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Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood–brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor β (ERβ), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17β-estradiol (E2) and the selective ERβ agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative Her2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERβ as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications. [ABSTRACT FROM AUTHOR]

Tumor diseases become a huge problem when they embark on a path that advances to malignancy, such as the process of metastasis. Cancer metastasis has been thoroughly investigated from a biological perspective in the past, whereas it has still been less explored from a physical perspective. Until now, the intraluminal pathway of cancer metastasis has received the most attention, while the interaction of cancer cells with macrophages has received little attention. Apart from the biochemical characteristics, tumor treatments also rely on the tumor microenvironment, which is recognized to be immunosuppressive and, as has recently been found, mechanically stimulates cancer cells and thus alters their functions. The review article highlights the interaction of cancer cells with other cells in the vascular metastatic route and discusses the impact of this intercellular interplay on the mechanical characteristics and subsequently on the functionality of cancer cells. For instance, macrophages can guide cancer cells on their intravascular route of cancer metastasis, whereby they can help to circumvent the adverse conditions within blood or lymphatic vessels. Macrophages induce microchannel tunneling that can possibly avoid mechanical forces during extra- and intravasation and reduce the forces within the vascular lumen due to vascular flow. The review article highlights the vascular route of cancer metastasis and discusses the key players in this traditional route. Moreover, the effects of flows during the process of metastasis are presented, and the effects of the microenvironment, such as mechanical influences, are characterized. Finally, the increased knowledge of cancer metastasis opens up new perspectives for cancer treatment. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the epidemiology of impacted and transmigrated mandibular canines in a large orthodontic population referred to the University of Turin. Methods: Panoramic radiographs, intraoral photographs, and dental casts of 2119 patients referred to the Department of Orthodontics at the University of Turin, Italy, between 1995 and 2022 were reviewed. These patients were divided into two groups. Group A included 1479 patients found in the Dental School archive before 2017, more specifically between 1995 and 2017. These patients were examined in order to calculate the prevalence of impacted and transmigrated mandibular canines. From 2017 to 2022, the records of 640 new patients were examined (GROUP B) in order to calculate the incidence of these occurrences. Results: The prevalence of mandibular canine impaction in Group A was found to be 1.7%, with a total of 25 patients having mandibular canine impaction. A prevalence of 0.3% was found for mandibular canine transmigration (Group A). The incidence of mandibular canine impaction was found to be 2%, with a total of 13 patients with mandibular canine impaction (Group B). Mandibular canine transmigration was found in 1 of 640 participants (Group B). Conclusions: Twenty-five of 1479 patients had impacted mandibular canines, resulting in a prevalence value of 1.7%. The incidence was found to be 2%, with 13 of 640 patients having impacted mandibular canines. These results show higher prevalence and incidence rates of mandibular canine impaction when compared with previously published data. [ABSTRACT FROM AUTHOR]

The development policies implemented in Jambi Province, Indonesia, since the New Order era, have encouraged transformations in demography, regional paradigms, growth base sectors, and growth actors. This study aims to understand how the central government's demographic policies and plantation development program have impacted regional land cover change, rural development transformation, and economic development in Sumatra Island's biodiversity-rich rainforest region (Jambi Province). This study explores the shifts in village typology that have occurred. Descriptive analysis and cluster analysis were applied to collect data at the provincial level that included population, poverty rate, levels of education, HDI, GRDP, Gini index, and land cover. Village Potential Data at the village level was then used to build an infrastructure index and a diversity of activities index. The results of this study indicated that macro development indicators are in a positive trend: HDI, educational levels, GRDP per capita, and the proportion of the tertiary sector in GRDP have all increased. The growth of the tertiary sector was largely driven by the trade and motorized-vehicle repair sectors. The provincial landscape has changed significantly due to the expansion of oil palm plantations. At the village level, the infrastructure index and diversity index show an increase in the number of facilities and variations in economic activity in most villages. Some shifts in rural typology are highlighted: the increase in urban villages and in villages that specialize in oil palm plantation or other industrial plantation crops. [ABSTRACT FROM AUTHOR]

In endothelial cells (ECs), stimulation of Toll-like receptor 4 (TLR4) by the endotoxin lipopolysaccharide (LPS) induces the release of diverse pro-inflammatory mediators, beneficial in controlling bacterial infections. However, their systemic secretion is a main driver of sepsis and chronic inflammatory diseases. Since distinct and rapid induction of TLR4 signaling is difficult to achieve with LPS due to the specific and non-specific affinity to other surface molecules and receptors, we engineered new light-oxygen-voltage-sensing (LOV)-domain-based optogenetic endothelial cell lines (opto-TLR4-LOV LECs and opto-TLR4-LOV HUVECs) that allow fast, precise temporal, and reversible activation of TLR4 signaling pathways. Using quantitative mass-spectrometry, RT-qPCR, and Western blot analysis, we show that pro-inflammatory proteins were not only expressed differently, but also had a different time course when the cells were stimulated with light or LPS. Additional functional assays demonstrated that light induction promoted chemotaxis of THP-1 cells, disruption of the EC monolayer and transmigration. In contrast, ECs incorporating a truncated version of the TLR4 extracellular domain (opto-TLR4 ΔECD2-LOV LECs) revealed high basal activity with fast depletion of the cell signaling system upon illumination. We conclude that the established optogenetic cell lines are well suited to induce rapid and precise photoactivation of TLR4, allowing receptor-specific studies. [ABSTRACT FROM AUTHOR]

Slowly progressive spastic paraparesis with bladder dysfunction, the main clinical feature of human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by inflammatory cytokines, etc., induced under the interaction between infiltrated HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells, has been considered implicated for the induction of chronic inflammation. As this bystander mechanism is triggered conceivably by the transmigration of HTLV-1-infected CD4+ T cells to the spinal cord, heightened transmigrating activity of HTLV-1-infected CD4+ T cells to the spinal cord might play a crucial role as the first responder in the development of HAM/TSP. This review evaluated the functions of HTLV-1-infected CD4+ T cells in HAM/TSP patients as the prerequisite for the acquisition of the activity such as adhesion molecule expression changes, small GTPases activation, and expression of mediators involved in basement membrane disruption. The findings suggest that HTLV-1-infected CD4+ T cells in HAM/TSP patients have enough potential to facilitate transmigration into the tissues. Future HAM/TSP research should clarify the molecular mechanisms leading to the establishment of HTLV-1-infected CD4+ T cells as the first responder in HAM/TSP patients. In addition, a regimen with an inhibitory activity against the transmigration of HTLV-1-infected CD4+ T cells into the spinal cord might be recommended as one of the therapeutic strategies against HAM/TSP patients. [ABSTRACT FROM AUTHOR]

A substantial number of studies have been completed with respect to human mobility, linguistic diversity, and social sustainability in the Global North, but very few have been undertaken in relation to the Global South. Mobility, diversity, and sustainability are not recent phenomena, but little, if anything, is understood as regards how human mobility leads to linguistic diversity and social sustainability. This article fills this gap by explaining how the transmigrants of Javanese, Balinese, and Sasak ethnic backgrounds, along with the Bima and Dompu host communities, have established the ethnically and linguistically multi-diverse transmigrant communities of Manggelewa on the Indonesian island of Sumbawa. Data were collected from the participant ethnographic observations of the communities. The main strategies for data collection included taking notes, collecting documents, distributing questionnaires concerning human mobility, sociolinguistic diversity, and social sustainability, interviewing key informants, and recording conversations. Employing qualitative, quantitative, and ethnographic analyses, the study exhibits the community's dynamic mobility, sociolinguistic diversity, and social sustainability. The study displays how human mobility leads to sociolinguistic diversity and how the diversity is used as a resource for sustaining a better interethnic relationship. The dimensions of mobility, sociolinguistic diversity, and social sustainability are discussed, and the factors that are essential for symbolic social sustainability are statistically attested. [ABSTRACT FROM AUTHOR]

Simple Summary: Transmigrated canines represent a rare eruptive entity that usually occurs at the mandible. The diagnosis is usually made after radiographic examinations, such as panoramic radiography. Its observation should be analyzed in detail with computerized scanner studies of the CBCT type. Although, in most cases, they are usually asymptomatic, the appearance of odontomas or the risk of developing tooth cysts should be considered. The age of diagnosis and its position will be decisive to assess dental replacement by orthodontic treatment. When this is not possible, surgical treatment is advised. The aim of this study was to analyze the prevalence of transmigrated canines in a Spanish population by evaluating their clinical and radiological characteristics. The descriptive observational study obtained 6840 orthopantomographs from all patients seeking dental care in the years 2017–21 via the Patient Reception Service and Dentistry Service at the Faculty of Dentistry at the Complutense University of Madrid and the Central Hospital of the Red Cross of Madrid (Spain). In total, 52 patients presented transmigrated canines, establishing a prevalence of 0.76%. This sample comprised 28 women and 24 men. Whenever a transmigrated canine was identified, a CBCT scan was obtained and used to evaluate the clinical and radiological variables associated with canine transmigration. The predominant side of the transmigration was the left (57.69%) compared to the right side (42.30%). The position of the canine, in order of frequency, according to the Mupparapu classification, corresponded to type IV (42.30%), type II (36.53%), type I (15.38%), and type V (5.76%), with no type III transmigrations found. Clinical manifestations were only recorded in 17.30% of cases, and 11.53% of the radiological findings showed the presence of tooth cysts that were confirmed by histopathological studies. Other impactions, in addition to the transmigrated canine, were found in five patients (9.61%), with the majority being the presence of third molars. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory neurodegenerative disorder of the central nervous system (CNS). The migration of immune cells into the CNS is essential for its development, and plasma membrane molecules play an important role in triggering and maintaining the inflammation. We previously identified ninjurin2, a plasma membrane protein encoded by NINJ2 gene, as involved in the occurrence of relapse under Interferon-β treatment in MS patients. The aim of the present study was to investigate the involvement of NINJ2 in inflammatory conditions and in the migration of monocytes through the blood–brain barrier (BBB). We observed that NINJ2 is downregulated in monocytes and in THP-1 cells after stimulation with the pro-inflammatory cytokine LPS, while in hCMEC/D3 cells, which represent a surrogate of the BBB, LPS stimulation increases its expression. We set up a transmigration assay using an hCMEC/D3 transwell-based model, finding a higher transmigration rate of monocytes from MS subjects compared to healthy controls (HCs) in the case of an activated hCMEC/D3 monolayer. Moreover, a positive correlation between NINJ2 expression in monocytes and monocyte migration rate was observed. Overall, our results suggest that ninjurin2 could be involved in the transmigration of immune cells into the CNS in pro-inflammatory conditions. Further experiments are needed to elucidate the exact molecular mechanisms. [ABSTRACT FROM AUTHOR]

Compound odontoma is a malformation typical of young adults below the age of 20, with a slight preference for the male gender and the anterior region of the maxilla. Clinically asymptomatic, it can be detected during a radiological investigation in connection with the persistence of deciduous dental elements and the impaction of definitive ones. The treatment of choice is excisional surgery and recurrence is a rare event. The need for orthodontic therapy for impacted elements is usually not necessary because in most cases, odontomas are small, circumscribed lesions the size of a permanent tooth. In this article, the diagnostic and therapeutic surgical excision procedure is presented in three patients at developmental age with large compound odontomas associated with at least one retained canine, and in two of the cases, with serious transmigration to the impacted tooth elements. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) mediates cellular and molecular passage between the central nervous system (CNS) and peripheral circulation. Compromised BBB integrity has been linked to neurocognitive deficits in multiple diseases and various infections, including those associated with HIV-1 infection. Understanding the impact of exposure to pharmaceuticals, such as those utilized for pain management by patients suffering from CNS disease, on BBB regulation and function is clinically important. In this study, we modelled two different BBB systems; a primary human co-culture and a cell line monoculture. These systems were both exposed to three daily repeat doses of morphine and examined for alterations to BBB integrity via permeability, PBMC transmigration, and chemokine gradient changes. We did not find any significant changes to either BBB system with repeat morphine dosing, suggesting that repeat morphine exposure may not play a significant role in BBB changes. [ABSTRACT FROM AUTHOR]

Proinflammatory chemokine ligand 26 (CCL26, eotaxin-3) mediates transendothelial cell migration of eosinophils by binding and activating the G-protein-coupled (GPC) chemokine receptor 3 on the surface of eosinophilic cells. Here we have investigated the role of glycosaminoglycans (GAGs) as potential co-receptors in the process of CCL26-induced eosinophil chemotaxis. For this purpose, we have first identified the GAG-binding site of CCL26 by a site-directed mutagenesis approach in the form of an alanine screening. A panel of GAG-binding-deficient mutants has been designed, generated, and analyzed with respect to their binding affinities to heparan sulphate (HS) by isothermal fluorescence titration studies. This showed that basic amino acids in the α-helical part of CCL26 are strongly involved in GAG-binding. In chemotaxis experiments, we found that decreased GAG-binding affinity correlated with decreased chemotactic activity, which indicates an involvement of GAGs in eosinophil migration. This was further proven by the negative impact of heparinase III treatment and, independently, by the incubation of eosinophils with an anti heparan sulfate antibody. We finally investigated eosinophils' proteoglycan (PG) expression patterns by real-time PCR, which revealed the highest expression level for serglycin. Including an anti-serglycin antibody in CCL26-induced eosinophil migration experiments reduced the chemotaxis of these immune cells, thereby proving the dependence of eosinophil mobilization on the proteoglycan serglycin. [ABSTRACT FROM AUTHOR]

Neutrophils are classically characterized as merely reactive innate effector cells. However, the microbiome is known to shape the education and maturation process of neutrophils, improving their function and immune-plasticity. Recent reports demonstrate that murine neutrophils possess the ability to exert adaptive responses after exposure to bacterial components such as LPS (Gram-negative bacteria) or LTA (Gram-positive bacteria). We now ask whether small extracellular vesicles (EVs) from the gut may directly mediate adaptive responses in neutrophils in vitro. Murine bone marrow-derived neutrophils were primed in vitro by small EVs of high purity collected from colon stool samples, followed by a second hit with LPS. We found that low-dose priming with gut microbiota-derived small EVs enhanced pro-inflammatory sensitivity as indicated by elevated levels of TNF-α, IL-6, ROS and MCP-1 and increased migratory and phagocytic activity. In contrast, high-dose priming resulted in a tolerant phenotype, marked by increased IL-10 and decreased transmigration and phagocytosis. Alterations in TLR2/MyD88 as well as TLR4/MyD88 signaling were correlated with the induction of adaptive cues in neutrophils in vitro. Taken together, our study shows that small EVs from stools can drive adaptive responses in neutrophils in vitro and may represent a missing link in the gut–immune axis. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) is considered to be an immunologically unique site, in large part given its extensive protection by the blood–brain barrier (BBB). As our knowledge of the complex interaction between the peripheral immune system and the CNS expands, the mechanisms of immune privilege are being refined. Here, we studied the interaction of dendritic cells (DCs) with the BBB in steady–state conditions and observed that transmigrated DCs display an activated phenotype and stronger T cell-stimulatory capacity as compared to non-migrating DCs. Next, we aimed to gain further insights in the processes underlying activation of DCs following transmigration across the BBB. We investigated the interaction of DCs with endothelial cells as well as the involvement of actin cytoskeletal reorganization. Whereas we were not able to demonstrate that DCs engulf membrane fragments from fluorescently labelled endothelial cells during transmigration across the BBB, we found that blocking actin restructuring of DCs by latrunculin-A significantly impaired in vitro migration of DC across the BBB and subsequent T cell-stimulatory capacity, albeit no effect on migration-induced phenotypic activation could be demonstrated. These observations contribute to the current understanding of the interaction between DCs and the BBB, ultimately leading to the design of targeted therapies capable to inhibit autoimmune inflammation of the CNS. [ABSTRACT FROM AUTHOR]

A small fraction of HIV-1-infected T cells forms populations of latently infected cells when they are a naive T-cell subset or in transit to a resting memory state. Latently HIV-1-infected cells reside in lymphoid tissues and serve as viral reservoirs. However, whether they systemically recirculate in the body and re-enter the lymphoid nodes are unknown. Here, we employed two in-vitro cell coculture systems mimicking the lymphatic endothelium in lymph nodes and investigated the homing potential, specifically the transendothelial migration (TEM), of two latently HIV-1-infected cell lines (J1.1 and ACH-2). In trans-well coculture systems, J1.1 and ACH-2 showed higher TEM efficiencies than their parental uninfected and acutely infected cells. The efficiency of TEM was enhanced by the presence of stromal cells, such as HS-5 and fibroblastic reticular cells. In an in-vitro reconstituted, three-dimensional coculture system in which stromal cells are embedded in collagen matrices, J1.1 showed slightly higher TEM efficiency in the presence of HS-5. In accordance with these phenotypes, latently infected cells adhered to the endothelial cells more efficiently than uninfected cells. Together, our study showed that latently HIV-1-infected cells enhanced cell adhesion and TEM abilities, suggesting their potential for efficient homing to lymph nodes. [ABSTRACT FROM AUTHOR]

The endothelium is the inner layer of all blood vessels and it regulates hemostasis. It also plays an active role in the regulation of the systemic inflammatory response. Systemic inflammatory disease often results in alterations in vascular endothelium barrier function, increased permeability, excessive leukocyte trafficking, and reactive oxygen species production, leading to organ damage. Therapeutics targeting endothelium inflammation are urgently needed, but strong concerns regarding the level of phenotypic heterogeneity of microvascular endothelial cells between different organs and species have been expressed. Microvascular endothelial cell heterogeneity in different organs and organ-specific variations in endothelial cell structure and function are regulated by intrinsic signals that are differentially expressed across organs and species; a result of this is that neutrophil recruitment to discrete organs may be regulated differently. In this review, we will discuss the morphological and functional variations in differently originated microvascular endothelia and discuss how these variances affect systemic function in response to inflammation. We will review emerging in vivo and in vitro models and techniques, including microphysiological devices, proteomics, and RNA sequencing used to study the cellular and molecular heterogeneity of endothelia from different organs. A better understanding of microvascular endothelial cell heterogeneity will provide a roadmap for developing novel therapeutics to target the endothelium. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection. [ABSTRACT FROM AUTHOR]

To efficiently cross the endothelial barrier during inflammation, neutrophils first firmly adhere to the endothelial surface using the endothelial adhesion molecule ICAM-1. Upon actual transmigration, the release from ICAM-1 is required. While Integrin LFA1/Mac1 de-activation is one described mechanism that leads to this, direct cleavage of ICAM-1 from the endothelium represents a second option. We found that a disintegrin and metalloprotease 10 (ADAM10) cleaves the extracellular domain of ICAM-1 from the endothelial surface. Silencing or inhibiting endothelial ADAM10 impaired the efficiency of neutrophils to cross the endothelium, suggesting that neutrophils use endothelial ADAM10 to dissociate from ICAM-1. Indeed, when measuring transmigration kinetics, neutrophils took almost twice as much time to finish the diapedesis step when ADAM10 was silenced. Importantly, we found increased levels of ICAM-1 on the transmigrating neutrophils when crossing an endothelial monolayer where such increased levels were not detected when neutrophils crossed bare filters. Using ICAM-1-GFP-expressing endothelial cells, we show that ICAM-1 presence on the neutrophils can also occur by membrane transfer from the endothelium to the neutrophil. Based on these findings, we conclude that endothelial ADAM10 contributes in part to neutrophil transendothelial migration by cleaving ICAM-1, thereby supporting the release of neutrophils from the endothelium during the final diapedesis step. [ABSTRACT FROM AUTHOR]