Pathological Situations Research Articles

ARAP3 protects from excessive formylated peptide-induced microvascular leakage by acting on endothelial cells and neutrophils.

Vascular permeability is temporarily heightened during inflammation, but excessive inflammation-associated microvascular leakage can be detrimental, as evidenced in the inflamed lung. Formylated peptides regulate vascular leakage indirectly via formylated peptide receptor-1 (FPR1)-mediated recruitment and activation of neutrophils. Here we identify how the GTPase-activating protein ARAP3 protects against formylated peptide-induced microvascular permeability via endothelial cells and neutrophils. In vitro, Arap3-/- endothelial monolayers were characterised by enhanced formylated peptide-induced permeability due to upregulated endothelial FPR1 and enhanced vascular endothelial cadherin internalisation. In vivo, enhanced inflammation-associated microvascular leakage was observed in Arap3-/- mice. Leakage of plasma protein into the lungs of Arap3-/- mice increased within hours of formylated peptide administration. Adoptive transfer experiments indicated this was dependent upon ARAP3 deficiency in both immune and non-immune cells. Bronchoalveolar lavages of formylated peptide-challenged Arap3-/- mice contained neutrophil extracellular traps (NETs). Pharmacological inhibition of NET formation abrogated excessive microvascular leakage, indicating a critical function of NETs in this context. The observation that Arap3-/- mice developed more severe influenza suggests these findings are pertinent to pathological situations characterised by abundant formylated peptides. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Highly homologous miR-135a and miR-135b converting non-small cell lung cancer from suppression to progression via enhancer switching.

microRNAs (miRNAs) are short non-coding RNAs that have been increasingly recognized for their significant roles in the progression of cancer. Distinct miRNAs exhibit diverse functions attributed to variations in their sequences. As a result of possessing highly homologous seed sequences, these miRNAs target overlapping or similar gene sets, thus performing analogous roles. However, different from this sight, our study discovered that miR-135a-5p and miR-135b-5p, despite differing by only one nucleotide, exhibit distinct functional roles. Using non-small cell lung cancer (NSCLC) as a paradigm, our findings unveiled the downregulation of miR-135a-5p and upregulation of miR-135b-5p within NSCLC through TCGA database. Consequently, we further investigated their functional differences in A549 cells. Overexpression of miR-135b-5p enhanced the proliferation and migration capabilities of A549 cells, whereas miR-135a-5p transfection exhibited the opposite effect. We demonstrated that the activation of specific enhancers serves as a crucial mechanism underlying the disparate functions exerted by miR-135a-5p and miR-135b-5p in the context of NSCLC, consequently instigating a shift from inhibition to activation in NSCLC progression. Finally, we validated through animal experiments that miR-135b-5p promoted tumor progression, while miR-135a-5p exerted inhibitory effects on NSCLC development. This study offers a novel perspective for researchers to elucidate functional disparities exhibited by highly homologous miRNAs (miR-135a-5p and miR-135b-5p) in the context of NSCLC, along with the transition from inhibitory to progressive states in NSCLC. This study provides a solid foundation for future investigations into the functional roles of highly homologous miRNAs in pathological situation.

Enteral nutrition for elderly patients in intensive care unit settings

Nutrition plays a fundamental role in the management of frail elderly patients. Indeed, effective management can reduce common pathological situations, such as malnutrition, refeeding syndrome, and aspiration pneumonia, which can increase morbidity and mortality in intensive care unit settings. To optimize this management, it is essential to have knowledge of basic aspects such as timing, route, and composition of nutrition, as well as the prevention and management of the most common adverse events.

Physiological values of phagocytic capacity in marine mammals and alterations during pathological situations.

The study of the immune function in marine mammals is essential to understand their physiology and can help to improve their welfare in the aquariums. Dedicating efforts to studying marine mammal physiology, pathophysiology, and implementing new diagnostic and therapeutic tools promote progress towards preventive medicine in aquariums by facilitating early detection and treatment of diseases. However, biological and clinical research on marine mammals is currently very limited due to difficult access to these species and their biological samples. With this objective, our group has adapted to marine mammals a commercially available assay routinely used to evaluate the phagocytic capacity of monocytes and granulocytes in human whole blood samples. We adapted IngoflowEx kit to bottlenose dolphins (Tursiops truncatus), beluga whales (Delphinapterus leucas), walruses (Odobenus rosmarus), Patagonian sea lions (Otaria flavescens), and harbor (Phoca vitulina). In this paper, we report the modifications carried out on the original protocol for their correct functioning in marine mammals. We obtained physiological values of phagocytic capacity in each species after repeated sampling for 4 years in various individuals of each species. Specific results revealed that the % phagocytic cells that ingested E.coli in bottlenose dolphins were 59.6 ± 1.27, in walruses 62.6 ± 2.17, in sea lions 57.5 ± 4.3, and in beluga whales 61.7 ± 1.4. In the case of the % phagocytic cells producing respiratory burst in bottlenose dolphins were 34.2 ± 3.6, in walruses 36.3 ± 4.3, in sea lions 40.8 ± 10.2, and in beluga whales 26.3 ± 3.7. These preliminary results can be used as a reference to detect alterations in phagocytic capacity either by immunosuppression or by exacerbation of the response in infectious inflammatory processes. Clinical applicability of the assay was verified in two clinical cases in which Ingoflow was useful to detect immune alterations in two diseased individuals, before and after the onset of clinical signs.

Galanin diminishes cortical spreading depolarization across rodents – A candidate for treatment?

Galanin (Gal) is a neuropeptide with the potential to ameliorate cortical spreading depolarization (CSD), an electrophysiological phenomenon occurring after brain injury or in migraine aura. Gal is expressed in all cortical neurons both in rat and in mouse cortices. Here we investigated whether the effect of Gal on CSD previously described in the rat is conserved in the mouse cortex. In rats, the topical application of Gal to the cortex for 1 h did not induce any change in CSD amplitudes, propagation velocity, or threshold of elicitation. Rather, topical application of Gal for 3 h was necessary to obtain a significant decrease in these CSD parameters and to develop a remarkable increase in the KCl threshold to elicit a CSD in rat cortex. In contrast, the topical application of Gal on cortical surface for 1 h in mice was sufficient to significantly attenuate CSD amplitudes and increase threshold. A thinner cortex, a faster diffusion or different affinity/expression of receptors for Gal are possible reasons to explain this difference in the time course between rats and mice. Our data are relevant to postulate Gal as a potential target for inhibition of CSD under pathological situations such as stroke or ischemia. Significance statementThe neuropeptide Galanin (Gal) is expressed in all neurons throughout the cerebral cortex, both in rats and mice, and is able to reduce or even inhibit Cortical Spreading Depolarization, thus, Gal has the potential to control neuronal excitability that may identify Gal as a target in drug development against CSD.

LncRNA FTH1P3: A New Biomarker for Cancer-Related Therapeutic Development.

Cancer is a persistent and urgent health problem that affects the entire world. Not long ago, regulatory biomolecules referred to as long noncoding RNAs (lncRNAs) might have value for their innate abundance and stability. These single-stranded RNAs potentially interfere with several physiological and biochemical cellular processes involved in many human pathological situations, particularly cancer diseases. Ferritin heavy chain1 pseudogene 3 (FTH1P3), a lncRNA that is ubiquitously transcribed and belongs to the ferritin heavy chain (FHC) family, represents a novel class of lncRNAs primarily found in oral squamous cell carcinoma. Further research has shown that FTH1P3 is involved in other malignancies such as uveal melanoma, glioma, esophageal squamous cell carcinoma, non-small cell lung cancer, breast cancer, laryngeal squamous cell carcinoma, and cervical cancer. Accordingly, FTH1P3 significantly enhances cancer symptoms, including cell proliferation, invasion, metastasis, chemoresistance, and inhibition of apoptosis through many specific mechanisms. Notably, the clinical data significantly demonstrated the association of FTH1P3 overexpression with poor prognosis and poor overall survival within the examined samples. Here, we summarize all the research published to date (13 articles) on FTH1P3, focusing on the biological function underlying the regulatory mechanism and its possible clinical relevance.

An Overview of Red Blood Cell Properties and Functions

Haematopoiesis, the process of forming blood cells, changes dynamically throughout life. It starts in the yolk sac and moves to the liver around the sixth week, where it produces small erythrocytes. After three months of foetal development, haemoglobin converts into foetal myoglobin, and the spleen becomes a new site for haematopoiesis. Blood-forming cells begin to colonise the medullary chambers of all bones in the fourth month, and this process continues until the child is four years old. Except for the axial skeleton, peripheral bone cavities become hematopoietically dormant when they fill with adipose tissue during adulthood. In some pathological situations, the liver and spleen may re-establish hematopoietic sites. The article discusses RBCs' unique structure, including their biconcave form, lack of a nucleus, and excess haemoglobin, which gives them their distinctive red colour. The article provides a detailed explanation of RBCs' role in oxygen transport, emphasising the importance of haemoglobin in binding and releasing oxygen. The article also discusses the role of RBCs in overall health, such as preventing anaemia and other blood disorders. The article also discusses several medical diseases that can impact red blood cells, such as sickle cell anaemia and thalassemia. Overall, this article gives a thorough summary of RBC structure, function, and importance.

Hydroxytyrosol, a Promising Supplement in the Management of Human Stroke: An Exploratory Study.

Hydroxytyrosol (HT) is a bioactive olive oil phenol with beneficial effects in a number of pathological situations. We have previously demonstrated that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic-stroke-associated damage in mice. Our exploratory pilot study examined this effect in humans. Particularly, a nutritional supplement containing 15 mg of HT/day was administered to patients 24 h after the onset of stroke, for 45 days. Biochemical and oxidative-stress-related parameters, blood pressure levels, serum proteome, and neurological and functional outcomes were evaluated at 45 and 90 days and compared to a control group. The main findings were that the daily administration of HT after stroke could: (i) favor the decrease in the percentage of glycated hemoglobin and diastolic blood pressure, (ii) control the increase in nitric oxide and exert a plausible protective effect in oxidative stress, (iii) modulate the evolution of the serum proteome and, particularly, the expression of apolipoproteins, and (iv) be beneficial for certain neurological and functional outcomes. Although a larger trial is necessary, this study suggests that HT could be a beneficial nutritional complement in the management of human stroke.

Hypoxia delays steroid-induced developmental maturation in Drosophila by suppressing EGF signaling.

Animals often grow and develop in unpredictable environments where factors like food availability, temperature, and oxygen levels can fluctuate dramatically. To ensure proper sexual maturation into adulthood, juvenile animals need to adapt their growth and developmental rates to these fluctuating environmental conditions. Failure to do so can result in impaired maturation and incorrect body size. Here we describe a mechanism by which Drosophila larvae adapt their development in low oxygen (hypoxia). During normal development, larvae grow and increase in mass until they reach critical weight (CW), after which point a neuroendocrine circuit triggers the production of the steroid hormone ecdysone from the prothoracic gland (PG), which promotes maturation to the pupal stage. However, when raised in hypoxia (5% oxygen), larvae slow their growth and delay their maturation to the pupal stage. We find that, although hypoxia delays the attainment of CW, the maturation delay occurs mainly because of hypoxia acting late in development to suppress ecdysone production. This suppression operates through a distinct mechanism from nutrient deprivation, occurs independently of HIF-1 alpha and does not involve dilp8 or modulation of Ptth, the main neuropeptide that initiates ecdysone production in the PG. Instead, we find that hypoxia lowers the expression of the EGF ligand, spitz, and that the delay in maturation occurs due to reduced EGFR/ERK signaling in the PG. Our study sheds light on how animals can adjust their development rate in response to changing oxygen levels in their environment. Given that hypoxia is a feature of both normal physiology and many diseases, our findings have important implications for understanding how low oxygen levels may impact animal development in both normal and pathological situations.

Analysing and Evaluating the Performance of Deep-Learning-Based Arrhythmia Detection Using Electrocardiogram Signals

Cardiac arrhythmia is a cardiac irregularity that impacts a significant number of individuals globally. Certain arrhythmias may be benign or occur only once, while recurring arrhythmias have the potential to cause organ failure, increase the risk of stroke by a factor of five, and even lead to sudden cardiac death. Thus, in order to identify and treat arrhythmia and prevent potentially fatal cardiac problems, the rapid detection and categorization of Electrocardiogram (ECG) signals is of paramount importance. The non-invasive technique employs electrodes to examine the electrical potentials of the heart, facilitating the detection of structural and functional irregularities that contribute to the diagnosis of cardiovascular illnesses. Nevertheless, the high likelihood of manual interpretation, which is both time-consuming and susceptible to error caused by weariness, poses a significant challenge for cardiologists in identifying and diagnosing cardiac issues. In recent times, there has been a growing utilization of Deep Learning (DL) models in the field of arrhythmia prediction, with the aim of enhancing clinical decision-making and potentially mitigating the likelihood of valetudinarian fatality. These models enhance the diagnostic capabilities of electrocardiography by detecting pathological situations, extracting anatomically meaningful data, evaluating cardio-motion, and assessing the quality of echo images. As a result, they serve as an alternative tool for precise diagnosis and treatment of arrhythmias. In order to forecast and categorize arrhythmias based on ECG signal data, this study provides a comprehensive review of various deep learning approaches. The initial section of the study provides a concise overview of various deep learning-based prediction models that have been developed by multiple researchers for echocardiography systems. Subsequently, a comparative analysis is undertaken to comprehend the limitations of those algorithms and propose a novel approach to improve the accuracy of cardiac view classification in echocardiography systems.

Identifying anomalous patterns in ecological communities’ diversity: leveraging functional boxplots and clustering of normalized Hill’s numbers and their integral functions

AbstractDiversity is fundamental in many disciplines, such as ecology, business, biology, and medicine. From a statistical perspective, calculating a measure of diversity, whatever the context of reference, always poses the same methodological challenges. For example, in the ecological field, although biodiversity is widely recognised as a positive element of an ecosystem, and there are decades of studies in this regard, there is no consensus measure to evaluate it. The problem is that diversity is a complex, multidimensional, and multivariate concept. Limiting to the idea of diversity as variety, recent studies have presented functional data analysis to deal with diversity profiles and their inherently high-dimensional nature. A limitation of this recent research is that the identification of anomalies currently still focuses on univariate measures of biodiversity. This study proposes an original approach to identifying anomalous patterns in environmental communities’ biodiversity by leveraging functional boxplots and functional clustering. The latter approaches are implemented to standardised and normalised Hill’s numbers treating them as functional data and Hill’s numbers integral functions. Each of these functional transformations offers a peculiar and exciting point of view and interpretation. This research is valuable for identifying warning signs that precede pathological situations of biodiversity loss and the presence of possible pollutants.

Diophantine conditions in the law of the iterated logarithm for lacunary systems

AbstractIt is a classical observation that lacunary function systems exhibit many properties which are typical for systems of independent random variables. However, it had already been observed by Erdős and Fortet in the 1950s that probability theory’s limit theorems may fail for lacunary sums $$\sum f(n_k x)$$ ∑ f ( n k x ) if the sequence $$(n_k)_{k \ge 1}$$ ( n k ) k ≥ 1 has a strong arithmetic “structure”. The presence of such structure can be assessed in terms of the number of solutions $$k,\ell $$ k , ℓ of two-term linear Diophantine equations $$a n_k - b n_\ell = c$$ a n k - b n ℓ = c . As the first author proved with Berkes in 2010, saving an (arbitrarily small) unbounded factor for the number of solutions of such equations compared to the trivial upper bound, rules out pathological situations as in the Erdős–Fortet example, and guarantees that $$\sum f(n_k x)$$ ∑ f ( n k x ) satisfies the central limit theorem (CLT) in a form which is in accordance with true independence. In contrast, as shown by the first author, for the law of the iterated logarithm (LIL) the Diophantine condition which suffices to ensure “truly independent” behavior requires saving this factor of logarithmic order. In the present paper we show that, rather surprisingly, saving such a logarithmic factor is actually the optimal condition in the LIL case. This result reveals the remarkable fact that the arithmetic condition required of $$(n_k)_{k \ge 1}$$ ( n k ) k ≥ 1 to ensure that $$\sum f(n_k x)$$ ∑ f ( n k x ) shows “truly random” behavior is a different one at the level of the CLT than it is at the level of the LIL: the LIL requires a stronger arithmetic condition than the CLT does.

Evaluation Effect Dexamethason and Paracetamol Post-Odontectomy 38 with Impaction IA Mesioangular

Introduction: Impacted teeth are a pathological situation where a tooth cannot or will not erupt into normal functional position. Odontectomy is one of the most frequently performed procedures and an invasive procedure that involves extensive tissue trauma and a considerable postoperative inflammatory response. However, to achieve adequate pain relief, monotherapy is difficult and multimodal analgesia is now accepted as the cornerstone of effective pain treatment. Objective: This case report was written with the aim of evaluating the effects of dexamethasone combined with paracetamol in post-operative patients. Case Report: A 24 year old male patient came complaining that his lower left, rearmost teeth often had food stuck in them and were difficult to clean. Patient complaints since 1 year ago and said it was difficult to clean the area even with a toothbrush. The patient wants the tooth to be removed immediately. On objective examination, there were 38 mesioangular impacted teeth with percussion (-), palpation (-), sondation (-), and vitality (+). On supporting examination, it could be seen that there was 38 class IA mesioangular impacted teeth. Result: An odontectomy was carried out on the impacted tooth 38 with a trapezium flap design and post-operative medication was given in the form of amoxicillin, dexamethasone, paracetamol and multivitamins. Control after 7 days of odontectomy to see the effectiveness of the medication given. Conclusion: The use of corticosteroids in the form of dexamethasone combined with paracetamol provides a shorter edema effect and adequate pain relief after surgery

Inflammation and Organic Cation Transporters Novel (OCTNs).

Inflammation is a physiological condition characterized by a complex interplay between different cells handled by metabolites and specific inflammatory-related molecules. In some pathological situations, inflammation persists underlying and worsening the pathological state. Over the years, two membrane transporters namely OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been shown to play specific roles in inflammation. These transporters form the OCTN subfamily within the larger SLC22 family. The link between these proteins and inflammation has been proposed based on their link to some chronic inflammatory diseases such as asthma, Crohn's disease (CD), and rheumatoid arthritis (RA). Moreover, the two transporters show the ability to mediate the transport of several compounds including carnitine, carnitine derivatives, acetylcholine, ergothioneine, and gut microbiota by-products, which have been specifically associated with inflammation for their anti- or proinflammatory action. Therefore, the absorption and distribution of these molecules rely on the presence of OCTN1 and OCTN2, whose expression is modulated by inflammatory cytokines and transcription factors typically activated by inflammation. In the present review, we wish to provide a state of the art on OCTN1 and OCTN2 transport function and regulation in relationships with inflammation and inflammatory diseases focusing on the metabolic signature collected in different body districts and gene polymorphisms related to inflammatory diseases.

Immune Analysis Using Vitreous Optical Coherence Tomography Imaging in Rats with Steroid-Induced Glaucoma.

Glaucoma is a multifactorial pathology involving the immune system. The subclinical immune response plays a homeostatic role in healthy situations, but in pathological situations, it produces imbalances. Optical coherence tomography detects immune cells in the vitreous as hyperreflective opacities and these are subsequently characterised by computational analysis. This study monitors the changes in immunity in the vitreous in two steroid-induced glaucoma (SIG) animal models created with drug delivery systems (microspheres loaded with dexamethasone and dexamethasone/fibronectin), comparing both sexes and healthy controls over six months. SIG eyes tended to present greater intensity and a higher number of vitreous opacities (p < 0.05), with dynamic fluctuations in the percentage of isolated cells (10 µm2), non-activated cells (10-50 µm2), activated cells (50-250 µm2) and cell complexes (>250 µm2). Both SIG models presented an anti-inflammatory profile, with non-activated cells being the largest population in this study. However, smaller opacities (isolated cells) seemed to be the first responder to noxa since they were the most rounded (recruitment), coinciding with peak intraocular pressure increase, and showed the highest mean Intensity (intracellular machinery), even in the contralateral eye, and a major change in orientation (motility). Studying the features of hyperreflective opacities in the vitreous using OCT could be a useful biomarker of glaucoma.

Computational insights in cell physiology

Physiological processes are governed by intricate networks of transcriptional and post-translational regulations. Inter-cellular interactions and signaling pathways further modulate the response of the cells to environmental conditions. Understanding the dynamics of these systems in healthy conditions and their alterations in pathologic situations requires a “systems” approach. Computational models allow to formalize and to simulate the dynamics of complex networks. Here, we briefly illustrate, through a few selected examples, how modeling helps to answer non-trivial questions regarding rhythmic phenomena, signaling and decision-making in cellular systems. These examples relate to cell differentiation, metabolic regulation, chronopharmacology and calcium dynamics.

Effects of chronic hydrogen peroxide exposure on mitochondrial oxidative stress genes, ROS production and lipid peroxidation in HL60 cells

Hydrogen peroxide (H2O2) is a reactive species that is also involved in the redox regulation of cells because of it is relative stability. In numerous pathological situations, a chronic increase in the production of reactive species is observed, which is related to oxidative stress and cellular damage. This study aimed to evaluate the effects of long-term exposure to different H2O2 concentrations on oxidative stress biomarkers and mitochondrial dynamics in HL60 cells. HL60 cells were treated with a sustained production (0.1, 1.0 and 10.0 nM/s) of H2O2 for one hour. H2O2 production and malondialdehyde (MDA) levels, as a lipid peroxidation marker, increased progressively in HL60 cells in accordance with higher H2O2 exposure, with significant differences between the 10 nM/s H2O2 group and the control and 0.1 nM/s groups. Similarly, progressive increased expression in genes related to the mitochondrial antioxidant defences and mitochondrial dynamics were also observed. Significantly increased gene expression in the 10 nM/s H2O2 with respect to the control group was observed for manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG1α), nuclear respiratory factor 2 (Nrf2), mitochondrial transcription factor A (Tfam), mitofusins 1 and 2 (Mfn1 and Mfn2) and uncoupling protein 3 (UCP3), whereas no significant changes were observed in the cytochrome c oxidase subunit IV (COXIV) gene expression. In conclusion, exposure to different sustained production of H2O2 is related to a progressive increase in the gene expression of mitochondrial dynamics and redox processes in HL60 cells, but also to oxidative damage at higher H2O2 production levels.

Role of Autophagy and Mitophagy in Neurodegenerative Disorders.

Autophagy is a self-destructive cellular process that removes essential metabolites and waste from inside the cell to maintain cellular health. Mitophagy is the process by which autophagy causes disruption inside mitochondria and the total removal of damaged or stressed mitochondria, hence enhancing cellular health. The mitochondria are the powerhouses of the cell, performing essential functions such as ATP (adenosine triphosphate) generation, metabolism, Ca2+ buffering, and signal transduction. Many different mechanisms, including endosomal and autophagosomal transport, bring these substrates to lysosomes for processing. Autophagy and endocytic processes each have distinct compartments, and they interact dynamically with one another to complete digestion. Since mitophagy is essential for maintaining cellular health and using genetics, cell biology, and proteomics techniques, it is necessary to understand its beginning, particularly in ubiquitin and receptor-dependent signalling in injured mitochondria. Despite their similar symptoms and emerging genetic foundations, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) have all been linked to abnormalities in autophagy and endolysosomal pathways associated with neuronal dysfunction. Mitophagy is responsible for normal mitochondrial turnover and, under certain physiological or pathological situations, may drive the elimination of faulty mitochondria. Due to their high energy requirements and post-mitotic origin, neurons are especially susceptible to autophagic and mitochondrial malfunction. This article focused on the importance of autophagy and mitophagy in neurodegenerative illnesses and how they might be used to create novel therapeutic approaches for treating a wide range of neurological disorders.

FABRICACIÓN ADITIVA DE FÓRCEPS CON FIBRA DE CARBONO CONTINUA PARA EL ENTRENAMIENTO VIRTUAL DEL PARTO

Vaginal delivery assisted with forceps (FAVD) is an obstetric technique that involves the extraction of the fetus by traction and/or expansion of the birth canal with an instrument. Currently, the use of forceps allows for the resolution of pathological situations that would otherwise require a cesarean section with the risks of morbidity and mortality that this surgery entails. For this reason, there is a growing interest in increasing the percentage of FAVD, after obstetricians feel more confident after practicing in simulation workshops with mannequins and acquiring the necessary competencies for their correct use. The forceps is an instrument that requires a precise introduction and placement, so an electromagnetic tracking tool has been developed that knows, with high precision, the position of the instrument both inside the vagina and around the fetal head. With this, childbirth training is complemented by a virtual simulation, in real-time, that allows the internal position of the forceps to be seen, thus facilitating the learning and improvement of the introduction and placement technique. For this, the instrument must not contain any ferrous residue that interferes electromagnetically, so commercial forceps (made of stainless steel) are not valid. In this context, the reproduction of forceps has been proposed through additive manufacturing based on material extrusion (MEX). To obtain forceps that are as realistic as possible in terms of rigidity compared to commercial models, a nylon filament reinforced with carbon microfibers (Onyx) has been used to which continuous carbon fiber is added in successive layers. Given the limitations in the printing volume of the technology used (Mark Two), numerical simulations were carried out by finite element analysis and different proposals for dividing each piece and subsequent union by adhesives were made, finally developing the final solution. Keywords: additive manufacturing; carbon fiber extrusion; vaginal delivery forceps; medical training; electromagnetic tracking.

Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer.

The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial-mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis. Amongst the different existing types of the EMT, type 3 is directly involved in carcinogenesis. A type 3 EMT occurs in neoplastic cells that have previously acquired genetic and epigenetic alterations, specifically affecting genes involved in promoting clonal outgrowth and invasion. Markers such as E-cadherin; N-cadherin; vimentin; and transcription factors (TFs) like Twist, Snail and ZEB are considered key molecules in the transition. The EMT process is also regulated by microRNA expression. Many miRNAs have been reported to repress EMT-TFs. Thus, Snail 1 is repressed by miR-29, miR-30a and miR-34a; miR-200b downregulates Slug; and ZEB1 and ZEB2 are repressed by miR-200 and miR-205, respectively. Occasionally, some microRNA target genes act downstream of the EMT master TFs; thus, Twist1 upregulates the levels of miR-10b. Melatonin is an endogenously produced hormone released mainly by the pineal gland. It is widely accepted that melatonin exerts oncostatic actions in a large variety of tumors, inhibiting the initiation, progression and invasion phases of tumorigenesis. The molecular mechanisms underlying these inhibitory actions are complex and involve a great number of processes. In this review, we will focus our attention on the ability of melatonin to regulate some key EMT-related markers, transcription factors and micro-RNAs, summarizing the multiple ways by which this hormone can regulate the EMT. Since melatonin has no known toxic side effects and is also known to help overcome drug resistance, it is a good candidate to be considered as an adjuvant drug to conventional cancer therapies.