Search

Background: The literature lacks a combined analysis of neurosurgical microvascular anastomosis training models. We performed a systematic literature search to provide an overview of the existing models and proposed a classification system based on the level of simulation and reproducibility of the microvascular anastomosis., Methods: The systematic literature search followed the PRISMA guidelines. We consulted MEDLINE, Web of Knowledge, and EMBASE independently for papers about bypass training models. Every training model was analyzed according to six tasks supposed to esteem their fidelity to the real operative setting by using a scoring system from zero to two. Finally, authors classified the models into five classes, from A to E, by summing the individual scores., Results: This study included 109 papers for analysis. Training models were grouped into synthetic tubes, ex vivo models (animal vessels, fresh human cadavers, human placentas) and in vivo simulators (live animals-rats, rabbits, pigs). By applying the proposed classification system, live animals and placentas obtained the highest scores, falling into class A (excellent simulators). Human cadavers and animal vessels (ex vivo) were categorized in class B (good simulators), followed by synthetic tubes (class C, reasonable simulators)., Conclusions: The proposed classification system helps the neurosurgeon to analyze the available training models for microvascular anastomosis critically, and to choose the most appropriate one according to the skills they need to improve.

The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans. Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts.

The abscisic acid (ABA)/LANC-like protein 1/2 (LANCL1/2) hormone/receptor system regulates glucose uptake and oxidation, mitochondrial respiration, and proton gradient dissipation in myocytes. Oral ABA increases glucose uptake and the transcription of adipocyte browning-related genes in rodent brown adipose tissue (BAT). The aim of this study was to investigate the role of the ABA/LANCL system in human white and brown adipocyte thermogenesis. Immortalized human white and brown preadipocytes, virally infected to overexpress or silence LANCL1/2, were differentiated in vitro with or without ABA, and transcriptional and metabolic targets critical for thermogenesis were explored. The overexpression of LANCL1/2 increases, and their combined silencing conversely reduces mitochondrial number, basal, and maximal respiration rates; proton gradient dissipation; and the transcription of uncoupling genes and of receptors for thyroid and adrenergic hormones, both in brown and in white adipocytes. The transcriptional enhancement of receptors for browning hormones also occurs in BAT from ABA-treated mice, lacking LANCL2 but overexpressing LANCL1. The signaling pathway downstream of the ABA/LANCL system includes AMPK, PGC-1α, Sirt1, and the transcription factor ERRα. The ABA/LANCL system controls human brown and "beige" adipocyte thermogenesis, acting upstream of a key signaling pathway regulating energy metabolism, mitochondrial function, and thermogenesis.

Abscisic acid (ABA), long known as a plant stress hormone, is present and functionally active in organisms other than those pertaining to the land plant kingdom, including cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. The ancient, cross-kingdom role of this stress hormone allows ABA and its signaling pathway to control cell responses to environmental stimuli in diverse organisms such as marine sponges, higher plants, and humans. Recent advances in our knowledge about the physiological role of ABA and of its mammalian receptors in the control of energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells allow us to foresee therapeutic applications for ABA in the fields of pre-diabetes, diabetes, and cardio- and neuro-protection. Vegetal extracts titrated in their ABA content have shown both efficacy and tolerability in preliminary clinical studies. As the prevalence of glucose intolerance, diabetes, and cardiovascular and neurodegenerative diseases is steadily increasing in both industrialized and rapidly developing countries, new and cost-efficient therapeutics to combat these ailments are much needed to ensure disease-free aging for the current and future working generations.

Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia.

ADP-ribosyl cyclases (ADPRCs) catalyze the synthesis of the Ca 2+ -active second messengers Cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD + as well as nicotinic acid adenine dinucleotide phosphate (NAADP + ) from NADP + . The best characterized ADPRC in mammals is CD38, a single-pass transmembrane protein with two opposite membrane orientations. The first identified form, type II CD38, is a glycosylated ectoenzyme, while type III CD38 has its active site in the cytosol. The ectoenzymatic nature of type II CD38 raised long ago the question of a topological paradox concerning the access of the intracellular NAD + substrate to the extracellular active site and of extracellular cADPR product to its intracellular receptors, ryanodine (RyR) channels. Two different transporters, equilibrative connexin 43 (Cx43) hemichannels for NAD + and concentrative nucleoside transporters (CNTs) for cADPR, proved to mediate cell-autonomous trafficking of both nucleotides. Here, we discussed how type II CD38, Cx43 and CNTs also play a role in mediating several paracrine processes where an ADPRC + cell supplies a neighboring CNT-and RyR-expressing cell with cADPR. Recently, type II CD38 was shown to start an ectoenzymatic sequence of reactions from NAD + /ADPR to the strong immunosuppressant adenosine; this paracrine effect represents a major mechanism of acquired resistance of several tumors to immune checkpoint therapy.

Abscisic acid (ABA), a plant hormone, has recently been shown to play a role in glycemia regulation in mammals, by stimulating insulin-independent glucose uptake and metabolism in skeletal muscle. The aim of this study was to test whether ABA could improve glycemic control in a murine model of type 1 diabetes (T1D). Mice were rendered diabetic with streptozotocin and the effect of ABA administration, alone or with insulin, was tested on glycemia. Diabetic mice treated with a single oral dose of ABA and low-dose subcutaneous insulin showed a significantly reduced glycemia profile compared with controls treated with insulin alone. In diabetic mice treated for four weeks with ABA, the effect of low-dose insulin on the glycemia profile after glucose load was significantly improved, and transcription both of the insulin receptor, and of glycolytic enzymes in muscle, was increased. Moreover, a significantly increased transcription and protein expression of AMPK, PGC1-α, and GLUT4 was observed in the skeletal muscle from diabetic mice treated with ABA, compared with untreated controls. ABA supplementation in conjunction with insulin holds the promise of reducing the dose of insulin required in T1D, reducing the risk of hypoglycemia, and improving muscle insulin sensitivity and glucose consumption.

Objectives: The present systematic review and meta-analysis aims to analyse the clinical performance of short compared to longer implants inserted in sites without the need for bone augmentation., Methods: The protocol of the present PRISMA-driven meta-analysis was registered on PROSPERO (CRD42021264781). Electronic and manual searches were performed up to January 2022. All Randomized Controlled Trials (RCTs) comparing short (≤6 mm) to longer (≥8.5 mm) implants placed in non-atrophic and non-augmented sites were included. The quality of the included studies was assessed using the Cochrane risk of bias tool for randomized clinical trials (RoB 2) and the quality of evidence was determined with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. A meta-analysis was performed on implant survival rate, marginal bone level change (MBLc), and technical and biological complications at the available follow-up time points. The power of the meta-analytic findings was determined by trial sequential analysis (TSA)., Results: From 1485 initial records, 13 articles were finally included. No significant difference was found in the survival rate between short and long implant at any follow-up (moderate quality of evidence). Significantly more bone loss for long implants at 1 and 5 years from implant placement and more technical complications with short implants at 10 years were found. No other significant inter-group differences in terms of MBLc and biological complications were detected., Conclusions: Moderate evidence exists suggesting that short implants perform as well as longer ones in the rehabilitation of edentulous sites without the need for bone augmentation. Further long-term, well-designed RCTs, however, are still needed to provide specific evidence-based clinical recommendations for an extended use of short implants in non-atrophic sites.

Diffuse gliomas are the most common primary malignant intracranial neoplasms. Aside from the challenges pertaining to their treatment-glioblastomas, in particular, have a dismal prognosis and are currently incurable-their pre-operative assessment using standard neuroimaging has several drawbacks, including broad differentials diagnosis, imprecise characterization of tumor subtype and definition of its infiltration in the surrounding brain parenchyma for accurate resection planning. As the pathophysiological alterations of tumor tissue are tightly linked to an aberrant vascularization, advanced hemodynamic imaging, in addition to other innovative approaches, has attracted considerable interest as a means to improve diffuse glioma characterization. In the present part A of our two-review series, the fundamental concepts, techniques and parameters of hemodynamic imaging are discussed in conjunction with their potential role in the differential diagnosis and grading of diffuse gliomas. In particular, recent evidence on dynamic susceptibility contrast, dynamic contrast-enhanced and arterial spin labeling magnetic resonance imaging are reviewed together with perfusion-computed tomography. While these techniques have provided encouraging results in terms of their sensitivity and specificity, the limitations deriving from a lack of standardized acquisition and processing have prevented their widespread clinical adoption, with current efforts aimed at overcoming the existing barriers.

Gliomas, and glioblastoma in particular, exhibit an extensive intra- and inter-tumoral molecular heterogeneity which represents complex biological features correlating to the efficacy of treatment response and survival. From a neuroimaging point of view, these specific molecular and histopathological features may be used to yield imaging biomarkers as surrogates for distinct tumor genotypes and phenotypes. The development of comprehensive glioma imaging markers has potential for improved glioma characterization that would assist in the clinical work-up of preoperative treatment planning and treatment effect monitoring. In particular, the differentiation of tumor recurrence or true progression from pseudoprogression, pseudoresponse, and radiation-induced necrosis can still not reliably be made through standard neuroimaging only. Given the abundant vascular and hemodynamic alterations present in diffuse glioma, advanced hemodynamic imaging approaches constitute an attractive area of clinical imaging development. In this context, the inclusion of objective measurable glioma imaging features may have the potential to enhance the individualized care of diffuse glioma patients, better informing of standard-of-care treatment efficacy and of novel therapies, such as the immunotherapies that are currently increasingly investigated. In Part B of this two-review series, we assess the available evidence pertaining to hemodynamic imaging for molecular feature prediction, in particular focusing on isocitrate dehydrogenase (IDH) mutation status, MGMT promoter methylation, 1p19q codeletion, and EGFR alterations. The results for the differentiation of tumor progression/recurrence from treatment effects have also been the focus of active research and are presented together with the prognostic correlations identified by advanced hemodynamic imaging studies. Finally, the state-of-the-art concepts and advancements of hemodynamic imaging modalities are reviewed together with the advantages derived from the implementation of radiomics and machine learning analyses pipelines.

Forkhead box E1 ( FOXE1 ) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1 -induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1 . Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1 -expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1 . These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.

The transcription factor Forkhead box E1 ( FOXE1 ) is a key player in thyroid development and function and has been identified by genome-wide association studies as a susceptibility gene for papillary thyroid cancer. Several cancer-associated polymorphisms fall into gene regulatory regions and are likely to affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression modulate thyroid cancer development has not been investigated. Here, we describe the effects of FOXE1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for FOXE1 null allele ( FOXE1 +/- ) were crossed with a BRAF V600E -inducible cancer model to develop thyroid cancer in either a FOXE1 +/+ or FOXE1 +/- genetic background. In FOXE1 +/+ mice, cancer histological features are quite similar to that of human high-grade papillary thyroid carcinomas, while cancers developed with reduced FOXE1 gene dosage maintain morphological features resembling less malignant thyroid cancers, showing reduced proliferation index and increased apoptosis as well. Such cancers, however, appear severely undifferentiated, indicating that FOXE1 levels affect thyroid differentiation during neoplastic transformation. These results show that FOXE1 dosage exerts pleiotropic effects on thyroid cancer phenotype by affecting histology and regulating key markers of tumor differentiation and progression, thus suggesting the possibility that FOXE1 could behave as lineage-specific oncogene in follicular cell-derived thyroid cancer.

Background and objectives: Periodontitis is a multifactorial chronic inflammatory infectious disease in which an infection is necessary, but not sufficient, for development of the condition. Individual susceptibility strictly linked to the immune and inflammatory response of the organism must also be present. Low-grade inflammation (LGI) is a systemic status of chronic sub-clinical production of inflammatory factors. This condition represents a risk factor for many chronic diseases including diabetes, cardiovascular disease, cerebrovascular disease, neurodegenerative disease and cancer. This scoping review aims to clarify, summarize and disseminate current knowledge on the possible link between periodontitis, LGI and systemic health. Materials and Methods: PRISMA Extension for Scoping Reviews guidelines were followed. An ad-hoc created keyword string was used to search the electronic databases of PubMed/Medline, Embase, The Cochrane Library and ClinicalTrials.gov. A hand search of specialized journals and their reference lists was also performed. Results: 14 studies that respected eligibility criteria were selected and analyzed. There is emerging evidence of strong links between periodontitis, LGI and systemic health. On the one hand, periodontitis influences the systemic status of LGI and on the other hand, the systemic production of inflammatory factors affects periodontitis with a bidirectional connection. Conclusions: LGI and the subsequent onset of a systemic inflammatory phenotype can be considered the common substrate of many chronic inflammatory diseases including periodontitis, with multiple mutual connections between them. Understanding of the biological principles and mechanisms underlying such a complex interrelationship could lead to significant improvements in the field of personalized diagnostics and therapeutic protocols., Competing Interests: The authors declare no conflict of interest.

The combination of enamel matrix derivative (EMD) with an autogenous bone graft in periodontal regeneration has been proposed to improve clinical outcomes, especially in case of deep non-contained periodontal defects, with variable results. The aim of the present systematic review and meta-analysis was to assess the efficacy of EMD in combination with autogenous bone graft compared with the use of EMD alone for the regeneration of periodontal intrabony defects. A literature search in PubMed and in the Cochrane Central Register of Controlled Trials was carried out on February 2019 using an ad-hoc search string created by two independent and calibrated reviewers. All randomized controlled trials (RCTs) comparing a combination of EMD and autogenous bone graft with EMD alone for the treatment of periodontal intrabony defects were included. Studies involving other graft materials were excluded. The requested follow-up was at least 6 months. There was no restriction on age or number of patients. Standard difference in means between test and control groups as well as relative forest plots were calculated for clinical attachment level gain (CALgain), probing depth reduction (PDred), and gingival recession increase (RECinc). Three RCTs reporting on 79 patients and 98 intrabony defects were selected for the analysis. Statistical heterogeneity was detected as significantly high in the analysis of PDred and RECinc (I 2 = 85.28%, p = 0.001; I 2 = 73.95%, p = 0.022, respectively), but not in the analysis of CALgain (I 2 = 59.30%, p = 0.086). Standard difference in means (SDM) for CALgain between test and control groups amounted to -0.34 mm (95% CI -0.77 to 0.09; p = 0.12). SDM for PDred amounted to -0.43 mm (95% CI -0.86 to 0.01; p = 0.06). SDM for RECinc amounted to 0.12 mm (95% CI -0.30 to 0.55. p = 0.57). Within their limits, the obtained results indicate that the combination of enamel matrix derivative and autogenous bone graft may result in non-significant additional clinical improvements in terms of CALgain, PDred, and RECinc compared with those obtained with EMD alone. Several factors, including the surgical protocol used (e.g. supracrestal soft tissue preservation techniques) could have masked the potential additional benefit of the combined approach. Further well-designed randomized controlled trials, with well-defined selection criteria and operative protocols, are needed to draw more definite conclusions.

Poly-d,l-lactic acid (PDLLA) has been proposed in dentistry for regenerative procedures in the form of membranes, screws, and pins. The aim of this review was to evaluate the efficacy of bone augmentation techniques using PDLLA devices. A literature search was carried out by two independent and calibrated reviewers. All interventional and observational studies assessing the efficacy of bone augmentation techniques using PDLLA devices were included. Six studies were included. The relevant variability of design and methods impeded any qualitative or quantitative comparison. Ease of handling, absence of a re-entry phase, moldability of foils, and good soft-tissue response were appreciated characteristics of PDLLA devices. Some drawbacks such as the risk of membrane exposition, a prolonged adsorbability, and a tendency to a fibrous encapsulation of the PDLLA devices have been described, although the clinical significance of these findings is unclear. Clinical data about PDLLA devices for bone regeneration are very scarce and heterogenous. Well-designed randomized controlled trials comparing the use of PDLLA foils and pins with conventional membranes for bone regeneration are strongly encouraged in order to understand the real clinical benefits/drawbacks of this technique., Competing Interests: The authors declare no conflict of interest.