCLUSION: Children aged 6-14 years born with a birth weight < 2.5 kg have low handgrip strength and cardiorespiratory fitness, which seems to be mediated partially by influences of both prenatal environment (e.g., birth weight) and biological variables (e.g., age, sex, BMI).

Pain Quality After Pediatric Pectus Excavatum Repair.

BACKGROUND: Neuropathic pain medications are included in multimodal postoperative analgesic strategies, but quality of perioperative pain is rarely assessed. AIMS: The purpose of this study was to describe adolescents' pain experiences after thoracoscopic pectus excavatum repair (Nuss procedure) using the Adolescent Pediatric Pain Tool. DESIGN: This prospective descriptive longitudinal study was designed to test the hypothesis that pain quality descriptors reported are consistent with neuropathic pain. METHODS: A convenience sample of 23 adolescents aged 12 to 17 years from a single urban, university affiliated, nonprofit children's hospital consented to self-report pain using the Adolescent Pediatric Pain Tool before and during hospitalization, and up to 14 months after Nuss procedure. Visual analytic techniques were used to analyze reported pain intensity, location, and affective, evaluative, sensory, and temporal qualities. RESULTS: Postoperative pain quality, intensity, number of sites, and surface area decreased over time. Word clouds illustrated that neuropathic sensory and temporal pain quality descriptors increased in frequency 2 to 6 weeks after surgery and were the predominant descriptors 2 to 4 months after surgery. Dot matrix charts illustrated an inconsistent relationship of pain quality and intensity with pain surface area. CONCLUSIONS: Pain quality should be assessed with valid, reliable, and developmentally appropriate tools. Visual analytics help illustrate pain quality at single points in time and longitudinally and may be helpful in guiding postoperative pain treatment.

Structural basis of the transmembrane domain dimerization and rotation in the activation mechanism of the TRKA receptor by nerve growth factor.

Tropomyosin-receptor kinases (TRKs) are essential for the development of the nervous system. The molecular mechanism of TRKA activation by its ligand nerve growth factor (NGF) is still unsolved. Recent results indicate that at endogenous levels most of TRKA is in a monomer-dimer equilibrium and that the binding of NGF induces an increase of the dimeric and oligomeric forms of this receptor. An unsolved issue is the role of the TRKA transmembrane domain (TMD) in the dimerization of TRKA and the structural details of the TMD in the active dimer receptor. Here, we found that the TRKA-TMD can form dimers, identified the structural determinants of the dimer interface in the active receptor, and validated this interface through site-directed mutagenesis together with functional and cell differentiation studies. Using in vivo cross-linking, we found that the extracellular juxtamembrane region is reordered after ligand binding. Replacement of some residues in the juxtamembrane region with cysteine resulted in ligand-independent active dimers and revealed the preferred dimer interface. Moreover, insertion of leucine residues into the TMD helix induced a ligand-independent TRKA activation, suggesting that a rotation of the TMD dimers underlies NGF-induced TRKA activation. Altogether, our findings indicate that the transmembrane and juxtamembrane regions of TRKA play key roles in its dimerization and activation by NGF.

Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation: A Pilot Study.

Background and Purpose: Sphenopalatine ganglion (SPG) electrical stimulation has been studied in the setting of acute ischemic stroke to enhance collateral flow. Capsaicin poses an alternative to chemically stimulate the sphenopalatine ganglion. Therefore, the objective of this study was to determine the safety and effect of increasing doses of capsaicin upon serial transcranial Doppler markers of cerebral blood flow. Methods: We performed serial transcranial Doppler testing in 30 healthy volunteers divided into 5 equal groups. Capsaicin doses ranged from 33 to 165 µMol. We recorded peak systolic and end-diastolic velocities in the middle cerebral artery, arterial pressure, and perceived pungency in 5-minute intervals up to 20 minutes. We then calculated the mean velocity, the pulsatility index, and the cerebral blood flow index. Results: The participants' median age was 21 years (range, 5 years); all reported consumption of capsaicin in their diets. After and during the study, none reported side effects. Perceived pungency peaked at 5 minutes, and by the 20-minute mark, none perceived any pungency. All the tested doses produced the same pattern, consisting of augmentation of the middle cerebral artery mean velocity with the pulsatility index's diminution. The effects peaked between the 5- and the 10-minute measurements and then returned to basal levels except for the 66-µMol doses, which produced a sustained effect. We found no correlation between perceived pungency and dose, but the middle cerebral artery mean velocity was strongly correlated with the dose administered. Conclusions: This study provides evidence supporting the safety and tolerability of oral capsaicin in a population of healthy volunteers. Capsaicin appears to produce effects similar to those of sphenopalatine ganglion electrical stimulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04545892.

Synthesis and in vitro study of nitro- and methoxy-2-phenylbenzofurans as human monoamine oxidase inhibitors.

A new series of 2-phenylbenzofuran derivatives were designed and synthesized to determine relevant structural features for the MAO inhibitory activity and selectivity. Methoxy substituents were introduced in the 2-phenyl ring, whereas the benzofuran moiety was not substituted or substituted at the positions 5 or 7 with a nitro group. Substitution patterns on both the phenyl ring and the benzofuran moiety determine the affinity for MAO-A or MAO-B. The 2-(3-methoxyphenyl)-5-nitrobenzofuran 9 was the most potent MAO-B inhibitor (IC50 = 0.024 µM) identified in this series, whereas 7-nitro-2-phenylbenzofuran 7 was the most potent MAO-A inhibitor (IC50 = 0.168 µM), both acting as reversible inhibitors. The number and position of the methoxyl groups on the 2-phenyl ring, have an important influence on the inhibitory activity. Molecular docking studies confirmed the experimental results and highlighted the importance of key residues in enzyme inhibition.

High prevalence of food insecurity, the adverse impact of COVID-19 in Brazilian favela.

OBJECTIVE: To investigate food insecurity (FI) prevalence in two favelas in Brazil in the early weeks of the social distancing policy, from 27 March 2020 to 1 June 2020. DESIGN: A cross-sectional study using an online questionnaire to elicit information on socio-economic and demographic characteristics, the types of stores visited to buy food, and FI screening. The FI experience was evaluated according to the Brazilian Food Insecurity Scale. Factors associated with moderate or severe FI were investigated using the logistic regression model. SETTING: São Paulo city, Brazil. PARTICIPANTS: Totally, 909 householders. RESULTS: Eighty-eight per cent of the households included young women working as cleaners or kitchen assistants and in sales services. One-fifth of the participants were involved in the federal cash transfer programme, called Bolsa Família. There were 92 % households with children. The most frequent experience reported was uncertainty about food acquisition or receiving more (89 %), eating less than one should (64 %), not being able to eat healthy and nutritious food (46 %), and skipping a meal (39 %). Forty-seven per cent of the participants experienced moderate or severe FI. Factors associated with moderate and severe FI were low income, being a Bolsa Família recipient, having a low level of education and living in a household without children. CONCLUSIONS: Half of the participants experienced moderate or severe FI, and almost 10 % experienced hunger. Our data suggest that families with children were at a lower risk of moderate to severe FI. It is possible that nationally established social programmes such as Bolsa Família were protecting those families.

Emerging evidence for the opposite role of circulating irisin levels and brown adipose tissue activity measured by infrared thermography in anthropometric and metabolic profile during childhood.

Irisin is an adipomyokine that increases browning of adipose tissue and thermogenesis, thereby protecting against obesity and insulin resistance. However, the correlation between irisin, brown adipose tissue (BAT), and childhood obesity, as well as its association with an increased risk of developing metabolic diseases, has not been completely elucidated. This study aimed to investigate the association between irisin levels and BAT activity measured by infrared thermography among children and verify their correlation with anthropometric and metabolic parameters. This study included 42 children with normal weight and 18 overweight/obese children. Anthropometric data, irisin levels, lipid and glucose profile were evaluated. The percentage of the thermally active portion of the supraclavicular area (%AreaSCR) before and after a cold stimulus was measured by infrared thermography, and the differences between the percentages of thermally active (Δ%AreaSCR) was calculated as an index of BAT activation. The results were correlated with anthropometric and metabolic parameters. Circulating irisin levels was positive correlated with age (rho=0.327, P= 0.011), body mass index (BMI) (rho=0.707, P<0.001), waist circumference (rho=0.624, P<0.001), total cholesterol (rho=0.361, P=0.044), triglycerides (rho=0.419, P=0.001), and low-density lipoprotein cholesterol (LDLc) (rho=0.381, P= 0.003). Active BAT was negatively correlated with BMI, waist circumference, triglycerides, LDLc and irisin levels. We observed that normal weight children increased significantly the Δ% AreaSCR as compared to overweight/obese children. In conclusion, circulating irisin levels and BAT activity appear to have opposing roles, since normal weight children had greater BAT activity and lower circulating levels of irisin.

Peroxynitrite supports a metabolic reprogramming in merlin-deficient Schwann cells and promotes cell survival.

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas. The NF2 gene encodes the tumor suppressor merlin, and loss of merlin activity promotes tumorigenesis and causes NF2. Cellular redox signaling has been implicated in different stages of tumor development. Among reactive nitrogen species, peroxynitrite is the most powerful oxidant produced by cells. We recently showed that peroxynitrite-mediated tyrosine nitration down-regulates mitochondrial metabolism in tumor cells. However, whether peroxynitrite supports a metabolic shift that could be exploited for therapeutic development is unknown. Here, we show that vestibular schwannomas from NF2 patients and human, merlin-deficient (MD) Schwann cells have high levels of endogenous tyrosine nitration, indicating production of peroxynitrite. Furthermore, scavenging or inhibiting peroxynitrite formation significantly and selectively decreased survival of human and mouse MD-Schwann cells. Using multiple complementary methods, we also found that merlin deficiency leads to a reprogramming of energy metabolism characterized by a peroxynitrite-dependent decrease of oxidative phosphorylation and increased glycolysis and glutaminolysis. In MD-Schwann cells, scavenging of peroxynitrite increased mitochondrial oxygen consumption and membrane potential, mediated by the up-regulation of the levels and activity of mitochondrial complex IV. This increase in mitochondrial activity correlated with a decrease in the glycolytic rate and glutamine dependence. This is the first demonstration of a peroxynitrite-dependent reprogramming of energy metabolism in tumor cells. Oxidized proteins constitute a novel target for therapeutic development not only for the treatment of NF2 schwannomas but also other tumors in which peroxynitrite plays a regulatory role.

Detection of a large spectrum of viral infections in conjunctival premalignant and malignant lesions.

To study the interaction between HIV and other carcinogenic infections in conjunctival squamous cell carcinoma (SCC), we evaluated the presence of a broad spectrum of human viruses in conjunctiva specimens. Beta Human papillomavirus (HPV; n = 46), gamma HPV (n = 52), polyomaviruses (n = 12) and herpes viruses (n = 3) was determined in DNA extracted from 67 neoplastic and 55 non-neoplastic conjunctival tissues of HIV-positive and HIV negative subjects by Luminex-based assays. Next-generation sequencing (NGS) was also used to further characterize the presence of cutaneous HPVs. Detection of beta-2 HPV infections was associated with the risk of neoplasia (adjusted odds ratio [aOR] 3.0; 95% confidence interval [CI] 1.3-6.8), regardless of HIV status (HIV positive, aOR 2.6, 95% CI 0.9-7.7; HIV negative, aOR 3.5, 95% CI 0.9-14.4). EBV was strongly associated with the risk of neoplasia (aOR 12.0, 95% CI 4.3-33.5; P < .01) mainly in HIV individuals (HIV positive, aOR 57.5; 95% CI: 10.1-327.1; HIV negative aOR 2.6; 95% CI: 0.2-34.7). NGS allowed to identify 13 putative novel HPVs in cases and controls. Our findings suggest a role of beta HPV types and EBV, in conjunctival SCC. However, additional studies of viral expression in tumor tissue are required to confirm the causal association.

L-selectin expression is regulated by CXCL8-induced reactive oxygen species produced during human neutrophil rolling.

Neutrophils destroy invading microorganisms by phagocytosis by bringing them into contact with bactericidal substances, among which ROS are the most important. However, ROS also function as important physiological regulators of cellular signaling pathways. Here, we addressed the involvement of oxygen derivatives in the regulation of human neutrophil rolling, an essential component of the inflammatory response. Flow experiments using dihydroethidium-preloaded human neutrophils showed that these cells initiate an early production of intracellular ROS during the rolling phase of the adhesion cascade, a phenomenon that required cell rolling, and the interaction of the chemokine receptor CXCR2 with their ligand CXCL8. Flow cytometry experiments demonstrated that L-selectin shedding in neutrophils is triggered by ROS through an autocrine-paracrine mechanism. Preincubation of neutrophils with the NADPH oxidase complex inhibitor diphenyleniodonium chloride significantly increased the number of rolling neutrophils on endothelial cells. Interestingly, the same effect was observed when CXCL8 signaling was interfered using either a blocking monoclonal antibody or an inhibitor of its receptor. These findings indicate that, in response to CXCL8, neutrophils initiate ROS production during the rolling phase of the inflammatory response. This very early ROS production might participate in the modulation of the inflammatory response by inducing L-selectin shedding in neutrophils.