Stereotactic Radiotherapy for penile metastasis: case report and systematic literature review.

Introduction Penile metastases (PM) are a rare clinical presentation mainly related to advanced stages of disease. Considering the low incidence, an optimal treatment approach has not yet been defined; surgery, chemotherapy, and radiotherapy are different options used in the vast majority with palliative intent. The advances in modern RT can represent an innovative tool in PM management and a curative option. This paper aims to report the case of a PM patient treated with Stereotactic Body Radiotherapy (SBRT) and perform a systematic literature review of current evidence on the RT approach to PM. Case report We reported the case of an 80-year-old patient with PM from primary bladder cancer. Following the surgical approach for the primary tumor, evidence of PM was shown, and the patient was admitted to SBRT treatment on PM after an adjuvant RT course on the pelvis. A 25 Gy in 5 fractions SBRT treatment was performed, and a complete clinical response was shown at the first follow-up. Methods A Pubmed/MEDLINE and Embase systematic review was carried out. The search strategy terms were [('penile metastasis'/exp OR 'penile metastasis' OR (penile AND ('metastasis'/exp OR metastasis))) AND ('radiotherapy'/exp OR radiotherapy)] and only original articles up to the 24.10.2023 were considered. Results A total of 174 studies were obtained using the previously mentioned search strategy, and the analysis was performed on 15 papers obtained following the complete selection process. All reported evidence was focused on the palliative approach of PM showing good results in terms of symptom control. Discussion The potential role of modern RT in the management of PM has yet to be defined. The reported case showed the feasibility and the clinical impact of SBRT in PM treatment.

CD38 restrains the activity of extracellular cGAMP in a model of multiple myeloma.

2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is the endogenous agonist of STING; as such, cGAMP has powerful immunostimulatory activity, due to its capacity to stimulate type I interferon-mediated immunity. Recent evidence indicates that cancer cells, under certain conditions, can release cGAMP extracellularly, a phenomenon currently considered important for therapeutic responses and tumor rejection. Nonetheless, the mechanisms that regulate cGAMP activity in the extracellular environment are still largely unexplored. In this work, we collected evidence demonstrating that CD38 glycohydrolase can inhibit extracellular cGAMP activity through its direct binding. We firstly used different cell lines and clinical samples to demonstrate a link between CD38 and extracellular cGAMP activity; we then performed extensive in silico molecular modeling and cell-free biochemical assays to show a direct interaction between the catalytic pocket of CD38 and cGAMP. Altogether, our findings expand the current knowledge about the regulation of cGAMP activity.

Split Gp41-1 intein splicing as a model to evaluate the cellular location of the oncosuppressor Maspin in an in vitro model of osteosarcoma.

Inteins are proteins involved in the protein splicing mechanism, an autoprocessing event, where sequences (exteins) separated by inteins become ligated each other after recombination. Two kinds of inteins have been described, contiguous inteins and split inteins. The former ones are transcribed and translated as a single peptide along with their exteins, while the latter are fragmented between two different genes and are transcribed and translated separately. The aim of this study is to establish a method to obtain a fluorescent eukaryotic protein to analyze its cellular localization, using the natural split gp41-1 inteins. We chose natural split inteins due to their distribution in all three domains of life. Two constructs were prepared, one containing the N-terminal split intein along with the N-moiety of the Red Fluorescent Protein (RFP) and a second construct containing the C-terminal of split intein, the C-moiety of RFP and the gene coding for Maspin, a tumor suppressor protein. The trans-splicing was verified by transfecting both N-terminal and C-terminal constructs into mammalian cells. The success of the recombination event was highlighted through the fluorescence produced by reconstituted RFP after recombination, along with the overlap of the red fluorescence produced by recombined RFP and the green fluorescence produced by the hybridization of the recombinant Maspin with a specific antibody. In conclusion, we opted to use this mechanism of recombination to obtain a fluorescent Maspin instead to express a large fusion protein, considering that it could interfere with Maspin's structure and function.

Paraneoplastic Cerebellar Degeneration Associated with Breast Cancer: A Case Report and a Narrative Review.

Paraneoplastic neurological syndromes (PNSs) are an uncommon complication of cancer, affecting nearby 1/10,000 subjects with a tumour. PNSs can involve all the central and peripheral nervous systems, the muscular system, and the neuromuscular junction, causing extremely variable symptomatology. The diagnosis of the paraneoplastic disease usually precedes the clinical manifestations of cancer, making an immediate recognition of the pathology crucial to obtain a better prognosis. PNSs are autoimmune diseases caused by the expression of common antigens by the tumour and the nervous system. Specific antibodies can help clinicians diagnose them, but unfortunately, they are not always detectable. Immunosuppressive therapy and the treatment of cancer are the cornerstones of therapy for PNSs. This paper reports a case of PNSs associated with breast tumours and focuses on the most common paraneoplastic neurological syndromes. We report a case of a young female with a clinical syndrome of the occurrence of rigidity in the right lower limb with postural instability with walking supported and diplopia, with a final diagnosis of paraneoplastic cerebellar degeneration and seronegative rigid human syndrome associated with infiltrating ductal carcinoma of the breast.

Recent Developments in Nanoparticle Formulations for Resveratrol Encapsulation as an Anticancer Agent.

Resveratrol is a polyphenolic compound that has gained considerable attention in the past decade due to its multifaceted therapeutic potential, including anti-inflammatory and anticancer properties. However, its anticancer efficacy is impeded by low water solubility, dose-limiting toxicity, low bioavailability, and rapid hepatic metabolism. To overcome these hurdles, various nanoparticles such as organic and inorganic nanoparticles, liposomes, polymeric nanoparticles, dendrimers, solid lipid nanoparticles, gold nanoparticles, zinc oxide nanoparticles, zeolitic imidazolate frameworks, carbon nanotubes, bioactive glass nanoparticles, and mesoporous nanoparticles were employed to deliver resveratrol, enhancing its water solubility, bioavailability, and efficacy against various types of cancer. Resveratrol-loaded nanoparticle or resveratrol-conjugated nanoparticle administration exhibits excellent anticancer potency compared to free resveratrol. This review highlights the latest developments in nanoparticle-based delivery systems for resveratrol, focusing on the potential to overcome limitations associated with the compound's bioavailability and therapeutic effectiveness.

The Role of the Cumulative Illness Rating Scale (CIRS) in Estimating the Impact of Comorbidities on Chronic Obstructive Pulmonary Disease (COPD) Outcomes: A Pilot Study of the MACH (Multidimensional Approach for COPD and High Complexity) Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous systemic syndrome that often coexists with multiple comorbidities. In highly complex COPD patients, the role of the Cumulative Illness Rating Scale (CIRS) as a risk predictor of COPD exacerbation is not known. OBJECTIVE: The objective of this study was determine the effectiveness of the CIRS score in detecting the association of comorbidities and disease severity with the risk of acute exacerbations in COPD patients. METHODS: In total, 105 adults with COPD (mean age 72.1 ± 9.0 years) were included in this prospective study. All participants at baseline had at least two moderate exacerbations or one leading to hospitalization. The primary outcome was a composite of moderate or severe COPD exacerbation during the 12 months of follow-up. RESULTS: The CIRS indices (CIRS total score, Severity Index and Comorbidity Index) showed a positive correlation with modified Medical Research Council (mMRC), COPD assessment test (CAT) and a negative correlation with forced expiratory volume in the first second (FEV1), Forced Vital Capacity (FVC), and FEV1/FVC. The three CIRS indices were able to predict the 12-month rate of moderate or severe exacerbation (CIRS Total Score: Hazard Ratio (HR) = 1.12 (95% CI: 1.08-1.21); CIRS Severity Index: HR = 1.21 (95% CI: 1.12-1.31); CIRS Comorbidity Index = 1.58 (95% CI: 1.33-1.89)). CONCLUSIONS: Among patients with COPD, the comorbidity number and severity, as assessed by the CIRS score, influence the risk in moderate-to-severe exacerbations. The CIRS score also correlates with the severity of respiratory symptoms and lung function.

Artificial Intelligence for Classifying the Relationship between Impacted Third Molar and Mandibular Canal on Panoramic Radiographs.

The purpose of this investigation was to evaluate the diagnostic performance of two convolutional neural networks (CNNs), namely ResNet-152 and VGG-19, in analyzing, on panoramic images, the rapport that exists between the lower third molar (MM3) and the mandibular canal (MC), and to compare this performance with that of an inexperienced observer (a sixth year dental student). Utilizing the k-fold cross-validation technique, 142 MM3 images, cropped from 83 panoramic images, were split into 80% as training and validation data and 20% as test data. They were subsequently labeled by an experienced radiologist as the gold standard. In order to compare the diagnostic capabilities of CNN algorithms and the inexperienced observer, the diagnostic accuracy, sensitivity, specificity, and positive predictive value (PPV) were determined. ResNet-152 achieved a mean sensitivity, specificity, PPV, and accuracy, of 84.09%, 94.11%, 92.11%, and 88.86%, respectively. VGG-19 achieved 71.82%, 93.33%, 92.26%, and 85.28% regarding the aforementioned characteristics. The dental student's diagnostic performance was respectively 69.60%, 53.00%, 64.85%, and 62.53%. This work demonstrated the potential use of deep CNN architecture for the identification and evaluation of the contact between MM3 and MC in panoramic pictures. In addition, CNNs could be a useful tool to assist inexperienced observers in more accurately identifying contact relationships between MM3 and MC on panoramic images.

Metabolic memory in diabetic foot syndrome (DFS): MICRO-RNAS, single nucleotide polymorphisms (SNPs) frequency and their relationship with indices of endothelial function and adipo-inflammatory dysfunction.

BACKGROUND: Diabetic foot is a significant cause of morbidity in diabetic patients, with a rate that is approximately twice that of patients without foot ulcers. "Metabolic memory" represents the epigenetic changes induced by chronic hyperglycaemia, despite the correction of the glucose levels themselves. These epigenetic modifications appear to perpetuate the damage caused by persistently elevated glucose levels even in their absence, acting at various levels, mostly affecting the molecular processes of diabetic ulcer healing. METHODS: The aim of our cross-sectional study was to analyse a cohort of patients with diabetes with and without lower limb ulcers. We examined the effects of epigenetic changes on miRNA 126, 305, and 217 expression and the frequency of the SNPs of genes encoding inflammatory molecules (e.g., IL-6 and TNF-alpha) and their correlations with serum levels of proangiogenic molecules (e.g., ENOS, VEGF and HIF-1alpha) and several adipokines as well as with endothelial dysfunction, assessed noninvasively by reactive hyperaemia peripheral artery tonometry. Between March 2021 and June 2022, 110 patients were enrolled into the study: 50 diabetic patients with diabetic foot injuries, 40 diabetic patients without ulcerative complications and 20 nondiabetic patients as the control group. RESULTS: Diabetic subjects with lower limb ulcerative lesions exhibited higher levels of inflammatory cytokines, such as VEGF (191.40 ± 200 pg/mL vs. 98.27 ± 56.92 pg/mL vs. 71.01 ± 52.96 pg/mL; p = 0.22), HIF-1alpha (40.18 ± 10.80 ng/mL vs. 33.50 ± 6.16 ng/mL vs. 33.85 ± 6.84 ng/mL; p = 0.10), and Gremlin-1 (1.72 ± 0.512 ng/mL vs. 1.31 ± 0.21 ng/mL vs. 1.11 ± 0.19 ng/mL; p < 0.0005), than those without lower limb ulcers and healthy controls. Furthermore, we observed that miR-217-5p and miR-503-5p were 2.19-fold (p < 0.05) and 6.21-fold (p = 0.001) more highly expressed in diabetic foot patients than in healthy controls, respectively. Additionally, diabetic patients without lower limb ulcerative complications showed 2.41-fold (p = 0) and 2.24-fold (p = 0.029) higher expression of miR-217-5p and miR-503-5p, respectively, than healthy controls. Finally, diabetic patients with and without ulcerative complications of the lower limbs showed higher expression of the VEGFC2578A CC polymorphism (p = 0.001) and lower expression of the VEGFC2578A AC polymorphism (p < 0.005) than the healthy control population. We observed a significant increase in Gremlin-1 levels in patients with diabetic foot, suggesting that this inflammatory adipokine may serve as a predictive marker for the diagnosis of diabetic foot. CONCLUSIONS: Our results highlighted that patients with diabetic foot showed predominant expression of the VEGF C2578A CC polymorphism and reduced expression of the AC allele. Additionally, we found an overexpression of miR-217-5p and miR-503-5p in diabetic patients with and without diabetic foot syndrome compared with healthy controls. These results align with those reported in the literature, in which the overexpression of miR-217-5p and miR-503-5p in the context of diabetic foot is reported. The identification of these epigenetic modifications could therefore be helpful in the early diagnosis of diabetic foot and the treatment of risk factors. However, further studies are necessary to confirm this hypothesis.

Platelet­to­lymphocyte ratio, neutrophil­to­lymphocyte ratio and monocyte­to­HDL cholesterol ratio as helpful biomarkers for patients hospitalized for deep vein thrombosis.

There is an increased interest for novel biomarkers in order to improve the diagnostic accuracy for deep vein thrombosis (DVT). Moreover, the link between inflammation and venous thromboembolism has attracted increasing research interests. The present study aimed to evaluate the role of the platelet­to­lymphocyte ratio (PLR), neutrophil­to­lymphocyte ratio (NLR) and monocyte­to­high­density lipoprotein cholesterol ratio (MHR) as biomarkers for acute DVT. For this purpose, 300 consecutive patients who were hospitalized were considered; 33 patients out of the 300 were admitted for acute DVT of the lower limbs. The PLR, NLR and MHR, as well as the acute phase inflammation markers (leukocytes, neutrophils, C­reactive protein and fibrinogen) were measured. The patients with DVT exhibited significantly higher levels of PLR, NLR and MHR compared to those without DVT (P<0.001). Simple binary linear regression analysis (without confounding factors) between the NLR, PLR and MHR highest quartile and DVT revealed an odds ratio of 3.149 (P=0.01) for PLR, and an odds ratio of 4.191 (P=0.001) for MHR. Following the correction for the main confounding factors, PLR maintained a significant association with DVT (odds ratio, 3.379; P=0.007) and MHR maintained a stronger significant association with DVT (odds ratio, 4.378; P=0.001). It was thus hypothesized that the assessment of PLR and MHR, but not of NLR may help clinicians to improve the laboratory evaluation in elderly hospitalized patients with suspected DVT.

Anti-Arthritic and Anti-Cancer Activities of Polyphenols: A Review of the Most Recent In Vitro Assays.

Polyphenols have gained widespread attention as they are effective in the prevention and management of various diseases, including cancer diseases (CD) and rheumatoid arthritis (RA). They are natural organic substances present in fruits, vegetables, and spices. Polyphenols interact with various kinds of receptors and membranes. They modulate different signal cascades and interact with the enzymes responsible for CD and RA. These interactions involve cellular machinery, from cell membranes to major nuclear components, and provide information on their beneficial effects on health. These actions provide evidence for their pharmaceutical exploitation in the treatment of CD and RA. In this review, we discuss different pathways, modulated by polyphenols, which are involved in CD and RA. A search of the most recent relevant publications was carried out with the following criteria: publication date, 2012-2022; language, English; study design, in vitro; and the investigation of polyphenols present in extra virgin olive, grapes, and spices in the context of RA and CD, including, when available, the underlying molecular mechanisms. This review is valuable for clarifying the mechanisms of polyphenols targeting the pathways of senescence and leading to the development of CD and RA treatments. Herein, we focus on research reports that emphasize antioxidant properties.

Heart rate variability is associated with disease severity and portal hypertension in cirrhosis.

INTRODUCTION: Autonomic nervous system activity in cirrhotic portal hypertension is linked to hyperdynamic circulation. Heart rate variability (HRV) is a validated noninvasive method to assess the sympathovagal balance. To investigate the correlation between HRV parameters and degree of portal hypertension, we studied a cohort of patients with cirrhosis accounting for etiology and treatments. PATIENTS AND METHODS: In this cross-sectional, observational cohort study, 157 outpatients of both sex with nonalcoholic cirrhosis were assessed by upper gastrointestinal endoscopy to search for esophagogastric varices. Twenty-four-hour electrocardiogram Holter monitoring with 3 HRV parameters measurement [SD of the NN intervals, root mean square successive difference of NN intervals, and SD of the averages of NN intervals (SDANN)] according to time-domain analysis were performed in all patients. Sixteen patients with large esophagogastric varices underwent measurements of the HVPG and assessment of HRV parameters at baseline and after 45 days on carvedilol. RESULTS: The liver dysfunction, expressed by Child-Pugh class or MELD score, was directly related to root mean square successive difference of NN intervals and inversely related to SDANN. Presence of ascites was inversely related to SDANN and to SD of the NN intervals. Treatment with carvedilol had an inverse relation with SDANN. Presence and size of esophagogastric varices had an inverse relation to SDANN and SD of the NN intervals. Upon multivariate analysis the associations between SDANN and Child-Pugh class, size of varices and ascites were confirmed. In the subgroup of 16 patients undergoing HVPG measurement, pressure gradient was unrelated to heart rate and HRV parameters. CONCLUSIONS: Time-domain HRV parameters in patients with cirrhosis, confirm the autonomic nervous system alteration, and their correlation to the degree of portal hypertension suggesting a role of the ANS in hepatic decompensation.

Vascular health in subjects with rheumatoid arthritis: assessment of endothelial function indices and serum biomarkers of vascular damage.

BACKGROUND: The cardiovascular risk (CVD) in patients with rheumatoid arthritis (RA) is 1.5-2 times higher than that in individuals of the same age and sex. AIMS: To analyse the degree of endothelial dysfunction, the atherogenic immunoinflammatory serum background and the relationships among some vascular indices, cardiovascular comorbidities, and cognitive performance in subjects with RA. PATIENTS AND METHODS: All consecutive patients with a rheumatoid arthritis diagnosis admitted to the Rheumatology Ward of "Policlinico Paolo Giaccone" Hospital of Palermo were enrolled from July 2019 to September 2020. We evaluated our patients' cognitive functions by administering the Mini-Mental State Examination (MMSE). Reactive Hyperaemia Index (RHI) was evaluated for assessment of endothelial function. Serum levels of angiopoietin 2, osteopontin and pentraxin 3 were assessed by blood collection. RESULTS: Fifty-eight consecutive patients with RA and 40 control subjects were analysed. RA patients showed significantly lower mean RHI values, significantly higher mean Augmentation Index (AIX) values and significantly lower mean Mini-Mental State Examination (MMSE) score values than the control group. Patients with rheumatoid arthritis also showed higher mean serum values of pentraxin 3 and angiopoietin 2 than healthy controls. Multivariate logistic regression analysis showed a significant association between pentraxin 3 and angiopoietin 2 and the presence of RA. DISCUSSION: Angiopoietin 2 and pentraxin 3 could be considered surrogate biomarkers of endothelial activation and vascular disease, as they could play an essential role in the regulation of endothelial integrity and inflammation.

Echocardiographic Evaluation of the Cardiac Chambers in Asthmatic Patients: The BADA (Blood Pressure Levels, Clinical Features and Markers of Subclinical Cardiovascular Damage of Asthma Patients) Study-ECO.

The "Blood pressure levels, clinical features and markers of subclinical cardiovascular Damage of Asthma patients" (BADA) study is aimed at defining the cardiovascular risk profile and the markers of subclinical and clinical vascular and cardiac damage in asthmatic patients. Very few studies have assessed asthmatic patients without concomitant heart disease through a transthoracic echocardiogram. The goal of the present study is to investigate the prevalence of morphology and/or function changes in the cardiac chambers of a sample of 86 patients with chronic asthma, referred to the dedicated outpatient unit of the Division of Respiratory Diseases of the AOUP "P. Giaccone" of the University of Palermo, and the results obtained were compared with those of a control group without respiratory or cardiovascular diseases. Patients with asthma showed a marked and widespread involvement of the four cardiac chambers compared with the controls: enlargement of the two atria, greater left ventricular remodeling with interventricular septal thickening, increased indexed left ventricular mass with a significantly greater percentage of patients with overt left ventricular hypertrophy, worse left ventricular diastolic function proven by the significant difference in the E/A ratio, and worse right ventricular systolic function with global right ventricular dysfunction estimated by the Myocardial Performance Index (Tei Index). Multivariate regression analysis, after adjustment for essential hypertension, hypertension severity, diabetes, Body Mass Index, and creatinine clearance, seems to indicate that the indexed left ventricular mass, right atrial volume, and right ventricular Tei index (but not left ventricular hypertrophy) correlate significantly with asthma, severe asthma, and FEV1 (and to a lesser extent with asthma duration). No correlation is apparent between inhaled therapy (ICS, SABA) and myocardial involvement. These results seem to confirm that a more in-depth cardiovascular evaluation in patients with chronic respiratory disease allows the identification of unrecognized cardiovascular involvement. A transthoracic echocardiogram performed in asthmatic patients without clinically overt signs or symptoms of cardiovascular impairment has identified some features indicative of an early subclinical cardiac impairment not found in the control group. These findings, considering also the higher frequency of hypertension in the asthma group, deserve further validation in the future.

Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.

Effects of Mediterranean Diet Combined with CrossFit Training on Trained Adults' Performance and Body Composition.

CrossFit is a high-intensity training discipline increasingly practiced in recent years. Specific nutritional approaches are usually recommended to maximize performance and improve body composition in high-intensity training regimens; notwithstanding, to date there are no targeted nutritional recommendations for CrossFit athletes. The Mediterranean Diet (MD) is a diet approach with a well-designed proportion of macronutrients, using only available/seasonal food of the Mediterranean area, whose health benefits are well demonstrated. No studies have evaluated this dietary strategy among CrossFit athletes and practitioners; for this reason, we tested the effects of 8 weeks of MD on CrossFit athletes' performance and body composition. Participants were assigned to two groups: a diet group (DG) in which participants performed CrossFit training plus MD, and a control group (CG) in which participants partook in the CrossFit training, continuing their habitual diet. Participants were tested before and after the 8 weeks of intervention. At the end of the study, no significant difference was noted in participants' body composition, whereas improvements in anaerobic power, explosive strength of the lower limbs, and CrossFit-specific performance were observed only in the DG. Our results suggest that adopting a MD in CrossFit athletes/practitioners could be a useful strategy to improve specific strength, endurance, and anaerobic capacity while maintaining overall body composition.

Precision Medicine for Chronic Diseases: Focus on Lifestyle Changes.

Virtually all chronic diseases are sustained by lifestyle factors [...].

Non-Coding RNA Networks as Potential Novel Biomarker and Therapeutic Target for Sepsis and Sepsis-Related Multi-Organ Failure.

According to "Sepsis-3" consensus, sepsis is a life-threatening clinical syndrome caused by a dysregulated inflammatory host response to infection. A rapid identification of sepsis is mandatory, as the extent of the organ damage triggered by both the pathogen itself and the host's immune response could abruptly evolve to multiple organ failure and ultimately lead to the death of the patient. The most commonly used therapeutic strategy is to provide hemodynamic and global support to the patient and to rapidly initiate broad-spectrum empiric antibiotic therapy. To date, there is no gold standard diagnostic test that can ascertain the diagnosis of sepsis. Therefore, once sepsis is suspected, the presence of organ dysfunction can be assessed using the Sepsis-related Organ Failure Assessment (SOFA) score, although the diagnosis continues to depend primarily on clinical judgment. Clinicians can now rely on several serum biomarkers for the diagnosis of sepsis (e.g., procalcitonin), and promising new biomarkers have been evaluated, e.g., presepsin and adrenomedullin, although their clinical relevance in the hospital setting is still under discussion. Non-codingRNA, including long non-codingRNAs (lncRNAs), circularRNAs (circRNAs) and microRNAs (miRNAs), take part in a complex chain of events playing a pivotal role in several important regulatory processes in humans. In this narrative review we summarize and then analyze the function of circRNAs-miRNA-mRNA networks as putative novel biomarkers and therapeutic targets for sepsis, focusing only on data collected in clinical settings in humans.

Exploring CCRL2 chemerin binding using accelerated molecular dynamics.

Chemokine (C-C motif) receptor-like 2 (CCRL2), is a seven transmembrane receptor closely related to the chemokine receptors CCR1, CCR2, CCR3, and CCR5. Nevertheless, CCRL2 is unable to activate conventional G-protein dependent signaling and to induce cell directional migration. The only commonly accepted CCRL2 ligand is the nonchemokine chemotactic protein chemerin (RARRES2). The chemerin binding to CCLR2 does induce leukocyte chemotaxis, yet, genetic targeting of CCRL2 was shown to modulate the inflammatory response in different experimental models. This mechanism was shown to be crucial for lung dendritic cell migration, neutrophil recruitment, and Natural Killer cell-dependent immune surveillance in lung cancer. To gain more insight in the interactions involved in the CCRL2-chemerin, the binding complexes were generated by protein-protein docking, then submitted to accelerated molecular dynamics. The obtained trajectories were inspected by principal component analyses followed by kernel density estimation to identify the ligand-receptor regions most frequently involved in the binding. To conclude, the reported analyses led to the identification of the putative hot-spot residues involved in CCRL2-chemerin binding.