miRNAs Related to Immune Checkpoint Inhibitor Response: A Systematic Review.

The advent of immune checkpoint inhibitors (ICIs) has represented a breakthrough in the treatment of many cancers, although a high number of patients fail to respond to ICIs, which is partially due to the ability of tumor cells to evade immune system surveillance. Non-coding microRNAs (miRNAs) have been shown to modulate the immune evasion of tumor cells, and there is thus growing interest in elucidating whether these miRNAs could be targetable or proposed as novel biomarkers for prognosis and treatment response to ICIs. We therefore performed an extensive literature analysis to evaluate the clinical utility of miRNAs with a confirmed direct relationship with treatment response to ICIs. As a result of this systematic review, we have stratified the miRNA landscape into (i) miRNAs whose levels directly modulate response to ICIs, (ii) miRNAs whose expression is modulated by ICIs, and (iii) miRNAs that directly elicit toxic effects or participate in immune-related adverse events (irAEs) caused by ICIs.

Oxidative stress and metabolism meet epigenetic modulation in physical exercise.

Physical exercise is established as an important factor of health and generally is recommended for its positive effects on several tissues, organs, and systems. These positive effects come from metabolic adaptations that also include oxidative eustress, in which physical activity increases ROS production and antioxidant mechanisms, although this depends on the intensity of the exercise. Muscle metabolism through mechanisms such as aerobic and anaerobic glycolysis, tricarboxylic acid cycle, and oxidative lipid metabolism can produce metabolites and co-factors which directly impact the epigenetic machinery. In this review, we clearly reinforce the evidence that exercise regulates several epigenetic mechanisms and explain how these mechanisms can be regulated by metabolic products and co-factors produced during exercise. In fact, recent evidence has demonstrated the importance of epigenetics in the gene expression changes implicated in metabolic adaptation after exercise. Importantly, intermediates of the metabolism generated by continuous, acute, moderate, or strenuous exercise control the activity of epigenetic enzymes, therefore turning on or turning off the gene expression of specific programs which can lead to physiological adaptations after exercise.

Utility of exome sequencing for the diagnosis of pediatric-onset neuromuscular diseases beyond diagnostic yield: a narrative review.

Diagnosis of neuromuscular diseases (NMD) can be challenging because of the heterogeneity of this group of diseases. This review aimed to describe the diagnostic yield of whole exome sequencing (WES) for pediatric-onset neuromuscular disease diagnosis, as well as other benefits of this approach in patient management since WES can contribute to appropriate treatment selection in NMD patients. WES increases the possibility of reaching a conclusive genetic diagnosis when other technologies have failed and even exploring new genes not previously associated with a specific NMD. Moreover, this strategy can be useful when a dual diagnosis is suspected in complex congenital anomalies and undiagnosed cases.

MicroRNAs in Gingival Crevicular Fluid: An Observational Case-Control Study of Differential Expression in Periodontitis.

OBJECTIVES: microRNAs (miRNAs) present in the gingival crevicular fluid (GCF) of patients with chronic periodontitis may serve as biomarkers of periodontal disease. The aim of this study was to perform a miRNA-sequencing study of all miRNAs present in GCF, comparing miRNA expression level profiles between advanced chronic periodontitis (CP) patients and healthy subjects (HS). MATERIALS AND METHODS: GCF samples were collected from the single-rooted teeth of patients with severe CP (n = 11) and of HS (n = 12). miRNAs were isolated from GCF using an miRNeasy Serum/Plasma kit(Qiagen GmbH, Hilden, Germany). Reverse transcription polymerase chain reaction (qRT-PCR) was used to determine the expression levels of miRNA candidates involved in periodontal pathogenesis. RESULTS: Of all the sequenced miRNAs, miR-199, miR-146a, miR-30a, and miR-338 were identified as best representing the CP patient samples. The validation study identified miR-199 as the most powerful biomarker used to define periodontitis. CONCLUSIONS: Upon sequencing all known miRNAs in GCF for the first time, we uncovered several potential biomarkers to define periodontitis. Identifying miRNAS in the GCF using high-throughput approaches will clarify the role of these molecules in periodontitis and provide biomarkers with potential applications.

Validation of circulating histone detection by mass spectrometry for early diagnosis, prognosis, and management of critically ill septic patients.

BACKGROUND: As leading contributors to worldwide morbidity and mortality, sepsis and septic shock are considered a major global health concern. Proactive biomarker identification in patients with sepsis suspicion at any time remains a daunting challenge for hospitals. Despite great progress in the understanding of clinical and molecular aspects of sepsis, its definition, diagnosis, and treatment remain challenging, highlighting a need for new biomarkers with potential to improve critically ill patient management. In this study we validate a quantitative mass spectrometry method to measure circulating histone levels in plasma samples for the diagnosis and prognosis of sepsis and septic shock patients. METHODS: We used the mass spectrometry technique of multiple reaction monitoring to quantify circulating histones H2B and H3 in plasma from a monocenter cohort of critically ill patients admitted to an Intensive Care Unit (ICU) and evaluated its performance for the diagnosis and prognosis of sepsis and septic shock (SS). RESULTS: Our results highlight the potential of our test for early diagnosis of sepsis and SS. H2B levels above 121.40 ng/mL (IQR 446.70) were indicative of SS. The value of blood circulating histones to identify a subset of SS patients in a more severe stage with associated organ failure was also tested, revealing circulating levels of histones H2B above 435.61 ng/ml (IQR 2407.10) and H3 above 300.61 ng/ml (IQR 912.77) in septic shock patients with organ failure requiring invasive organ support therapies. Importantly, we found levels of H2B and H3 above 400.44 ng/mL (IQR 1335.54) and 258.25 (IQR 470.44), respectively in those patients who debut with disseminated intravascular coagulation (DIC). Finally, a receiver operating characteristic curve (ROC curve) demonstrated the prognostic value of circulating histone H3 to predict fatal outcomes and found for histone H3 an area under the curve (AUC) of 0.720 (CI 0.546-0.895) p < 0.016 on a positive test cut-off point at 486.84 ng/mL, showing a sensitivity of 66.7% and specificity of 73.9%. CONCLUSIONS: Circulating histones analyzed by MS can be used to diagnose SS and identify patients at high risk of suffering DIC and fatal outcome.

Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells

Extracellular histones have been reported to aggravate different pathophysiological processes by increasing vascular permeability, coagulopathy, and inflammation. In the present study, we elucidate how extracellular histones (10–100 µg/mL) concentration dependently increase cytosolic reactive oxygen species (ROS) production using human umbilical vein endothelial cells (HUVECs). Furthermore, we identify cyclooxygenase (COX) and NADPH oxidase (NOX) activity as sources of ROS production in extracellular histone-treated HUVEC. This COX/NOX-mediated ROS production is also involved in enhanced NF-kB activity and cell adhesion molecules (VCAM1 and ICAM1) expression in histone-treated HUVEC. Finally, by using different toll-like receptor (TLR) antagonists, we demonstrate the role of TLR4 in CAMs overexpression triggered by extracellular histones in endothelial cells. In conclusion, our data suggest that through TLR4 signaling, extracellular histones increase endothelial cell activation, a mechanism involving increased COX- and NOX-mediated ROS. These findings increase our understanding on how extracellular histones enhance systemic inflammatory responses in diseases in which histone release occurs as part of the pathological processes. (AU)

Oxidative Stress and Epigenetics: miRNA Involvement in Rare Autoimmune Diseases.

Autoimmune diseases (ADs) such as Sjögren's syndrome, Kawasaki disease, and systemic sclerosis are characterized by chronic inflammation, oxidative stress, and autoantibodies, which cause joint tissue damage, vascular injury, fibrosis, and debilitation. Epigenetics participate in immune cell proliferation and differentiation, which regulates the development and function of the immune system, and ultimately interacts with other tissues. Indeed, overlapping of certain clinical features between ADs indicate that numerous immunologic-related mechanisms may directly participate in the onset and progression of these diseases. Despite the increasing number of studies that have attempted to elucidate the relationship between miRNAs and oxidative stress, autoimmune disorders and oxidative stress, and inflammation and miRNAs, an overall picture of the complex regulation of these three actors in the pathogenesis of ADs has yet to be formed. This review aims to shed light from a critical perspective on the key AD-related mechanisms by explaining the intricate regulatory ROS/miRNA/inflammation axis and the phenotypic features of these rare autoimmune diseases. The inflamma-miRs miR-155 and miR-146, and the redox-sensitive miR miR-223 have relevant roles in the inflammatory response and antioxidant system regulation of these diseases. ADs are characterized by clinical heterogeneity, which impedes early diagnosis and effective personalized treatment. Redox-sensitive miRNAs and inflamma-miRs can help improve personalized medicine in these complex and heterogeneous diseases.

The Intricate Role of Non-Coding RNAs in Sepsis-Associated Disseminated Intravascular Coagulation.

Disseminated Intravascular Coagulation (DIC) is a type of tissue and organ dysregulation in sepsis, due mainly to the effect of the inflammation on the coagulation system. Unfortunately, the underlying molecular mechanisms that lead to this disorder are not fully understood. Moreover, current biomarkers for DIC, including biological and clinical parameters, generally provide a poor diagnosis and prognosis. In recent years, non-coding RNAs have been studied as promising and robust biomarkers for a variety of diseases. Thus, their potential in the diagnosis and prognosis of DIC should be further studied. Specifically, the relationship between the coagulation cascade and non-coding RNAs should be established. In this review, microRNAs, long non-coding RNAs, and circular RNAs are studied in relation to DIC. Specifically, the axis between these non-coding RNAs and the corresponding affected pathway has been identified, including inflammation, alteration of the coagulation cascade, and endothelial damage. The main affected pathway identified is PI3K/AKT/mTOR axis, where several ncRNAs participate in its regulation, including miR-122-5p which is sponged by circ_0005963, ciRS-122, and circPTN, and miR-19a-3p which is modulated by circ_0000096 and circ_0063425. Additionally, both miR-223 and miR-24 were found to affect the PI3K/AKT pathway and were regulated by lncGAS5 and lncKCNQ1OT1, respectively. Thus, this work provides a useful pipeline of inter-connected ncRNAs that future research on their impact on DIC can further explore.

Age-Related microRNA Overexpression in Lafora Disease Male Mice Provides Links between Neuroinflammation and Oxidative Stress.

Lafora disease is a rare, fatal form of progressive myoclonus epilepsy characterized by continuous neurodegeneration with epileptic seizures, characterized by the intracellular accumulation of aberrant polyglucosan granules called Lafora bodies. Several works have provided numerous evidence of molecular and cellular alterations in neural tissue from experimental mouse models deficient in either laforin or malin, two proteins related to the disease. Oxidative stress, alterations in proteostasis, and deregulation of inflammatory signals are some of the molecular alterations underlying this condition in both KO animal models. Lafora bodies appear early in the animal's life, but many of the aforementioned molecular aberrant processes and the consequent neurological symptoms ensue only as animals age. Here, using small RNA-seq and quantitative PCR on brain extracts from laforin and malin KO male mice of different ages, we show that two different microRNA species, miR-155 and miR-146a, are overexpressed in an age-dependent manner. We also observed altered expression of putative target genes for each of the microRNAs studied in brain extracts. These results open the path for a detailed dissection of the molecular consequences of laforin and malin deficiency in brain tissue, as well as the potential role of miR-155 and miR-146a as specific biomarkers of disease progression in LD.

Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells.

Extracellular histones have been reported to aggravate different pathophysiological processes by increasing vascular permeability, coagulopathy, and inflammation. In the present study, we elucidate how extracellular histones (10-100 µg/mL) concentration dependently increase cytosolic reactive oxygen species (ROS) production using human umbilical vein endothelial cells (HUVECs). Furthermore, we identify cyclooxygenase (COX) and NADPH oxidase (NOX) activity as sources of ROS production in extracellular histone-treated HUVEC. This COX/NOX-mediated ROS production is also involved in enhanced NF-kB activity and cell adhesion molecules (VCAM1 and ICAM1) expression in histone-treated HUVEC. Finally, by using different toll-like receptor (TLR) antagonists, we demonstrate the role of TLR4 in CAMs overexpression triggered by extracellular histones in endothelial cells. In conclusion, our data suggest that through TLR4 signaling, extracellular histones increase endothelial cell activation, a mechanism involving increased COX- and NOX-mediated ROS. These findings increase our understanding on how extracellular histones enhance systemic inflammatory responses in diseases in which histone release occurs as part of the pathological processes.

Alterations in leukocyte DNA methylome are associated to immunosuppression in severe clinical phenotypes of septic patients.

Introduction: Sepsis patients experience a complex interplay of host pro- and anti-inflammatory processes which compromise the clinical outcome. Despite considering the latest clinical and scientific research, our comprehension of the immunosuppressive events in septic episodes remains incomplete. Additionally, a lack of data exists regarding the role of epigenetics in modulating immunosuppression, subsequently impacting patient survival. Methods: To advance the current understanding of the mechanisms underlying immunosuppression, in this study we explored the dynamics of DNA methylation using the Infinium Methylation EPIC v1.0 BeadChip Kit in leukocytes from patients suffering from sepsis, septic shock, and critically ill patients as controls, within the first 24 h after admission in the Intensive Care Unit of a tertiary hospital. Results and discussion: Employing two distinct analysis approaches (DMRcate and mCSEA) in comparing septic shock and critically ill patients, we identified 1,256 differentially methylated regions (DMRs) intricately linked to critical immune system pathways. The examination of the top 100 differentially methylated positions (DMPs) between septic shock and critically ill patients facilitated a clear demarcation among the three patient groups. Notably, the top 6,657 DMPs exhibited associations with organ dysfunction and lactate levels. Among the individual genes displaying significant differential methylation, IL10, TREM1, IL1B, and TNFAIP8 emerged with the most pronounced methylation alterations across the diverse patient groups when subjected to DNA bisulfite pyrosequencing analysis. These findings underscore the dynamic nature of DNA methylation profiles, highlighting the most pronounced alterations in patients with septic shock, and revealing their close association with the disease.

Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation.

NETosis is a key host immune process against a pathogenic infection during innate immune activation, consisting of a neutrophil "explosion" and, consequently, NET formation, containing mainly DNA, histones, and other nuclear proteins. During sepsis, an exacerbated immune host response to an infection occurs, activating the innate immunity and NETosis events, which requires histone H3 citrullination. Our group compared the circulating histone levels with those citrullinated H3 levels in plasma samples of septic patients. In addition, we demonstrated that citrullinated histones were less cytotoxic for endothelial cells than histones without this post-translational modification. Citrullinated histones did not affect cell viability and did not activate oxidative stress. Nevertheless, citrullinated histones induced an inflammatory response, as well as regulatory endothelial mechanisms. Furthermore, septic patients showed elevated levels of circulating citrullinated histone H3, indicating that the histone citrullination is produced during the first stages of sepsis, probably due to the NETosis process.

The Genetic Diversity and Dysfunctionality of Catalase Associated with a Worse Outcome in Crohn's Disease.

Chronic gut inflammation in Crohn's disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression.

Identification of circulating miRNAs differentially expressed in patients with Limb-girdle, Duchenne or facioscapulohumeral muscular dystrophies.

BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is a rare neuromuscular disease including a growing and heterogeneous number of subtypes with variable phenotype. Their clinical and histopathological characteristics frequently overlap with other neuromuscular dystrophies. Our goal was to identify, by a non-invasive method, a molecular signature including biochemical and epigenetic parameters with potential value for patient prognosis and stratification. RESULTS: Circulating miRNome was obtained by smallRNA-seq in plasma from LGMD patients (n = 6) and matched-controls (n = 6). Data, validated by qPCR in LGMD samples, were also examined in other common muscular dystrophies: Duchenne (DMD) (n = 5) and facioscapulohumeral muscular dystrophy (FSHD) (n = 4). Additionally, biochemical and clinical parameters were analyzed. miRNome analysis showed that thirteen differentially expressed miRs could separate LGMD vs control group by hierarchical clustering. Most of differentially expressed miRs in LGMD patients were up-regulated (miR-122-5p, miR-122b-3p, miR-6511a-3p, miR-192-5p, miR-574-3p, mir-885-3p, miR-29a-3p, miR-4646-3p, miR-203a-3p and miR-203b-5p) whilst only three of sequenced miRs were significantly down-regulated (miR-19b-3p, miR-7706, miR-323b-3p) when compared to matched controls. Bioinformatic analysis of target genes revealed cell cycle, muscle tissue development, regeneration and senescence as the most affected pathways. Four of these circulating miRs (miR-122-5p, miR-192-5p, miR-19b-3p and miR-323b-3p), together with the myomiR miR-206, were further analysed by qPCR in LGMD, DMD and FSHD. The receiver operating characteristic curves (ROC) revealed high area under the curve (AUC) values for selected miRs in all groups, indicating that these miRs have good sensitivity and specificity to distinguish LGMD, DMD and FSHD patients from healthy controls. miR-122-5p, miR-192-5p and miR-323-3p were differentially expressed compared to matched-controls in all groups but apparently, each type of muscular dystrophy showed a specific pattern of miR expression. Finally, a strong correlation between miRs and biochemical data was only found in LGMD patients: while miR-192-5p and miR-122-5p negatively correlated with CK, miR-192-5p positively correlated with vitamin D3 and ALP. CONCLUSIONS: Although limited by the small number of patients included in this study, we propose here a specific combination of circulating miR-122-5p/miR-192-5p/miR-323-3 and biochemical parameters as a potential molecular signature whose clinical value for LGMD patient prognosis and stratification should be further confirmed in a larger cohort of patients.

Extracellular Histones Activate Endothelial NLRP3 Inflammasome and are Associated with a Severe Sepsis Phenotype.

Introduction: Circulating extracellular histones acquire relevance as cytotoxic mediators in sepsis. Extracellular histones act as damage-associated molecular patterns (DAMPs), which induce oxidative stress and NLRP3 inflammasome activation. Inflammasome mediates pyroptosis, a programmed cell death mechanism that produces inflammation. Despite evidence for inflammasome activation in immune cells during sepsis, it was unknown whether extracellular histones can produce endothelial inflammasomes activation. Methods: We used human umbilical vein endothelial cells (HUVEC) to explore the activation of pyroptosis, endothelial function and inflammation by extracellular histones. We evaluated pyroptosis by flow cytometry, caspase-1 activity assay, and gene and protein expression analysis by RT-qPCR and Western blot, respectively. The upstream molecular responses involved in pyroptosis activation by extracellular histones were validated by means of using antioxidant glutathione ethyl ester and NLRP3 inflammasome inhibitors. Finally, using mass spectrometry, we measured circulating histones in blood from critically-ill patients and demonstrated that circulating histone levels correlated with the expression of pyroptosis-related cytokines, the release of endothelial adhesion factors and septic shock severity. Results: We found that extracellular histones mediate the activation of NLRP3 inflammasome and pyroptosis in endothelial cells by contributing to endothelial dysfunction and the dysregulation of the immune response mediated by endothelium. Likewise, we demonstrated how the hyperacetylation of extracellular histones or the use of antioxidants decreased pyroptosis. In addition, we showed that pyroptosis is a feasible process occurring in septic shock patients. Discussion: Circulating histone levels correlated with the expression of pro-inflammatory and pyroptosis-related cytokines, the release of endothelial adhesion factors and septic shock severity. We propose to block histone-mediated pyroptosis as a feasible therapeutic strategy in sepsis.

Use of Circular RNAs in Diagnosis, Prognosis and Therapeutics of Renal Cell Carcinoma.

Renal cell carcinoma is the most common type of kidney cancer, representing 90% of kidney cancer diagnoses, and the deadliest urological cancer. While the incidence and mortality rates by renal cell carcinoma are higher in men compared to women, in both sexes the clinical characteristics are the same, and usually unspecific, thereby hindering and delaying the diagnostic process and increasing the metastatic potential. Regarding treatment, surgical resection remains the main therapeutic strategy. However, even after radical nephrectomy, metastasis may still occur in some patients, with most metastatic renal cell carcinomas being resistant to chemotherapy and radiotherapy. Therefore, the identification of new biomarkers to help clinicians in the early detection, and treatment of renal cell carcinoma is essential. In this review, we describe circRNAs related to renal cell carcinoma processes reported to date and propose the use of some in therapeutic strategies for renal cell carcinoma treatment.

Neurodevelopmental Outcome and Epigenetic Changes at 2 Years Associated with the Oxygen Load Received upon Postnatal Stabilization: A Pilot Study.

INTRODUCTION: The oxygen load provided to preterm infants during postnatal stabilization caused significant modifications of DNA methylation in the preterm epigenome. We aimed to assess if there was an association between DNA methylation changes and neurodevelopmental outcomes. METHODS: Preterm infants were followed until 2 years after birth. Dried blood spots were processed, and DNA methylation was measured using the MassARRAY technology of Sequenom. We selected specific genes that corresponded to differentially methylated CpG sites that correlated with the oxygen load at 2 h after birth. Neurodevelopmental outcome was blindly assessed using Bayley-III scale. RESULTS: Of 32 eligible patients, we completed the methylation analysis in 19 patients and the neurodevelopmental evaluation in 22. Comparison of differential methylation analysis between time 0 (cord blood) and 2 h after birth showed 74 significant CpGs, out of which 14 correlated with the oxygen load received at birth. Out of these 14 genes, only TRAPPC9 showed statistically significant differences at 2 years of age between the infants who received >500 mL versus <500 mL O2/kg. Premature who received >500 mL O2/kg showed significantly lower motor composite scores. DISCUSSION/CONCLUSIONS: Premature who received higher oxygen load scored lower motor composite scores and showed a hypermethylation pattern of TRAPPC9 at 2 years of age. TRAPPC9 mutations are associated with neurodevelopmental delay and intellectual disability, so changes in the CpG methylation of this gene and its subsequent expression alteration can produce a similar phenotype. Further studies with a greater sample size are needed to confirm these findings.

MicroRNA-132 is overexpressed in fetuses with late-onset fetal growth restriction.

Background and Aims: To evaluate the expression of microRNA 132 (miR-132) in fetuses with normal growth and in fetuses with late-onset growth restriction (FGR). Methods: In a prospective cohort study, 48 fetuses (24 with late-onset FGR and 24 with normal growth) were scanned with Doppler ultrasound after 34 weeks to measure the umbilical artery and middle cerebral artery pulsatility indices and followed until birth. Subsequently, blood samples from the umbilical cord were collected to evaluate the expression of miR-132 by means of Real-time quantitative polymerase chain reaction, determining the existence of normality cut-offs and associations with birth weight (BW) centile, cerebroplacental ratio multiples of the median (CPR MoM), and intrapartum fetal compromise (IFC). Results: In comparison with normal fetuses, late-onset FGR fetuses showed upregulation of miR-132 (33.94 ± 45.04 vs. 2.88 ± 9.32 2-ddC t, p < 0.001). Using 5 as a cut-off we obtained a sensitivity of 50% and a specificity of 96% for the diagnosis of FGR, while for IFC these values were respectively 27% and 73%. Expression of miR-132 was associated with BW centile but not with CPR MoM. Finally, the best detection of IFC was achieved combining miR-132 expression and CPR MoM (AUC = 0.69, p < 0.05). Conclusion: Fetuses with late-onset FGR show upregulation of miR-132. Further studies are needed to investigate the role of miR-132 in the management of late-onset FGR.

Characterization of Early Peripheral Immune Responses in Patients with Sepsis and Septic Shock.

(1) Background: Sepsis is a life-threatening condition caused by an abnormal host response to infection that produces altered physiological responses causing tissue damage and can result in organ dysfunction and, in some cases, death. Although sepsis is characterized by a malfunction of the immune system leading to an altered immune response and immunosuppression, the high complexity of the pathophysiology of sepsis requires further investigation to characterize the immune response in sepsis and septic shock. (2) Methods: This study analyzes the immune-related responses occurring during the early stages of sepsis by comparing the amounts of cytokines, immune modulators and other endothelial mediators of a control group and three types of severe patients: critically ill non-septic patients, septic and septic shock patients. (3) Results: We showed that in the early stages of sepsis the innate immune system attempts to counteract infection, probably via neutrophils. Conversely, the adaptive immune system is not yet fully activated, either in septic or in septic shock patients. In addition, immunosuppressive responses and pro-coagulation signals are active in patients with septic shock. (4) Conclusions: The highest levels of IL-6 and pyroptosis-related cytokines (IL-18 and IL-1α) were found in septic shock patients, which correlated with D-dimer. Moreover, endothelial function may be affected as shown by the overexpression of adhesion molecules such as s-ICAM1 and E-Selectin during septic shock.

The Endothelial Glycocalyx and Neonatal Sepsis.

Sepsis carries a substantial risk of morbidity and mortality in newborns, especially preterm-born neonates. Endothelial glycocalyx (eGC) is a carbohydrate-rich layer lining the vascular endothelium, with important vascular barrier function and cell adhesion properties, serving also as a mechano-sensor for blood flow. eGC shedding is recognized as a fundamental pathophysiological process generating microvascular dysfunction, which in turn contributes to multiple organ failure and death in sepsis. Although the disruption of eGC and its consequences have been investigated intensively in the adult population, its composition, development, and potential mechanisms of action are still poorly studied during the neonatal period, and more specifically, in neonatal sepsis. Further knowledge on this topic may provide a better understanding of the molecular mechanisms that guide the sepsis pathology during the neonatal period, and would increase the usefulness of endothelial glycocalyx dysfunction as a diagnostic and prognostic biomarker. We reviewed several components of the eGC that help to deeply understand the mechanisms involved in the eGC disruption during the neonatal period. In addition, we evaluated the potential of eGC components as biomarkers and future targets to develop therapeutic strategies for neonatal sepsis.