Search

This series of three articles will explore the fundamentals related to anatomy, physiology and pathophysiology in relation to three important topics: the cardiac system, the respiratory system and the endocrine system. The series is intended to provide an informative and evidence-based summary of each topic for both students and clinicians. This third and final paper explores the maternal endocrine system, outlining the key physiological adaptations in pregnancy and summarising the key pathophysiological conditions that may occur. [ABSTRACT FROM AUTHOR]

Background: From an epidemic outbreak, coronavirus disease-2019 (COVID-19) has quickly developed. Thymosin α1 (Tα1) has the ability to boost the T-cell numbers, support T-cell differentiation, maturation, and reduce cell apoptosis. In this study, we have investigated the efficacy and safety of Tα1 in moderate-to-severe COVID-19 patients. Patients and methods: In this double-blind, multicenter, two-arm, randomized, placebo-controlled, phase III clinical study, patients were randomized to receive either Tα1 or placebo in combination with standard of care (SOC). The data on all-cause mortality, clinical progression/ deterioration, duration of hospital/intensive care unit (ICU) stay, and safety data were collected. The patients were telephonically followed up on Day 28. Results: A total of (n = 105) COVID-19 patients were included in the study, of which 40 and 65 were severe and moderate, respectively. Thymosin arm (11.1%) had a statistically lower death rate in comparison to the placebo arm (38.5%). A total of 67 adverse events were reported in 42 patients among 105 dosed patients during the study. Among them, 43 adverse events were of mild in nature, 16 adverse events were of moderate in nature, and 8 serious adverse events (death) occurred during the study. Conclusion: This study provides evidence that Tα1 can lower death rate in severe COVID-19 patients, reduce the load on hospitals by shortening the required number of days of hospitalization and help in abbreviating the requirement of oxygen support by positively impacting the recovery rate and time taken for recovery. [ABSTRACT FROM AUTHOR]

Background: Propofol has been reported to be related to the migration, invasion, and epithelial‐mesenchymal transition (EMT) of esophageal cancer (EC) cells. However, the detailed mechanism has not yet been fully reported. The purpose of this research was to elucidate the function of long non‐coding RNA TMPO antisense RNA 1 (lncRNA TMPO‐AS1) and microRNA‐498 (miR‐498) in propofol‐regulated EC. Methods: Transwell assay was performed to assess cell migratory and invasive abilities. Western blot assay was employed to determine the levels of EMT markers and hypoxia inducible factor‐1 (HIF‐1α). Quantitative real‐time polymerase chain reaction (qRT‐PCR) was carried out to detect the levels of TMPO‐AS1 and miR‐498. Moreover, the interaction between TMPO‐AS1 and miR‐498 was predicted by starBase, and then confirmed by the dual‐luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Results: Propofol suppressed hypoxia‐induced EC cell migration, invasion, and EMT. Both TMPO‐AS1 overexpression and miR‐498 knockdown weakened the effect of propofol on hypoxia‐induced EC cell progression. Interestingly, TMPO‐AS1 targeted miR‐498 and suppressed miR‐498 expression. TMPO‐AS1 regulated EC cell progression via downregulating miR‐498 expression. Conclusions: Collectively, our findings demonstrated that propofol inhibited hypoxia‐induced EC cell mobility through modulation of the TMPO‐AS1/miR‐498 axis, providing a theoretical basis for the treatment of EC. [ABSTRACT FROM AUTHOR]

Abstract Neoplastic cells display altered biosynthetic and bioenergetic machinery to support cell survival. Therefore, cancer cells optimally utilize all available fuel resources to pump their highly upregulated metabolic pathways. While glucose is the main carbon source, transformed cells also utilize other molecules, which can be utilized in metabolic pathways, designated as alternative fuels. Acetate is one of such alternative metabolic fuels, which is mainly consumed in carbohydrate and lipid metabolism. However, studies demonstrate the contradictory effects of acetate on tumor cell survival. Moreover, the mechanisms of its antitumor actions remain poorly understood. Further, the spectrum of acetate susceptible tumor targets needs to be characterized in order to optimize the use of acetate in maneuvering tumor progression as a therapeutic strategy. As the effect of acetate on survival properties of the tumor cells of thymic origin is not worked out, in the present study the effect of acetate was investigated against tumor cells derived from a murine thymoma designated as Dalton's Lymphoma (DL). Acetate treatment of tumor cells inhibited tumor cell survival accompanied by induction of apoptotic cell death, associated with modulated expression of cell survival regulatory HIF1α, ROS, p53, Caspase 3, Bax and HSP70 along with the elevated level of cytosolic cytochrome c. Acetate treatment also modulated the expression of pH regulators MCT-1 and V-ATPase accompanied by altered pH homeostasis. Expression of MDR and lipid metabolism regulatory molecules was also inhibited in tumor cells upon acetate exposure. Further, pre-exposure of tumor cells to α-CHC (α-cyano-4-hydroxycinnamate), an inhibitor of MCT-1, partially abrogated the cytotoxic action of acetate. These findings shed a new light regarding the effect and mechanisms of the exogenous acetate on the biology of tumor cells of thymic origin. Highlights • In vitro exposure of tumor cells to acetate causes metabolic inhibition • Acetate treatment triggers induction of apoptosis • Acetate exposed tumor cells show modulated cell survival regulation • Acetate exposure interferes with pH homeostasis [ABSTRACT FROM AUTHOR]

Résumé Si l'existence de liens entre consommation éthylique et symptômes thymiques paraît évidente, la nature et les mécanismes qui sous-tendent ces interactions s'avèrent en revanche très complexes et moins bien connus. Cet article, qui s'appuie essentiellement sur des données empiriques et destinées aux cliniciens, vise à décrire de quelle manière la compréhension de ces symptômes thymiques permet de dégager des pistes de travail ou leviers pour le travail clinique avec les patients alcoolo-dépendants. Nous développons en particulier la manière dont la consommation aiguë entraîne des réactions émotionnelles, hors contexte d'abus ou de dépendance (caractère syntone par rapport au cadre social de consommation, « binge-drinking »). Les consommations chroniques, menant à l'abus ou à la dépendance, sont par la suite abordées en détaillant de quelle manière leur interaction biologique avec le circuit de récompense cérébrale modifie notablement l'humeur, en fonction d'un principe d'allostasie. Nous mettons aussi en évidence le rôle de facteurs de personnalité tels que la conscience de Soi dans la relation qui peut exister entre dépression et « craving ». Nous insistons également sur des manifestations annexes aux symptômes thymiques que sont les troubles de cognition sociale fréquents chez les patients alcooliques, menant souvent à un isolement social ainsi qu'à des relations interpersonnelles conflictuelles qui peuvent à leur tour être des facteurs d'accentuation du vécu dépressif. Abstract Although the existence of links between alcohol consumption and thymic symptoms seems obvious, the nature and mechanisms underlying these interactions are, on the other hand, very complex and less well-known. This article, which relies mainly on empirical data and is intended for clinicians, aims to describe how understanding these thymic symptoms can identify avenues of work or levers for clinical work with alcohol-dependent patients. In particular, we develop the way in which acute consumption leads to emotional reactions, outside the context of abuse or dependence (symptom with the social framework of consumption, "binge-drinking"). Chronic consumption leading to abuse or dependence is then discussed, detailing how their biological interaction with the brain reward circuit significantly changes mood, based on a principle of allostasis. We also highlight the role of personality factors such as self-consciousness in the relationship between depression and craving. Furthermore we emphasize manifestations related to thymic symptoms such as social cognition disorders common in alcoholic patients, often leading to social isolation as well as conflicting interpersonal relationships which can in turn be factors of accentuation as far as depression symptoms are concerned. [ABSTRACT FROM AUTHOR]

During the entire processes of thymus organogenesis, maturation, and involution, gene regulation occurs post-transcriptionally via recently discovered microRNA (miRNA) transcripts. Numerous reports indicate that miRNAs may be involved in the construction of a normal thymic microenvironment, which constitutes a critical component to support T lymphocyte development. MiRNAs are also expressed in thymic stromal cells including thymic epithelial cells (TECs) during maturation and senescence. This review focuses on the function of miRNAs in thymic development and involution. A better understanding of these processes will provide new insights into the regulatory network of TECs and further comprehension of how genes control TECs to maintain the thymic microenvironment during thymus development and aging, thus supporting a normal cellular immune system. [ABSTRACT FROM AUTHOR]

Thymic carcinoma is a relatively rare and aggressive thymic epithelial tumor. Herein, we report successful treatment of thymic carcinoma with pembrolizumab. A 68-year-old woman was admitted to our hospital for evaluation of chest pain. Chest computed tomography showed a mass in the anterior mediastinum and lymphadenopathy in the left cervical lymph node. Analysis of biopsy specimens detected squamous cell carcinoma in the left cervical lymph node, and immunohistochemical analysis showed 100% expression of programmed death-ligand 1 (PD-L1). Masaoka-Koga stage IVb thymic carcinoma was ultimately diagnosed. Since 3 cycles of first-line chemotherapy did not result in improvement, pembrolizumab was administered as second-line treatment every 3 weeks at a dosage of 200 mg. After 3 cycles of pembrolizumab treatment, the size of the anterior mediastinal tumor and metastatic lesions had notably decreased. Pembrolizumab may prove to be an effective therapy for thymic carcinoma with high PD-L1 expression. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the present study was to describe different biological aspects of Ehrlich tumor in mice, such as body weight evolution, tumor growth rate, histological organization and systemic immune response after treatment with high-diluted thymulin (10-9 M, named 5CH). Methods: Tumor assessment was focused on macro- and microscopic aspects; parameters included occurrence of necrosis, embolism and tumor development, in addition to quantitative analysis of apoptosis (caspase-3), cell proliferation (Ki-67) and angiogenesis (vascular endothelial growth factor - VEGF) by means of specific immunohistochemistry markers. Spleen cell populations were evaluated by flow cytometry analysis. Results: Mice treated with thymulin 5CH exhibited changes in the tumor microenvironment, such as reduced micro-embolism incidence and cytokeratin expression, with increased caspase-3 expression in the tumor cells. These findings indicate some apoptotic activity by the tumor cells induced by the treatment, even though no reduction of the macroscopic tumor mass occurred. No changes in the systemic immune response were detected, as the balance among spleen cell populations remained unchanged. Conclusions: The results indicate that treatment of mice bearing Ehrlich tumor with thymulin 5CH induces some specific changes in the tumor environment. However, it did not influence systemic immunity parameters. Adjuvant use of thymulin 5CH in oncological clinical practice is still a matter of discussion. [ABSTRACT FROM AUTHOR]

The features of the thymic morphology in hens and ducks were studied. Samples were obtained from 3 adult birds of each species. They were studied by light microscopy using classical methods of morphological research. The tissue samples were fixed in 10% neutral buffered formalin and embedded in paraffin block and finally the sections were cut at 5-10 μm thickness using sliding microtome and stained with hematoxylin and eosin, according to Van Gizon and Weigert and impregnated with silver nitrate according to Kelemen. It was established that the thymus of birds was represented by isolated cervical parts, which, in the form of strands, were located under the skin on the lateral surfaces of the neck, along the trachea, along the course of the neurovascular bundle, and consisted of individual lobes. In hens 5 to 8 lobes were included in each thymus and extended from the 3-cervical vertebra to the start of the thoraco-abdominal cavity. Thymus of ducks consisted of 3-4 lobes and was located in the posterior third of the neck. Its cranial end was at the level of 10-11 cervical vertebrae, and caudal end reached 12 cervical vertebra. Individual lobes of duck's thymus had a greater absolute mass than the lobes of hen's thymus. They were also more separated from each other. Lobes of hen's and duck's thymus had a variety of shapes. Among them, there were mainly oval, convex-oval, beanshaped, rounded, flat and, sometimes, sickle-shaped. Morphofunctional units of the thymus were lobules, which consisted of a cortex and a medulla. In birds the medulla occupied a larger area than the cortex. In the medulla, there were Hassall's corpuscles, that were better developed in ducks. [ABSTRACT FROM AUTHOR]

Thymic epithelial cells are one of the main components of the thymic microenvironment required for T-cell development. In this work, we describe an efficient method free of enzymatic and Facs-sorted methods to culture human medullary thymic epithelial cells without affecting the cell phenotypic, physiologic and functional features. Human medulla thymic epithelial cells (mTECs) are obtained by culturing thymic biopsies explants. After 7 days of primo-culture, mTECs keep their ability to express key molecules involved in immune tolerance processes such as autoimmune regulator, tissue-specific antigens, chemokines, and cytokines. In addition, the cells sensor their cultured environment and consequently adjust their gene expression network. Therefore, we describe and provide a human mTEC model that may be used to test the effect of various molecules on thymic epithelial cell homeostasis and physiology. This method should allow the investigations of the specificities and the knowledge of human mTECs in normal or pathological conditions and therefore discontinue the extrapolations done on the murine models. [ABSTRACT FROM AUTHOR]

Vγ9Vδ2+ lymphocytes are among the first T-cells to develop in the human fetus and are the predominant peripheral blood γδ T-cell population in most adults. Capable of broad polyclonal responses to pyrophosphate antigens (pAg), they are implicated in immunity to a diverse range of infections. Previously Vγ9Vδ2+ development was thought to involve postnatal selection and amplification of public Vγ9 clonotypes in response to microbial stimuli. However, recent data indicate the Vγ9Vδ2+ T-cell receptor (TCR) repertoire, which is generated early in gestation, is dominated by public Vγ9 clonotypes from birth. These chains bear highly distinct features compared to Vγ9 chains from Vδ1+ T-cells, due either to temporal differences in recombination of each subset and/or potentially prenatal selection of pAg-reactive clonotypes. While these processes result in a semi-invariant repertoire featuring Vγ9 sequences preconfigured for pAg recognition, alterations in TCRδ repertoires between neonate and adult suggest either peripheral selection of clonotypes responsive to microbial antigens or altered postnatal thymic output of Vγ9Vδ2+ T-cells. Interestingly, some individuals demonstrate private Vγ9Vδ2+ expansions with distinct effector phenotypes, suggestive of selective expansion in response to microbial stimulation. The Vγ9Vδ2+ T-cell subset, therefore, exhibits many features common to mouse γδ T-cell subsets, including early development, a semi-invariant TCR repertoire, and a reliance on butyrophilin-like molecules in antigen recognition. However, importantly Vγ9Vδ2+ T-cells retain TCR sensitivity after acquiring an effector phenotype. We outline a model for Vγ9Vδ2+ T-cell development and selection involving innate prenatal repertoire focusing, followed by postnatal repertoire shifts driven by microbial infection and/or altered thymic output. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism is overproduction of parathyroid hormone, causing hypercalcemia. Parathyroid adenomas have been found to be the etiology for 80% of cases of primary hyperparathyroidism, while almost a quarter of them are ectopic. We present a case of ectopic thymic parathyroid adenoma, treated by the thoracoscopic approach. Preoperative computed tomogram and technetium-99-sestamibi imaging showed an adenoma, located in the front mid-mediastinum, approximately 8 × 10 mm in size. Resection of the tumor was indicated according to the persistent hypercalcemia after unsuccessful surgical treatment performed 3 years ago. It was decided to perform a parathyroidectomy during thoracoscopy. The diagnosis of parathyroid adenoma was established on postoperative histopathology staining. The patient was discharged from hospital 5 days after the surgery. We found this minimally invasive operation to be an effective and well-tolerated treatment option, determined by the experience of the surgeon. [ABSTRACT FROM AUTHOR]

Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for T cell development in the thymus, and changes in the IL-7/IL-7R pathway have been implicated in age-associated thymic involution which results in a reduction of naïve T cell output. The aim of this study was to investigate the relationship between IL7 and IL7R genetic variation and thymic output in dogs. No single nucleotide polymorphisms (SNPs) were identified in the canine IL7 gene, but a number were present in the canine IL7R gene. Polymorphisms in the IL7R exon 8 and 3′UTR were found to be associated with signal joint T cell receptor excision circle (sj-TREC) values (a biomarker of thymic output) in young and geriatric Labrador retrievers. Additionally, one of the SNPs in the IL7R 3′UTR (SNP 14 c.1371 + 446 A > C) was found to cause a change in the seed-binding site for microRNA 185 which, a luciferase reporter assay demonstrated, caused changes in post-transcriptional regulation, and therefore might be capable of influencing IL-7R expression. The research findings suggest a genetic link between IL7R genotype and thymic output in dogs, which might impact on immune function as these animals age and provide further evidence of the involvement of IL-7/IL-7R pathway in age-associated thymic involution. [ABSTRACT FROM AUTHOR]

The immune system protects our bodies against infections and cancers. This review introduce readers to the thymus - a primary lymphoid organ - which is the site of development and maturation of functional T lymphocytes. Progenitor stem cells arise from the bone marrow and undergo sequential development in the thymus where non-self-reactive T cells are selected. Subsequently, post selection and maturation, the mature T cells exit the thymus as naïve T cells into the peripheral lymph nodes. Studies on the thymus are likely to enhance our understanding of T cell development and reduce disease burdens by improving the cellular immune response. [ABSTRACT FROM AUTHOR]

The thymus is critical in establishing and maintaining the appropriate microenvironment for promoting the development and selection of T cells. The function and structure of the thymus gland has been extensively studied, particularly as the thymus serves an important physiological role in the lymphatic system. Numerous studies have investigated the morphological features of thymic involution. Recently, research attention has increasingly been focused on thymic proteins as targets for drug intervention. Omics approaches have yielded novel insights into the thymus and possible drug targets. The present review addresses the signaling and transcriptional functions of the thymus, including the molecular mechanisms underlying the regulatory functions of T cells and their role in the immune system. In addition, the levels of cytokines secreted in the thymus have a significant effect on thymic functions, including thymocyte migration and development, thymic atrophy and thymic recovery. Furthermore, the regulation and molecular mechanisms of stress‑mediated thymic atrophy and involution were investigated, with particular emphasis on thymic function as a potential target for drug development and discovery using proteomics. [ABSTRACT FROM AUTHOR]

Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation toward a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4Rα and IL-13Rα1 give rise to myeloid cells but not T cells. In this article, we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment toward the myeloid cells. Indeed, HR+ ETPs, but not HR- ETPs, exhibit activated STAT6 transcription factor, which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, the myeloid-specific transcription factor C/EBPa, usually under the control of Notch1, is upregulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR+ ETPs, which regain T lineage potential. In addition, upon stimulation with IL-4 or IL-13, HR2 ETPs expressing virally transduced HR also exhibit STAT6 phosphorylation and downregulation of Notch1, leading to inhibition of lymphoid, but not myeloid, lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice, which would impact T cell development. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary autosomal dominant disorder associated with numerous neuroendocrine tumors (NETs). Recent advances in the management of MEN1 have led to a decrease in mortality due to excess hormones; however, they have also led to an increase in mortality from malignancy, particularly NETs. The main challenges are to localize these tumors, to select those that need therapy because of the risk of aggressive behavior and to select the appropriate therapy associated with minimal morbidity. This must be applied to a hereditary disease with a high risk of recurrence. The overall aim of management in MEN1 is to ensure that the patient remains disease- and symptom-free for as long as possible and maintains a good quality of life. Herein, we review the changes that occurred in the last 20 years in the surgical management of MEN1-associated functional and non-functional pancreaticoduodenal NETs and thymic and bronchial NETs. [ABSTRACT FROM AUTHOR]

Following thymic maturation, T cells egress as recent thymic emigrants to peripheral lymphoid organs where they undergo an additional maturation step to mature naive T cells that circulate through secondary lymphoid organs ready to be activated upon pathogenic challenges. Thymic maturation and peripheral T cell survival depend on several signaling cascades, but whether a dedicated mechanism exists that exclusively regulates homeostasis of mature naive T cells without affecting thymocytes and/or recent thymic emigrants remains unknown. In this article, we provide evidence for a specific and exclusive role of the WD repeat containing protein coronin 1 in the maintenance of naive T cells in peripheral lymphoid organs. We show that coronin 1 is dispensable for thymocyte survival and development, egress from the thymus, and survival of recent thymic emigrants. Importantly, coronin 1-deficient mice possessed comparable levels of peripheral T cells within the first 2 wk after birth but failed to populate the peripheral T cell compartment at later stages. Furthermore, dendritic cell- and IL-2/7-dependent T cell survival was found to be independent of coronin 1. Together, these results suggest the existence of a hitherto unrecognized coronin 1-dependent decision switch early during life that is responsible for peripheral naive T cell survival and homeostasis. [ABSTRACT FROM AUTHOR]

Recent studies show that the frequencies of circulating follicullar helper T (cTfh) cells are significantly higher in myasthenia gravis (MG) patients compared with healthy controls (HC). And, they are positively correlated with levels of serum anti-acetylcholine receptor antibody (anti-AchR Ab). It is unclear whether cTfh cell subset frequencies are altered and what role they play in MG patients. In order to clarify this, we examined the frequencies of cTfh cell counterparts, their subsets, and circulating plasmablasts in MG patients by flow cytometry. We determined the concentrations of serum anti-AChR Ab by enzyme-linked immunosorbent assay (ELISA). We assayed the function of cTfh cell subsets by flow cytometry and real-time polymerase chain reaction (RT-PCR). We found higher frequencies of cTfh cell counterparts, cTfh-Th17 cells, and plasmablasts in MG patients compared with HC. The frequencies of cTfh cell counterparts and cTfh-Th17 cells were positively correlated with the frequencies of plasmablasts and the concentrations of anti-AChR Ab in MG patients. Functional assays showed that activated cTfh-Th17 cells highly expressed key molecular features of Tfh cells including ICOS, PD-1, and IL-21. Results indicate that, just like cTfh cell counterparts, cTfh-Th17 cells may play a role in the immunopathogenesis and the production of anti-AChR Ab of MG. [ABSTRACT FROM AUTHOR]

Thymic epithelial cells (TECs) establish spatially distinct microenvironments in which developing T cells are selected to mature or die. A unique property of medullary TECs is their expression of thousands of tissue-restricted self-antigens that is largely under the control of the transcriptional regulator Aire. We previously showed that Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, is important for Aire protein expression and that transplantation of Jmjd6-deficient thymic stroma into athymic nude mice resulted in multiorgan autoimmunity. Here we report that TEC-specific deletion of Jmjd6 exacerbates development of autoimmune diabetes in a mouse model, which express both ovalbumin (OVA) under the control of the rat insulin gene promoter and OT-I T cell receptor specific for OVA peptide bound to major histocompatibility complex class I K b molecules. We found that Aire protein expression in mTECs was reduced in the absence of Jmjd6, with retention of intron 2 in Aire transcripts. Our results thus demonstrate the importance of Jmjd6 in establishment of immunological tolerance in a more physiological setting. [ABSTRACT FROM AUTHOR]

The contribution of the decline in thymic activity for the emergence of autoimmunity is still debatable. Immune-competent adults submitted to complete thymectomy early in life provide a unique model to address this question. We applied here strict criteria to identify adults lacking thymic activity based on sjTREC levels, to exclude thymic rebound and/or ectopic thymuses. In agreement, they featured severe naïve CD4 T-cell depletion and contraction of T-cell receptor diversity. Notwithstanding this, there was neither increased incidence of autoimmune disease in comparison with age-matched controls nor significant changes in their IgG/IgA/IgM/IgE autoreactivity profiles, as assessed through extensive arrays. We reasoned that the observed relative preservation of the regulatory T-cell compartment, including maintenance of naïve regulatory CD4 T-cells, may contribute to limit the emergence of autoimmunity upon thymectomy. Our findings have implications in other clinical settings with impaired thymic activity, and are particularly relevant to studies of autoimmunity in ageing. [ABSTRACT FROM AUTHOR]

Background & Aims The liver is an immunologically-privileged organ. Breakdown of liver immune privilege has been reported in chronic liver disease; however, the role of adaptive immunity in liver injury is poorly defined. Nuclear factor-κB-inducing kinase (NIK) is known to regulate immune tissue development, but its role in maintaining liver homeostasis remains unknown. This study aimed to assess the role of NIK, particularly thymic NIK, in regulating liver adaptive immunity. Methods NIK was deleted systemically or conditionally using the Cre/loxp system. Cluster of differentiation [CD]4 + or CD8 + T cells were depleted using anti-CD4 or anti-CD8 antibody. Donor bone marrows or thymi were transferred into recipient mice. Immune cells were assessed by immunohistochemistry and flow cytometry. Results Global, but not liver-specific or hematopoietic lineage cell-specific, deletion of NIK induced fatal liver injury, inflammation, and fibrosis. Likewise, adoptive transfer of NIK -null, but not wild-type, thymi into immune-deficient mice induced liver inflammation, injury, and fibrosis in recipients. Liver inflammation was characterized by a massive expansion of T cells, particularly the CD4 + T cell subpopulation. Depletion of CD4 + , but not CD8 + , T cells fully protected against liver injury, inflammation, and fibrosis in NIK -null mice. NIK deficiency also resulted in inflammation in the lung, kidney, and pancreas, but to a lesser degree relative to the liver. Conclusions Thymic NIK suppresses development of autoreactive T cells against liver antigens, and NIK deficiency in the thymus results in CD4 + T cell-orchestrated autoimmune hepatitis and liver fibrosis. Thus, thymic NIK is essential for the maintenance of liver immune privilege and liver homeostasis. Lay summary We found that global or thymus-specific ablation of the NIK gene results in fatal autoimmune liver disease in mice. NIK-deficient mice develop liver inflammation, injury, and fibrosis. Our findings indicate that thymic NIK is essential for the maintenance of liver integrity and homeostasis. [ABSTRACT FROM AUTHOR]

Thymulin is a well-characterized thymic hormone that exists as a nonapeptide coupled to equimolar amounts of Zn2+. Thymulin is known to have multiple biological roles, including T cell differentiation, immune regulation, and analgesic functions. It has been shown that thymulin is produced by the reticulo-epithelial cells of the thymus, and it circulates in the blood from the moment of birth, maintain its serum level until puberty diminishing thereafter in life. To study the localization of this hormone, we prepared polyclonal and monoclonal antibodies against the commercial peptide and utilized immunocytochemical techniques for visualization. The results indicate that thymulin stains the thymic reticular cells, the outer layers of Hassall's corpuscles and a large round cellular type, which is keratin-negative and does not show affinity for the common leukocyte antigen (CD-45). In mice, this thymulin-positive cell remains in the thymus throughout life and even appears in relatively increased numbers in old involuted thymi. It also appears in thymus-dependent areas of the spleen and lymph nodes, demonstrating that at least one of the thymus cells containing this peptide can be found in peripheral lymphoid tissue.

Background: Thymosin beta 10 (TMSB10) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to determine the biological roles and clinical significance of TMSB10 in breast cancer and to identify whether TMSB10 might be used as a serum marker for the diagnosis of breast cancer.Methods: TMSB10 expression was evaluated by immunohistochemical analysis (IHC) of 253 breast tumors and ELISA of serum from 80 patients with breast cancer. Statistical analysis was performed to explore the correlation between TMSB10 expression and clinicopathological features in breast cancer. Univariate and multivariate Cox regression analysis were performed to examine the association between TMSB10 expression and overall survival and metastatic status. In vitro and in vivo assays were performed to assess the biological roles of TMSB10 in breast cancer. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the tumor-promoting role of TMSB10.Results: We found TMSB10 was upregulated in breast cancer cells and tissues. Univariate and multivariate analysis demonstrated that high TMSB10 expression significantly correlated with clinicopathological features, poor prognosis and distant metastases in patients with breast cancer. Overexpression of TMSB10 promotes, while silencing of TMSB10 inhibits, proliferation, invasion and migration of breast cancer cells in vitro and in vivo. Our results further reveal that TMSB10 promotes the proliferation, invasion and migration of breast cancer cells via AKT/FOXO signaling, which is antagonized by the AKT kinase inhibitor perifosine. Importantly, the expression of TMSB10 is significantly elevated in the serum of patients with breast cancer and is positively associated with clinical stages of breast cancer.Conclusion: TMSB10 may hold promise as a minimally invasive serum cancer biomarker for the diagnosis of breast cancer and a potential therapeutic target which will facilitate the development of a novel therapeutic strategy against breast cancer. [ABSTRACT FROM AUTHOR]

Background. The persistence of an inverted CD4/CD8 ratio has been extensively associated with the increased morbimortality of chronic human immunodeficiency virus (HIV)-infected subjects. Thymic function is crucial for the maintenance of T cell homeostasis. We explored the impact of thymic function on the CD4/CD8 ratio of HIV-infected subjects. Methods. In a cohort of 53 antiretroviral-naive HIV-infected subjects, the measure of thymic volume, as a representative marker for thymic function, was available at baseline and at 12, 24, and 48 weeks post antiretroviral treatment. Results. Baseline thymic volume was associated with the C,D4/CD8 ratio (p = 0.413, P = .002), being this association highly dependent on the CD4 T cell levels. In subjects who achieved undetectable viral load after treatment (n = 33), a higher baseline thymic volume was associated with a higher increase in CD4 T cell counts and a decreasing trend in CD8 T cell counts during follow-up. Moreover, the baseline thymic volume was independently associated with the normalization of the CD4/CD8 ratio after 96 weeks of treatment (odds ratio, 95% confidence interval: 1.95 (1.07-3.55); P = .03). Conclusions. Our data indicate the relevance of the remaining thymic function before the start of treatment to the CD4/CD8 ratio of HIV- infected subjects and, hence, potentially, in their clinical progression. [ABSTRACT FROM AUTHOR]

The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly to enforce the β-selection checkpoint during thymopoiesis, yet their molecular targets remain largely unknown. In this study, we identify these targets on a genome-wide scale in primary mouse thymocytes and show that Zfp36l1/l2 regulate DNA damage response and cell cycle transcripts to ensure proper β-selection. Double-negative 3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with postselected double-negative 3b cells despite the absence of intracellular TCRβ and reduced IL-7 signaling. Our findings show that in addition to controlling the timing of proliferation at β-selection, posttranscriptional control by Zfp36l1/l2 limits DNA damage responses, which are known to promote thymocyte differentiation. Zfp36l1/l2 therefore act as posttranscriptional safeguards against chromosomal instability and replication stress by integrating pre-TCR and IL-7 signaling with DNA damage and cell cycle control. [ABSTRACT FROM AUTHOR]

Atypical thymic carcinoid is an extremely rare thymic neuroendocrine tumor derived from the neuroendocrine system. The aims of this paper were to investigate the clinical features of atypical thymic carcinoid and collate information and experience to improve the diagnosis and treatment of this disease. We describe three cases of atypical carcinoid of the thymus; clinical features, pathological data, treatment modalities, and short-term patient outcomes were summarized and analyzed. The initial clinical symptoms and signs of all three patients were nonspecific and an anterior mediastinal mass was found in each patient on chest computed tomography scan. All three patients underwent surgical resection (total thymectomy and complete excision of the tumor), followed by postoperative radiotherapy, with or without chemotherapy. The diagnoses of three patients were confirmed by pathological and immunohistochemical evaluation. We also present a review of the literature to collate as much information as possible and provide a reference for proper diagnosis and treatment of atypical thyroid carcinoid. [ABSTRACT FROM AUTHOR]

The article provides the clinical signs and macroscopic and microscopic features of a thymic lymphoma in an arowana with a brief review of the literature. It cites a 1 year old gold crossback arowana presented to the Prasu-Arthorn animal hospital with a history of a weeklong period anorexia and delayed or lack of response to external stimuli. It describes the pathological and histophathologic findings associated with spontaneous thymic lymphoma in a gold crossback arowana.

Our understanding of how thymocytes differentiate into many subtypes has been increased progressively in its complexity. At early life, the thymus provides a suitable microenvironment with specific combination of stromal cells, growth factors, cytokines, and chemokines to induce the bone marrow lymphoid progenitor T-cell precursors into single-positive CD4+ and CD8+ T effectors and CD4+CD25+ T-regulatory cells (Tregs). At postthymic compartments, the CD4+ T-cells acquire distinct phenotypes which include the classical T-helper 1 (Th1), T-helper 2 (Th2), T-helper 9 (Th9), T-helper 17 (Th17), follicular helper T-cell (Tfh), and induced T-regulatory cells (iTregs), such as the regulatory type 1 cells (Tr1) and transforming growth factor-β- (TGF-β-) producing CD4+ T-cells (Th3). Tregs represent only a small fraction, 5–10% in mice and 1-2% in humans, of the overall CD4+ T-cells in lymphoid tissues but are essential for immunoregulatory circuits mediating the inhibition and expansion of all lineages of T-cells. In this paper, we first provide an overview of the major cell-intrinsic developmental programs that regulate T-cell lineage fates in thymus and periphery. Next, we introduce the SV40 immortomouse as a relevant mice model for implementation of new approaches to investigate thymus organogenesis, CD4 and CD8 development, and thymus cells tumorogenesis. [ABSTRACT FROM AUTHOR]

Background: Paracoccidioidomycosis, a chronic granulomatous fungal disease caused by Paracoccidioides brasiliensis yeast cells affects mainly rural workers, albeit recently cases in immunosuppressed individuals has been reported. Protective immune response against P. brasiliensis is dependent on the activity of helper T cells especially IFN-γ-producing Th1 cells. It has been proposed that Paracoccidioides brasiliensis is able to modulate the immune response towards a permissive state and that the thymus plays a major role in it.Methods: In this paper, we show that acute infection of BALB/c mice with P. brasiliensis virulent isolate (Pb18) might cause alterations in the thymic environment as well as the prohibitive TCR-expressing T cells in the spleens.Results: After seven days of infection, we found yeast cells on the thymic stroma, the thymic epithelial cells (TEC) were altered regarding their spatial-orientation and inflammatory mediators gene expression was increased. Likewise, thymocytes (differentiating T cells) presented higher migratory ability in ex vivo experiments. Notwithstanding, P. brasiliensis-infected mice showed an increased frequency of prohibitive TCR-expressing T cells in the spleens, suggesting that the selection processes that occur in the thymus may be compromised during the acute infection.Conclusion: In this paper, for the first time, we show that acute infection with Paracoccidioides brasiliensis yeast cells promotes thymic alterations leading to a defective repertoire of peripheral T cells. The data presented here may represent new mechanisms by which P. brasiliensis subverts the immune response towards the chronic infection observed in humans. [ABSTRACT FROM AUTHOR]

Objectives: To study the utility of fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting (1) the World Health Organization (WHO) histologic type and differentiating low-risk from high-risk types. (2) Tumor stage and differentiate early from advanced stage disease.Materials and Methods: Patients with thymic epithelial neoplasia who underwent a pretreatment FDG-PET study were included. Tumor maximum standardized uptake value (SUVmax) was correlated with the WHO histologic type and also with the Masaoka-Koga (MK) staging system. Patients with WHO Type A, AB, and B1 were classified as low risk and those with B2 and B3 as high risk. Thymic carcinomas belonged to Type C. Patients with MK Stage I and II disease were grouped as early stage and those with Stage III and IV as an advanced stage. Differences in SUVmax between the various groups were calculated.Results: The SUVmax of thymic carcinomas was significantly higher as compared to low-risk (P = 0.001) and high-risk groups (P = 0.007). The SUVmax of high-risk group was also significantly higher than the low-risk group (P = 0.002). SUVmax cutoff of 6.5 was able to differentiate thymic carcinomas from thymomas with 100% sensitivity and 87.2% specificity. The SUVmax in patients with advanced stage disease showed a higher trend compared to those with early stage, but the difference was not significant (P = 0.167).Conclusion: PET can differentiate thymic carcinomas from rest of the thymoma subtypes by the virtue of their higher FDG uptake. It can also provide valuable information in differentiating high-risk from low-risk thymomas and in predicting disease stage. [ABSTRACT FROM AUTHOR]