Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla

PubMed Central

McCaughtry, Tom M.; Baldwin, Troy A.; Wilken, Matthew S.; Hogquist, Kristin A.

2008-01-01

The thymic medulla is generally held to be a specialized environment for negative selection. However, many self-reactive thymocytes first encounter ubiquitous self-antigens in the cortex. Cortical epithelial cells are vital for positive selection, but whether such cells can also promote negative selection is controversial. We used the HYcd4 model, where T cell receptor for antigen (TCR) expression is appropriately timed and a ubiquitous self-antigen drives clonal deletion in male mice. We demonstrated unambiguously that this deletion event occurs in the thymic cortex. However, the kinetics in vivo indicated that apoptosis was activated asynchronously relative to TCR activation. We found that radioresistant antigen-presenting cells and, specifically, cortical epithelial cells do not efficiently induce apoptosis, although they do cause TCR activation. Rather, thymocytes undergoing clonal deletion were preferentially associated with rare CD11c+ cortical dendritic cells, and elimination of such cells impaired deletion. PMID:18936237

Thymic cytoarchitecture changes in mice exposed to vanadium.

PubMed

Ustarroz-Cano, Martha; Garcia-Pelaez, Isabel; Cervantes-Yepez, Silvana; Lopez-Valdez, Nelly; Fortoul, Teresa I

2017-12-01

The thymus is a vital immune system organ wherein selection of T-lymphocytes occurs in a process regulated by dendritic and epithelial thymic cells. Previously, we have reported that in a mouse model of vanadium inhalation, a decrease in CD11c dendritic cells was observed. In the present study, we report on a thymic cortex-medulla distribution distortion in these hosts due to apparent effects of the inhaled vanadium on cytokeratin-5 (K5 + ) epithelial cells in the same mouse model - after 1, 2, and 4 weeks of exposure - by immunohistochemistry. These cells - together with dendritic cells - eliminate autoreactive T-cell clones and regulate the production of regulatory T-cells in situ. Because both cell types are involved in the negative selection of autoreactive clones, a potential for an increase in development of autoimmune conditions could be a possible consequence among individuals who might be exposed often to vanadium in air pollution, including dwellers of highly polluted cities with elevated levels of particulate matter onto which vanadium is often adsorbed.

Competing Contingencies for Escape Behavior: Effects of Negative Reinforcement Magnitude and Quality

ERIC Educational Resources Information Center

Hammond, Jennifer L.

2009-01-01

Previous research has shown that problem behavior maintained by social-negative reinforcement can be treated without escape extinction by enhancing the quality of positive reinforcement for an appropriate alternative response such as compliance. By contrast, negative reinforcement (escape) for compliance generally has been ineffective in the…

Cholinergic chemosensory cells of the thymic medulla express the bitter receptor Tas2r131.

PubMed

Soultanova, Aichurek; Voigt, Anja; Chubanov, Vladimir; Gudermann, Thomas; Meyerhof, Wolfgang; Boehm, Ulrich; Kummer, Wolfgang

2015-11-01

The thymus is the site of T cell maturation which includes positive selection in the cortex and negative selection in the medulla. Acetylcholine is locally produced in the thymus and cholinergic signaling influences the T cell development. We recently described a distinct subset of medullary epithelial cells in the murine thymus which express the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT) and components of the canonical taste transduction cascade, i.e. transient receptor potential melastatin-like subtype 5 channel (TRPM5), phospholipase Cβ(2), and Gα-gustducin. Such a chemical phenotype is characteristic for chemosensory cells of mucosal surfaces which utilize bitter receptors for detection of potentially hazardous compounds and cholinergic signaling to initiate avoidance reflexes. We here demonstrate mRNA expression of bitter receptors Tas2r105, Tas2r108, and Tas2r131 in the murine thymus. Using a Tas2r131-tauGFP reporter mouse we localized the expression of this receptor to cholinergic cells expressing the downstream elements of the taste transduction pathway. These cells are distinct from the medullary thymic epithelial cells which promiscuously express tissue-restricted self-antigens during the process of negative selection, since double-labeling immunofluorescence showed no colocalization of autoimmune regulator (AIRE), the key mediator of negative selection, and TRPM5. These data demonstrate the presence of bitter taste-sensing signaling in cholinergic epithelial cells in the thymic medulla and opens a discussion as to what is the physiological role of this pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Escapism among players of MMORPGs--conceptual clarification, its relation to mental health factors, and development of a new measure.

PubMed

Hagström, David; Kaldo, Viktor

2014-01-01

Previous studies show that the concept of escapism needs to be clarified and that its relation to problematic online gaming and other factors needs further examination. This study uses well-established, basic learning theory to clarify the concept of escapism, and examines its relation to problematic gaming, psychological distress, and satisfaction with life among players of massively multiplayer online role-playing games (MMORPGs). MMORPG players (n=201) answered an online questionnaire where these factors were measured and correlated with a previously developed scale on motivation to play (MTPI), including extra items to cover positive and negative aspects of escapism. Factor analysis and construct validation show that positive aspects of escapism are theoretically and empirically unstable and that escapism is best clarified as purely "negative escapism," corresponding to playing being negatively reinforced as a way of avoiding everyday hassles and distress. Negative escapism had a stronger relationship to symptoms of Internet addiction, psychological distress, and life satisfaction than other variables and other more positive motivations to play. Future studies should use the revised subscale for escapism (in the MTPI-R) presented in the present study, for example when screening for Internet addiction.

Thymoma and Thymic Carcinoma—Health Professional Version

Cancer.gov

Thymomas and thymic carcinomas are epithelial tumors of the thymus. A thymic epithelial tumor that exhibits cytologic atypia and histologic features no longer specific to the thymus is known as a thymic carcinoma. Find evidence-based information on thymoma and thymic carcinoma treatment.

Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras.

PubMed

Papapetrou, Eirini P; Kovalovsky, Damian; Beloeil, Laurent; Sant'angelo, Derek; Sadelain, Michel

2009-01-01

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression by targeting complementary sequences, referred to as miRNA recognition elements (MREs), typically located in the 3' untranslated region of mRNAs. miR-181a is highly expressed in developing thymocytes and markedly downregulated in post-thymic T cells. We investigated whether endogenous miR-181a can be harnessed to segregate expression of chimeric antigen receptors (CARs) and TCRs between developing and mature T cells. Lentiviral-encoded antigen receptors were tagged with a miR-181a-specific MRE and transduced into mouse BM cells that were used to generate hematopoietic chimeras. Expression of a CAR specific for human CD19 (hCD19) was selectively suppressed in late double-negative and double-positive thymocytes, coinciding with the peak in endogenous miR-181a expression. Receptor expression was fully restored in post-thymic resting and activated T cells, affording protection against a subsequent challenge with hCD19+ tumors. Hematopoietic mouse chimeras engrafted with a conalbumin-specific TCR prone to thymic clonal deletion acquired peptide-specific T cell responsiveness only when the vector-encoded TCR transcript was similarly engineered to be subject to regulation by miR-181a. These results demonstrate the potential of miRNA-regulated transgene expression in stem cell-based therapies, including cancer immunotherapy.

Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome

PubMed Central

Lorenzo, Laureanne P E; Shatynski, Kristen E; Clark, Sarah; Yarowsky, Paul J; Williams, Mark S

2013-01-01

In addition to archetypal cognitive defects, Down syndrome (DS) is characterized by altered lymphocyte development and function, including premature thymic involution and increased incidence of infections. However, the potential mechanisms for these changes have not been fully elucidated. The current study used the Ts65Dn mouse model of DS to assess deficiencies in T-cell development and possible molecular alterations. Ts65Dn mice exhibited premature thymic involution and a threefold to fourfold decrease in the number and proportion of immature, double-negative thymocyte progenitors. In addition, there were twofold fewer double-positive and CD4 single-positive thymocytes in Ts65Dn thymuses. Reflecting this deficient thymic function, there were fewer naive T cells in the spleen and polyclonal stimulation of peripheral T cells exhibited a marked reduction in proliferation, suggesting a senescent phenotype. In contrast, B-cell progenitors were unchanged in the bone marrow of Ts65Dn mice, but in the spleen, there were decreased transitional and follicular B cells and these cells proliferated less upon antigen receptor stimulus but not in response to lipopolysaccharide. As a potential mechanism for diminished thymic function, immature thymocyte populations expressed diminished levels of the cytokine receptor interleukin-7Rα, which was associated with decreased proliferation and increased apoptosis. Increased oxidative stress and inhibition of the Notch pathway were identified as possible mediators of decreased interleukin-7Rα expression in Ts65Dn mice. The data suggest that immature thymocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signalling may alter lymphocyte development in Ts65Dn mice. PMID:23432468

Computed tomography of the abnormal thymus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baron, R.L.; Lee, J.K.T.; Sagel, S.S.

1982-01-01

Computed tomography (CT) should be the imaging method of choice following plain chest radiographs when a suspected thymic abnormality requires further evaluation. Based upon a six-year experience, including the evaluation of 25 patients with thymic pathology, CT was found useful in suggesting or excluding a diagnosis of thymoma and in distinguishing thymic hyperplasis from thymoma in patients with myasthenia gravis. The thickness of the thymic lobes determined by CT was found to be a more accurate indicator of infiltrative disease (thymic hyperplasia and lymphoma) than the width. CT was helpful in differentiating benign thymic cysts from solid tumors, and inmore » defining the extent of a thymic neoplasms. On occasion, CT may suggest the specific histologic nature of a thymic lesion.« less

Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

PubMed

Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

2014-01-01

Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

Massive thymic hemorrhage and hemothorax occurring in utero.

PubMed

Gargano, Giancarlo; Paltrinieri, Anna Lucia; Gallo, Claudio; Di Pancrazio, Luciana; Roversi, Maria Federica; Ferrari, Fabrizio

2015-11-14

Thymic enlargement is a common and physiological finding in children and neonates' X-rays, but it is usually asymptomatic. Occasionally it can cause respiratory distress. In most cases the aetiology of this expansion remains unclear and it is diagnosed as a thymic hyperplasia. True thymic hyperplasia is defined as a gland expansion, both in size and weight, while maintaining normal microscopic architecture. Often it is a diagnosis of exclusion and prognosis is good. Thymic haemorrhage is an unusual condition related to high foetal and neonatal mortality. We report a case of spontaneous massive thymic haemorrhage in a newborn developing at birth acute respiratory distress associated with severe bilateral haemothorax. Thymic enlargement was evident after pleural evacuation and confirmed by radiographic, Computed Tomography (CT) images and Magnetic Resonance Imaging (MRI) sequences. The spontaneous resolution of this enlargement seen with CT scan and MRI sequences suggested a thymic haemorrhage; surgery was not necessary. Thymic haemorrhage should be considered in newborn infants with pleural effusion, mediastinal space enlargement and Respiratory Distress.

Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression

PubMed Central

Garfin, Phillip M.; Min, Dullei; Bryson, Jerrod L.; Serwold, Thomas; Edris, Badreddin; Blackburn, Clare C.; Richie, Ellen R.; Weinberg, Kenneth I.; Manley, Nancy R.; Viatour, Patrick

2013-01-01

Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow–independent mechanism, identifying a novel pathway to target to increase thymic function in patients. PMID:23669396

Inhibition of Thymic Adipogenesis by Caloric Restriction Is Coupled with Reduction in Age-Related Thymic Involution1

PubMed Central

Yang, Hyunwon; Youm, Yun-Hee; Dixit, Vishwa Deep

2009-01-01

Aging of thymus is characterized by reduction in naive T cell output together with progressive replacement of lymphostromal thymic zones with adipocytes. Determining how calorie restriction (CR), a prolongevity metabolic intervention, regulates thymic aging may allow identification of relevant mechanisms to prevent immunosenescence. Using a mouse model of chronic CR, we found that a reduction in age-related thymic adipogenic mechanism is coupled with maintenance of thymic function. The CR increased cellular density in the thymic cortex and medulla and preserved the epithelial signatures. Interestingly, CR prevented the age-related increase in epithelial-mesenchymal transition (EMT) regulators, FoxC2, and fibroblast-specific protein-1 (FSP-1), together with reduction in lipid-laden thymic fibroblasts. Additionally, CR specifically blocked the age-related elevation of thymic proadipogenic master regulator, peroxisome proliferator activated receptor γ (PPARγ), and its upstream activator xanthine-oxidoreductase (XOR). Furthermore, we found that specific inhibition of PPARγ in thymic stromal cells prevented their adipogenic transformation in an XOR-dependent mechanism. Activation of PPARγ-driven adipogenesis in OP9-DL1 stromal cells compromised their ability to support T cell development. Conversely, CR-induced reduction in EMT and thymic adipogenesis were coupled with elevated thymic output. Compared with 26-mo-old ad libitum fed mice, the T cells derived from age-matched CR animals displayed greater proliferation and higher IL-2 expression. Furthermore, CR prevented the deterioration of the peripheral TCR repertoire diversity in older animals. Collectively, our findings demonstrate that reducing proadipogenic signaling in thymus via CR may promote thymopoiesis during aging. PMID:19648267

Thymic Fatness and Approaches to Enhance Thymopoietic Fitness in Aging

PubMed Central

Dixit, Vishwa Deep

2010-01-01

Summary With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. As the thymus involutes, reduction in thymocytes and thymic epithelial cells precede the emergence of mature lipid-laden adipocytes. Dogma dictates that adipocytes are ‘passive’ cells that occupy non-epithelial thymic space or ‘infiltrate’ the non cellular thymic niches. The provenance and purpose of ectopic thymic adipocytes during aging in an organ that is required for establishment and maintenance of T cell repertoire remains an unsolved puzzle. Nonetheless, tantalizing clues about elaborate reciprocal relationship between thymic fatness and thymopoietic fitness are emerging. Blocking or bypassing the route towards thymic adiposity may complement the approaches to rejuvenate thymopoiesis and immunity in elderly. PMID:20650623

Thymic fatness and approaches to enhance thymopoietic fitness in aging.

PubMed

Dixit, Vishwa Deep

2010-08-01

With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. As the thymus involutes, reduction in thymocytes and thymic epithelial cells precede the emergence of mature lipid-laden adipocytes. Dogma dictates that adipocytes are 'passive' cells that occupy non-epithelial thymic space or 'infiltrate' the non-cellular thymic niches. The provenance and purpose of ectopic thymic adipocytes during aging in an organ that is required for establishment and maintenance of T cell repertoire remains an unsolved puzzle. Nonetheless, tantalizing clues about elaborate reciprocal relationship between thymic fatness and thymopoietic fitness are emerging. Blocking or bypassing the route toward thymic adiposity may complement the approaches to rejuvenate thymopoiesis and immunity in elderly. Copyright 2010 Elsevier Ltd. All rights reserved.

The effects of variable-time delivery of food items and praise on problem behavior reinforced by escape.

PubMed

Lomas, Joanna E; Fisher, Wayne W; Kelley, Michael E

2010-01-01

Prior research indicates that reinforcement of an appropriate response (e.g., compliance) can produce concomitant reductions in problem behavior reinforced by escape when problem behavior continues to produce negative reinforcement (e.g., Lalli et al., 1999). These effects may be due to a preference for positive over negative reinforcement or to positive reinforcement acting as an abolishing operation, rendering demands less aversive and escape from demands less effective as negative reinforcement. In the current investigation, we delivered a preferred food item and praise on a variable-time 15-s schedule while providing escape for problem behavior on a fixed-ratio 1 schedule in a demand condition for 3 participants with problem behavior maintained by negative reinforcement. Results for all 3 participants showed that variable-time delivery of preferred edible items reduced problem behavior even though escape continued to be available for these responses. These findings are discussed in the context of motivating operations.

Choices between positive and negative reinforcement during treatment for escape-maintained behavior.

PubMed

DeLeon, I G; Neidert, P L; Anders, B M; Rodriguez-Catter, V

2001-01-01

Positive reinforcement was more effective than negative reinforcement in promoting compliance and reducing escape-maintained problem behavior for a child with autism. Escape extinction was then added while the child was given a choice between positive or negative reinforcement for compliance and the reinforcement schedule was thinned. When the reinforcement requirement reached 10 consecutive tasks, the treatment effects became inconsistent and reinforcer selection shifted from a strong preference for positive reinforcement to an unstable selection pattern.

Images in pediatrics: the thymic sail sign and thymic wave sign.

PubMed

Alves, Nuno D; Sousa, Marta

2013-01-01

The authors present a radiographic image portraying the "thymic sail sign" and the "thymic wave sign," both normal findings in infant radiographs and present a short description of these signs. These are distinguished from pathologic findings such as the "spinnaker-sail sign" in pneumomediastinum.

The Wnt signaling antagonist Kremen1 is required for development of thymic architecture.

PubMed

Osada, Masako; Ito, Emi; Fermin, Hector A; Vazquez-Cintron, Edwin; Venkatesh, Tadmiri; Friedel, Roland H; Pezzano, Mark

2006-01-01

Wnt signaling has been reported to regulate thymocyte proliferation and selection at several stages during T cell ontogeny, as well as the expression of FoxN1 in thymic epithelial cells (TECs). Kremen1 (Krm1) is a negative regulator of the canonical Wnt signaling pathway, and functions together with the secreted Wnt inhibitor Dickkopf (Dkk) by competing for the lipoprotein receptor-related protein (LRP)-6 co-receptor for Wnts. Here krm1 knockout mice were used to examine krm1 expression in the thymus and its function in thymocyte and TEC development. Krm1 expression was detected in both cortical and medullary TEC subsets, as well as in immature thymocyte subsets, beginning at the CD25+CD44+ (DN2) stage and continuing until the CD4+CD8+(DP) stage. Neonatal mice show elevated expression of krm1 in all TEC subsets. krm1(-/-) mice exhibit a severe defect in thymic cortical architecture, including large epithelial free regions. Much of the epithelial component remains at an immature Keratin 5+ (K5) Keratin 8(+)(K8) stage, with a loss of defined cortical and medullary regions. A TOPFlash assay revealed a 2-fold increase in canonical Wnt signaling in TEC lines derived from krm1(-/-) mice, when compared with krm1(+/+) derived TEC lines. Fluorescence activated cell sorting (FACS) analysis of dissociated thymus revealed a reduced frequency of both cortical (BP1(+)EpCAM(+)) and medullary (UEA-1(+) EpCAM(hi)) epithelial subsets, within the krm1(-/-) thymus. Surprisingly, no change in thymus size, total thymocyte number or the frequency of thymocyte subsets was detected in krm1(-/-) mice. However, our data suggest that a loss of Krm1 leads to a severe defect in thymic architecture. Taken together, this study revealed a new role for Krm1 in proper development of thymic epithelium.

Induction of epithelial to mesenchymal transition (EMT) and inhibition on adipogenesis: Two different sides of the same coin? Feasible roles and mechanisms of transforming growth factor β1 (TGF-β1) in age-related thymic involution.

PubMed

Tan, Jianxin; Wang, Yajun; Zhang, Nannan; Zhu, Xike

2016-08-01

Age-related thymic involution is characterized by a loss of thymic epithelial cells (TECs) and a concomitant increase in adipocytes, but the mechanisms involved in thymic adipogenesis are still not clear. Transforming growth factor β1 (TGF-β1) is a pleiotropic cytokine that has been reported to be up-regulated with age in thymic stromal cells in both human and mouse. However, the exact role of TGF-β1 in age-related thymic involution remains to be further elucidated. On the basis of previous findings, we propose a novel hypothesis that TGF-β1 functions a dual role in age-related thymic involution. On one hand, up-regulation of TGF-β1 promotes epithelial to mesenchymal transition (EMT) process in TECs via activating forkhead box protein C2 (FoxC2). On the other hand, TGF-β1 inhibits the transdifferentiation of EMT-derived mesenchymal cells to adipocytes in the thymus. If confirmed, our hypothesis will not only provide further evidence supporting that the transdifferentiation of TECs into pre-adipocytes represents a source of thymic adiposity during age-related thymic involution, but also uncover a unique role of TGF-β1 in the transdifferentiation of TECs into pre-adipocytes. Collectively, the inhibition of TGF-β1 may serve as a strategy to hinder age-related thymic involution or even to restore thymic function in the elderly. © 2016 International Federation for Cell Biology.

Thymoma and Thymic Carcinoma—Patient Version

Cancer.gov

Thymomas and thymic carcinomas are rare tumors that form in cells on the thymus. Thymomas grow slowly and rarely spread beyond the thymus. Thymic carcinoma grows faster, often spreads to other parts of the body, and is harder to treat. Start here to find information on thymoma and thymic carcinoma treatment.

Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review).

PubMed

Yan, Fenggen; Mo, Xiumei; Liu, Junfeng; Ye, Siqi; Zeng, Xing; Chen, Dacan

2017-11-01

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.

Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence.

PubMed

Dixit, Vishwa Deep

2012-10-01

Emerging evidence indicates that the immune and metabolic interactions control several aspects of the aging process and associated chronic diseases. Among several sites of immune-metabolic interactions, thymic demise represents a particularly puzzling phenomenon because even in metabolically healthy middle-aged individuals the majority of thymic space is replaced with ectopic lipids. The new T cell specificities can only be generated in a functional thymus and, peripheral proliferation of pre-existing T cell clones provides limited immune-vigilance in the elderly. Therefore, it is hypothesized that the strategies that enhance thymic-lymphopoiesis may extend healthspan. Recent data suggest that byproducts of thymic fatty acids and lipids result in accumulation of 'lipotoxic DAMPs' (damage associated molecular patterns), which triggers the innate immune-sensing mechanism like inflammasome activation which links aging to thymic demise. The immune-metabolic interaction within the aging thymus produces a local pro-inflammatory state that directly compromises the thymic stromal microenvironment, thymic-lymphopoiesis and serves a precursor of systemic immune-dysregulation in the elderly. New evidence also suggests that ectopic thymic adipocytes may develop from specific intrathymic stromal cell precursors instead of a passive process that is simply a consequence of thymic lymphopenia. Thus the complex bidirectional interactions between metabolic and immune systems may link aging to health, T cell senescence, and associated diseases. This review discusses the immune-metabolic mechanisms during aging - with implications for developing future therapeutic strategies for living well beyond the expected. Copyright © 2012 Elsevier Ltd. All rights reserved.

Thiazolidinedione treatment and constitutive-PPARγ activation induces ectopic adipogenesis and promotes age-related thymic involution

PubMed Central

Youm, Yun-Hee; Yang, Hyunwon; Amin, Raj; Smith, Steven R.; Leff, Todd; Dixit, Vishwa Deep

2010-01-01

Age-related thymic involution is characterized by reduction in T cell production together with ectopic adipocyte development within the hematopoietic and thymic niches. PPARγ is required for adipocyte development, glucose homeostasis and is a target for several insulin-sensitizing drugs. Our prior studies showed that age-related elevation of PPARγ expression in thymic stromal cells is associated with thymic involution. Here, using clinically relevant pharmacological and genetic manipulations in mouse models, we provide evidence that activation of PPARγ leads to reduction in thymopoiesis. Treatment of aged mice with anti-hyperglycemic PPARγ-ligand class of Thiazolidinedione drug, Rosiglitazone caused robust thymic expression of classical pro-adipogenic transcripts. Rosiglitazone reduced thymic cellularity, lowered the naïve T cell number and T cell receptor excision circles (TRECs) indicative of compromised thymopoiesis. To directly investigate whether PPARγ activation induces thymic involution, we created transgenic mice with constitutive-active PPARγ (CA-PPARg) fusion protein in cells of adipogenic lineage. Importantly, CA-PPARγ transgene was expressed in thymus and in Fibroblast Specific Protein-1/S100A4 (FSP1+) cells, a marker of secondary mesenchymal cells. The CAPPARγ fusion protein mimicked the liganded PPARγ receptor and the transgenic mice displayed increased ectopic thymic adipogenesis and reduced thymopoiesis. Furthermore, the reduction in thymopoiesis in CA-PPARγ mice was associated with higher bone marrow adiposity and lower hematopoietic stem cell progenitor pool. Consistent with lower thymic output, CAPPARγ transgenic mice had restricted T cell receptor (TCR) repertoire diversity. Collectively, our data suggest that activation of PPARγ accelerates thymic aging and thymus-specific PPARγ antagonist may forestall age-related decline in T cell diversity. PMID:20374200

Thymic hormone containing cells. III. Evidence for a feed-back regulation of the secretion of the serum thymic factor (FTS) by thymic epithelial cells.

PubMed Central

Savino, W; Dardenne, M; Bach, J F

1983-01-01

Cells containing the serum thymic factor (FTS), as measured by indirect immunofluorescence, were studied in mice either FTS depleted by injection of anti-FTS monoclonal antibodies or immunization against FTS coupled to bovine serum albumin (FTS-BSA), or FTS enriched by multiple injections of synthetic thymulin (FTS-Zn). Injections of thymulin did not significantly depress FTS secretion. Conversely, long term elimination of FTS from peripheral blood caused a great increase in the thymic intracellular content of FTS, as evidenced by the higher number of FTS containing cells observed with immunofluorescence. These data could provide the first evidence of a feed-back control of thymic endocrine function. PMID:6683135

Characterization of Thymic Settling Progenitors in the Mouse Embryo Using In Vivo and In Vitro Assays

PubMed Central

Ramond, Cyrille; Bandeira, Antonio; Berthault, Claire; Pereira, Pablo; Cumano, Ana; Burlen-Defranoux, Odile

2015-01-01

Characterizing thymic settling progenitors is important to understand the pre-thymic stages of T cell development, essential to devise strategies for T cell replacement in lymphopenic patients. We studied thymic settling progenitors from murine embryonic day 13 and 18 thymi by two complementary in vitro and in vivo techniques, both based on the “hanging drop” method. This method allowed colonizing irradiated fetal thymic lobes with E13 and/or E18 thymic progenitors distinguished by CD45 allotypic markers and thus following their progeny. Colonization with mixed populations allows analyzing cell autonomous differences in biologic properties of the progenitors while colonization with either population removes possible competitive selective pressures. The colonized thymic lobes can also be grafted in immunodeficient male recipient mice allowing the analysis of the mature T cell progeny in vivo, such as population dynamics of the peripheral immune system and colonization of different tissues and organs. Fetal thymic organ cultures revealed that E13 progenitors developed rapidly into all mature CD3+ cells and gave rise to the canonical γδ T cell subset, known as dendritic epithelial T cells. In comparison, E18 progenitors have a delayed differentiation and were unable to generate dendritic epithelial T cells. The monitoring of peripheral blood of thymus-grafted CD3-/- mice further showed that E18 thymic settling progenitors generate, with time, larger numbers of mature T cells than their E13 counterparts, a feature that could not be appreciated in the short term fetal thymic organ cultures. PMID:26131754

Thymic Carcinoma Management Patterns among International Thymic Malignancy Interest Group (ITMIG) Physicians with Consensus from the Thymic Carcinoma Working Group.

PubMed

Shepherd, Annemarie; Riely, Gregory; Detterbeck, Frank; Simone, Charles B; Ahmad, Usman; Huang, James; Korst, Robert; Rajan, Arun; Rimner, Andreas

2017-04-01

Thymic carcinomas are rare epithelial malignancies with limited data to guide management. To identify areas of agreement and variability in current clinical practice, a 16-question electronic survey was given to members of the International Thymic Malignancy Interest Group (ITMIG). Areas of controversy were discussed with the Thymic Carcinoma Working Group and consensus was achieved, as described. A total of 100 ITMIG members responded. There was general agreement regarding the role for multimodality therapy with definitive surgical resection in physically fit patients with advanced but resectable disease. Areas of controversy included the need for histologic confirmation before surgery, the role of adjuvant therapy, the optimal first-line chemotherapy regimen, and the recommended treatment course for marginally resectable disease with invasion into the great vessels, pericardium, and lungs. The results of the questionnaire provide a description of the management of thymic carcinoma by 100 ITMIG members with a specific interest or expertise in thymic malignancies. Although there was agreement in some areas, clinical practice appears to vary significantly. There is a great need for collaborative research to identify optimal evaluation and treatment strategies. Given the need for multimodality therapy in many cases, a multidisciplinary discussion of the management of patients with thymic carcinoma is critical. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Mutational status of EGFR and KIT in thymoma and thymic carcinoma.

PubMed

Yoh, Kiyotaka; Nishiwaki, Yutaka; Ishii, Genichiro; Goto, Koichi; Kubota, Kaoru; Ohmatsu, Hironobu; Niho, Seiji; Nagai, Kanji; Saijo, Nagahiro

2008-12-01

This study was conducted to evaluate the prevalence of EGFR and KIT mutations in thymomas and thymic carcinomas as a means of exploring the potential for molecularly targeted therapy with tyrosine kinase inhibitors. Genomic DNA was isolated from 41 paraffin-embedded tumor samples obtained from 24 thymomas and 17 thymic carcinomas. EGFR exons 18, 19, and 21, and KIT exons 9, 11, 13, and 17, were analyzed for mutations by PCR and direct sequencing. Protein expression of EGFR and KIT was evaluated immunohistochemically. EGFR mutations were detected in 2 of 20 thymomas, but not in any of the thymic carcinomas. All of the EGFR mutations detected were missense mutations (L858R and G863D) in exon 21. EGFR protein was expressed in 71% of the thymomas and 53% of the thymic carcinomas. The mutational analysis of KIT revealed only a missense mutation (L576P) in exon 11 of one thymic carcinoma. KIT protein was expressed in 88% of the thymic carcinomas and 0% of the thymomas. The results of this study indicate that EGFR and KIT mutations in thymomas and thymic carcinomas are rare, but that many of the tumors express EGFR or KIT protein.

Ghrelin promotes thymopoiesis during aging

PubMed Central

Dixit, Vishwa Deep; Yang, Hyunwon; Sun, Yuxiang; Weeraratna, Ashani T.; Youm, Yun-Hee; Smith, Roy G.; Taub, Dennis D.

2007-01-01

The decline in adaptive immunity, T lymphocyte output, and the contraction of the TCR repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic hormone ghrelin is expressed by immune cells and regulates T cell activation and inflammation. Here we report that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved the age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving TCR diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow–derived Lin–Sca1+cKit+ cells, while ghrelin- and growth hormone secretagogue receptor–deficient (GHS-R–deficient) mice displayed enhanced age-associated thymic involution. Leptin also enhanced thymopoiesis in aged but not young mice. Our findings demonstrate what we believe to be a novel role for ghrelin and its receptor in thymic biology and suggest a possible therapeutic benefit of harnessing this pathway in the reconstitution of thymic function in immunocompromised subjects. PMID:17823656

Thymic involution in the suspended rat - Adrenal hypertrophy and glucocorticoid receptor content

NASA Technical Reports Server (NTRS)

Steffen, J. M.; Musacchia, X. J.

1986-01-01

The relationship between thymic involution and adrenal hypertrophy is studied. The thymus, adrenal glands, and tissue water content are evaluated in male Sprague rats suspended in antiorthostatic (AO) or orthostatic (O) positions. A 50 percent decrease in the wet weight of the thymus and hypertrophy of the adrenal glands are observed during the seven days of AO suspension. After seven days of recovery the thymus weight is increased to control level; however, the hypertrophy of the adrenal glands remains unchanged. Thymic and renal responses in O postioned rats are similar to AO reactions. Thymic glucocorticoid (GC) receptor concentrations in the rats are analyzed; a 20 percent decrease in GC receptor site concentration, which is related to thymic involution, is detected in both AO and O rats. It is concluded that there is a temporal correlation between thymic involution and adrenal hypertrophy, which is not affected by AO positioning, and thymic involution is not associated with an increased sensitivity to GC.

Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development

PubMed Central

Pinto, Ana Isabel; Smith, Jennifer; Kissack, Miriam R.; Hogg, Karen G.; Green, E. Allison

2018-01-01

Type 1 diabetes (T1D) results from a coordinated autoimmune attack of insulin producing beta cells in the pancreas by the innate and adaptive immune systems, beta cell death being predominantly T cell-mediated. In addition to T cells, peripheral B cells are important in T1D progression. The thymus of mice and man also contains B cells, and lately they have been linked to central tolerance of T cells. The role of thymic B cells in T1D is undefined. Here, we show there are abnormalities in the thymic B cell compartment before beta cell destruction and T1D manifestation. Using non-obese diabetic (NOD) mice, we document that preceding T1D development, there is significant accumulation of thymic B cells-partly through in situ development- and the putative formation of ectopic germinal centers. In addition, in NOD mice we quantify thymic plasma cells and observe in situ binding of immunoglobulins to undefined antigens on a proportion of medullary thymic epithelial cells (mTECs). By contrast, no ectopic germinal centers or pronounced intrathymic autoantibodies are detectable in animals not genetically predisposed to developing T1D. Binding of autoantibodies to thymic stroma correlates with apoptosis of mTECs, including insulin-expressing cells. By contrast, apoptosis of mTECs was decreased by 50% in B cell-deficient NOD mice suggesting intrathymic autoantibodies may selectively target certain mTECs for destruction. Furthermore, we observe that these thymic B cell-associated events correlated with an increased prevalence of premature thymic emigration of T cells. Together, our data suggest that the thymus may be a principal autoimmune target in T1D and contributes to disease progression.

MiR-467a is Upregulated in Radiation-Induced Mouse Thymic Lymphomas and Regulates Apoptosis by Targeting Fas and Bax

PubMed Central

Gao, Fu; Chen, Song; Sun, Mingjuan; Mitchel, Ronald E.J.; Li, Bailong; Chu, Zhiyong; Cai, Jianming; Liu, Cong

2015-01-01

It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a-transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a-knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR-467a target sequences in the 3'UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a-upregulated EL4 cells. Then we found that both Fas- and Bax-overexpression decreased cell viability with increase of apoptosis rate, indicating that downregulation of Fas and Bax may be at least partly responsible for apoptosis suppression by miR-467a. These data suggest that miR-467a may have oncogenic functions in radiation-induced thymic lymphoma cells and that its increased expression may confer a growth advantage on tumor cells via aberrant expression of Fas and Bax. PMID:25552935

Treatment Results and Prognostic Indicators in Thymic Epithelial Tumors: A Clinicopathological Analysis of 45 Patients

PubMed Central

Ansari, Mansour; Dehsara, Farzin; Mohammadianpanah, Mohammad; Mosalaei, Ahmad; Omidvari, Shapour; Ahmadloo, Niloofar

2014-01-01

Background: Thymomas are rare epithelial tumors arising from thymus gland. This study aims at investigating the clinical presentation, prognostic factors and treatment outcome of forty five patients with thymoma and thymic carcinoma. Methods: Forty-five patients being histologically diagnosed with thymoma or thymic carcinoma that were treated and followed-up at a tertiary academic hospital during January 1987 and December 2008 were selected for the present study. Twelve patients were solely treated with surgery, 14 with surgery followed by adjuvant radiotherapy, 12 with sequential combined treatment of surgery, radiotherapy and/or chemotherapy and 7 with non-surgical approach including radiotherapy and/or chemotherapy.  Tumors were classified based on the new World Health Organization (WHO) histological classification. Results: There were 18 women and 27 men with a median age of 43 years. Twelve patients (26.7%) had stage I, 7 (17.8%) had stage II, 23 (51%) had stage III and 2 (4.5%) had stage IV disease. Tumors types were categorized as type A (n=4), type AB (n=10), type B1 (n=9), type B2 (n=10), type B3 (n=5) and type C (n=7). In univariate analysis for overall survival, disease stage (P=0.001), tumor size (P=0.017) and the extent of surgical resection (P<0.001) were prognostic factors. Regarding the multivariate analysis, only the extent of the surgical resection (P<0.001) was the independent prognostic factor and non-surgical treatment had a negative influence on the survival. The 5-year and 10-year overall survival rates were 70.8% and 62.9%, respectively. Conclusion: Complete surgical resection is the most important prognostic factor in patients with thymic epithelial tumors. PMID:25031486

Treatment results and prognostic indicators in thymic epithelial tumors: a clinicopathological analysis of 45 patients.

PubMed

Ansari, Mansour; Dehsara, Farzin; Mohammadianpanah, Mohammad; Mosalaei, Ahmad; Omidvari, Shapour; Ahmadloo, Niloofar

2014-07-01

Thymomas are rare epithelial tumors arising from thymus gland. This study aims at investigating the clinical presentation, prognostic factors and treatment outcome of forty five patients with thymoma and thymic carcinoma. Forty-five patients being histologically diagnosed with thymoma or thymic carcinoma that were treated and followed-up at a tertiary academic hospital during January 1987 and December 2008 were selected for the present study. Twelve patients were solely treated with surgery, 14 with surgery followed by adjuvant radiotherapy, 12 with sequential combined treatment of surgery, radiotherapy and/or chemotherapy and 7 with non-surgical approach including radiotherapy and/or chemotherapy.  Tumors were classified based on the new World Health Organization (WHO) histological classification. There were 18 women and 27 men with a median age of 43 years. Twelve patients (26.7%) had stage I, 7 (17.8%) had stage II, 23 (51%) had stage III and 2 (4.5%) had stage IV disease. Tumors types were categorized as type A (n=4), type AB (n=10), type B1 (n=9), type B2 (n=10), type B3 (n=5) and type C (n=7). In univariate analysis for overall survival, disease stage (P=0.001), tumor size (P=0.017) and the extent of surgical resection (P<0.001) were prognostic factors. Regarding the multivariate analysis, only the extent of the surgical resection (P<0.001) was the independent prognostic factor and non-surgical treatment had a negative influence on the survival. The 5-year and 10-year overall survival rates were 70.8% and 62.9%, respectively. Complete surgical resection is the most important prognostic factor in patients with thymic epithelial tumors.

Targeted deletion of Atg5 reveals differential roles of autophagy in keratin K5-expressing epithelia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sukseree, Supawadee; Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok; Rossiter, Heidemarie

2013-01-11

Highlights: Black-Right-Pointing-Pointer We generated mice lacking Atg5 and autophagy in keratin K5-positive epithelia. Black-Right-Pointing-Pointer Suppression of autophagy in thymic epithelium was not associated with signs of autoimmunity. Black-Right-Pointing-Pointer Autophagy was required for normal terminal differentiation of preputial gland cells. Black-Right-Pointing-Pointer Autophagy-deficient cells of the preputial glands degraded nuclear DNA prematurely. -- Abstract: Autophagy contributes to the homeostasis of many tissues, yet its role in epithelia is incompletely understood. A recent report proposed that Atg5-dependent autophagy in thymic epithelial cells is essential for their function in the negative selection of self-reactive T-cells and, thus, for the suppression of tissue inflammation. Heremore » we crossed mice carrying floxed alleles of the Atg5 gene with mice expressing the Cre recombinase under the control of the keratin K5 promoter to suppress autophagy in all K5-positive epithelia. The efficiency of autophagy abrogation was confirmed by immunoanalyses of LC3, which was converted to the autophagy-associated LC3-II form in normal but not Atg5-deficient cells, and of p62, which accumulated in Atg5-deficient cells. Mice carrying the epithelium-specific deletion of Atg5 showed normal weight gain, absence of tissue inflammation, and a normal morphology of the thymic epithelium. By contrast, autophagy-deficient epithelial cells of the preputial gland showed aberrant eosinophilic staining in histology and premature degradation of nuclear DNA during terminal differentiation. Taken together, the results of this study suggest that autophagy is dispensable for the suppression of autoimmunity by thymic epithelial cells but essential for normal differentiation of the preputial gland in mice.« less

Thymic size in uninfected infants born to HIV-positive mothers and fed with pasteurized human milk.

PubMed

Jeppesen, D; Hasselbalch, H; Ersbøll, A K; Heilmann, C; Valerius, N H

2003-06-01

To examine the size of the thymus in uninfected infants born to HIV-positive mothers and to study the effects of feeding by human donor milk on the size of the thymus in these infants. The absolute and relative thymic size was assessed by sonography as thymic index (Ti), and the Ti/weight-ratio (Ti/w) at birth and at 4 mo of age in 12 healthy uninfected infants born to HlV-infected mothers. All infants were exclusively fed pasteurized donor milk. The results were compared with those obtained from a previous cohort of exclusively breastfed, partially breastfed and exclusively formula-fed infants. At birth the Ti was reduced in infants born to HIV-infected mothers in comparison with that in control infants but this difference disappeared when their birthweights were taken into consideration (Ti/w-ratio). At 4 mo of age the geometric mean Ti of infants fed donor milk was 23.8 and the mean Ti/w-ratio was 4.2. Compared with those of exclusively breastfed infants, the Ti and Ti/w-ratio of infants fed donor milk were significantly reduced (p < 0.01). The Ti/w-ratio increased in donor-milk-fed infants compared with that in the formula-fed infants (p = 0.02). At birth the size of the thymus was smaller in uninfected infants of HIV-positive mothers compared with infants of HIV-negative mothers but when birthweight was taken into account this difference disappeared. Feeding by human donor milk seemed to result in an increased size of the thymus at 4 mo of age compared with thymic size in infants that were exclusively formula fed.

General Information about Thymoma and Thymic Carcinoma

MedlinePlus

... and Thymic Carcinoma Treatment (PDQ®)–Patient Version General Information About Thymoma and Thymic Carcinoma Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

Thymoma and Thymic Carcinoma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Thymoma and thymic carcinoma treatment options include surgery, radiation therapy, chemotherapy, chemoradiation, and corticosteroids. Get detailed information about treatment of newly diagnosed and recurrent thymoma and thymic cancer in this summary for clinicians.

A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance.

PubMed

Feng, Yongqiang; van der Veeken, Joris; Shugay, Mikhail; Putintseva, Ekaterina V; Osmanbeyoglu, Hatice U; Dikiy, Stanislav; Hoyos, Beatrice E; Moltedo, Bruno; Hemmers, Saskia; Treuting, Piper; Leslie, Christina S; Chudakov, Dmitriy M; Rudensky, Alexander Y

2015-12-03

T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection) or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs. Here we explore in mice whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.

Adenocarcinoma of the thymus, enteric type: report of 2 cases, and proposal for a novel subtype of thymic carcinoma.

PubMed

Moser, Bernhard; Schiefer, Ana Iris; Janik, Stefan; Marx, Alexander; Prosch, Helmut; Pohl, Wolfgang; Neudert, Barbara; Scharrer, Anke; Klepetko, Walter; Müllauer, Leonhard

2015-04-01

We report 2 cases of primary thymic adenocarcinoma with enteric differentiation. One carcinoma occurred in a 41-year-old man as a 7-cm-diameter cystic tumor and the other one in a 39-year-old woman as a 6-cm-diameter solid mass. Both tumors were located in the anterior mediastinum. Clinical staging did not reveal any extrathymic tumor. Histologically, the tumors were classified as adenocarcinoma, not otherwise specified, and a mucinous (colloid) carcinoma, respectively. Immunohistochemically, both tumors were positive for cytokeratin 20 (CK20), CDX2, and carcinoembryonic antigen, reflecting enteric differentiation. A review of the literature on 43 other cases of primary thymic adenocarcinomas suggested 11 further cases with enteric differentiation, as assessed by CK20 and/or CDX2 expression. We propose that thymic adenocarcinoma with enteric differentiation represents a novel subtype of thymic carcinoma. It is mostly of mucinous morphology and frequently associated with thymic cysts. The clinical outcome is variable. Recognition of primary thymic adenocarcinoma with enteric differentiation is helpful for the differentiation from metastatic disease, mainly from the gastrointestinal tract.

Administration of RANKL boosts thymic regeneration upon bone marrow transplantation.

PubMed

Lopes, Noella; Vachon, Hortense; Marie, Julien; Irla, Magali

2017-06-01

Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoiesis and a prolonged period of T-cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, we show that RANK ligand (RANKL) is upregulated in CD4 + thymocytes and lymphoid tissue inducer (LTi) cells during the early phase of thymic regeneration. Importantly, whereas RANKL neutralization alters TEC recovery after irradiation, ex vivo RANKL administration during BMT boosts the regeneration of TEC subsets including thymic epithelial progenitor-enriched cells, thymus homing of lymphoid progenitors, and de novo thymopoiesis. RANKL increases specifically in LTi cells, lymphotoxin α, which is critical for thymic regeneration. RANKL treatment, dependent on lymphotoxin α, is beneficial upon BMT in young and aged individuals. This study thus indicates that RANKL may be clinically useful to improve T-cell function recovery after BMT by controlling multiple facets of thymic regeneration. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Chronic shoulder pain referred from thymic carcinoma: a case report and review of literature

PubMed Central

Dee, Shu-Wei; Kao, Mu-Jung; Hong, Chang-Zern; Chou, Li-Wei; Lew, Henry L

2012-01-01

We report a case of thymic carcinoma presenting as unilateral shoulder pain for 13 months. Before an accurate diagnosis was made, the patient received conservative treatment, cervical discectomies, and myofascial trigger point injection, none of which relieved his pain. When thymic carcinoma was eventually diagnosed, he received total resection of the tumor and the shoulder pain subsided completely. Thymic carcinoma is a rare carcinoma, and our review of the literature did not show shoulder pain as its initial presentation except for one case report. The purpose of this report is to document our clinical experience so that other physiatrists can include thymic carcinoma in their differential diagnosis of shoulder pain. PMID:22969299

Thymic cystic degeneration, pseudoepitheliomatous hyperplasia, and hemorrhage in a dog with brodifacoum toxicosis.

PubMed

Rickman, B H; Gurfield, N

2009-05-01

Thymic cysts with pseudoepitheliomatous hyperplasia are described in a 7-month-old female American Eskimo Dog that died of complications from brodifacoum poisoning. Grossly, there was hemothorax with marked cranial mediastinal hemorrhage. Histologically, thymic lobules were expanded and distorted by irregular cysts, lined by single to multiple layers of plump to slightly attenuated polygonal squamous epithelial cells supported by a basement membrane (pseudoepitheliomatous hyperplasia). The thymus had a paucity of lymphocytes and lacked corticomedullary differentiation. Extensive hemorrhage within the cysts and thymic parenchyma extended into the adjacent adipose tissue. To the authors' knowledge, this is the first report of cystic thymic degeneration with pseudoepitheliomatous hyperplasia in a nonhuman species.

Thymic pathology and cardiac myxomas: Coincidence or a closer relationship?

PubMed

Moraitis, Sotirios D; Agrafiotis, Apostolos C; Pappas, Dimitrios; Pothitakis, Chrysovalantis; Stergianni, Maria; Koukis, Ioannis

2018-04-30

Myxomas are the most common benign cardiac tumors and are located more frequently in the left atrium. In the literature there are cases describing the coexistence of thymic tumors and cardiac myxomas. In the case reported herein, during the resection of a cardiac myxoma, an enlarged thymus gland was encountered and resected. The histological exam revealed a thymic hyperplasia. The aim of this case study is to assess the need of conducting further studies in order to identify a common histological pathway between thymic lesions and cardiac myxomas. The diagnosis of a cardiac myxoma could justify a further workup of the anterior mediastinum in order not to overlook a lesion of thymic origin.

Competition between positive and negative reinforcement in the treatment of escape behavior.

PubMed

Lalli, J S; Vollmer, T R; Progar, P R; Wright, C; Borrero, J; Daniel, D; Barthold, C H; Tocco, K; May, W

1999-01-01

We compared the effects of reinforcing compliance with either positive reinforcement (edible items) or negative reinforcement (a break) on 5 participants' escape-maintained problem behavior. Both procedures were assessed with or without extinction. Results showed that compliance was higher and problem behavior was lower for all participants when compliance produced an edible item rather than a break. Treatment gains were achieved without the use of extinction. Results are discussed regarding the use of positive reinforcement to treat escape behavior.

[Indication and procedure of video-assisted thoracoscopic surgery to thymic disease].

PubMed

Matsumura, Yuji; Kondo, Takashi

2006-07-01

We retrospective reviewed minimally invasive video-assisted thoracoscopic surgery (VATS) to thymic diseases. These procedures were performed using intercostal and infrasternal approach with a sternum-elevator. Indications of this method are benign thymic lesions [mature teratoma, thymic cyst and myasthenia gravis (MG)] and small thymoma (non-invasive Masaoka stage I-II, less than 5 cm in diameter and nontouching to the left brachiocephalic vein). Fifty patients underwent VATS for 13 hemithymectomies (7 thymomas, 5 mature teratomas and 1 thymic cyst) and 37 extended thymectomies (25 nonthymomatous MGs and 12 thymomatous MGs). Conversion to sternotomy was required in 3 cases of nonthymomatous MG because of bleeding from thymic vein in 1 case and pleural adhesion in 2 cases. Four cases of thymomatous MG were successfully treated with partial lung resection and/or small pericardial resection by VATS. New bipolar vessel sealing system (LigaSure V) is safer and more useful than metal clip and ultrasonic coagulator in VATS for thymic vein sealing, extraction of upper poles of thymus and incision of mediastinal pleura near phrenic nerve. VATS thymectomy should be useful from the standpoint of less invasive, less pain, rapid recovery, and good cosmetic results.

The effects of differential negative reinforcement of other behavior and noncontingent escape on compliance.

PubMed Central

Kodak, Tiffany; Miltenberger, Raymond G; Romaniuk, Cathryn

2003-01-01

The present study evaluated the effects of noncontingent escape and differential negative reinforcement of other behavior in reducing problem behaviors and increasing compliance in 2 children with disabilities. Results showed that both methods reduced problem behavior and increased compliance for both children. PMID:14596581

The effects of differential negative reinforcement of other behavior and noncontingent escape on compliance.

PubMed

Kodak, Tiffany; Miltenberger, Raymond G; Romaniuk, Cathryn

2003-01-01

The present study evaluated the effects of noncontingent escape and differential negative reinforcement of other behavior in reducing problem behaviors and increasing compliance in 2 children with disabilities. Results showed that both methods reduced problem behavior and increased compliance for both children.

Homeostatic signals do not drive post-thymic T cell maturation.

PubMed

Houston, Evan G; Boursalian, Tamar E; Fink, Pamela J

2012-01-01

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3 week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, naïve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86. Furthermore, while CCR7/CCL19,21-regulated homing of recent thymic emigrants to the T cell zones within the secondary lymphoid organs is not required for post-thymic T cell maturation, an intact dendritic cell compartment modulates this process. It is thus clear that, unlike T cell development and homeostasis, post-thymic maturation is focused not on interrogating the T cell receptor or the cell's responsiveness to homeostatic or costimulatory signals, but on some as yet unrecognized property. Copyright © 2012 Elsevier Inc. All rights reserved.

Homeostatic Signals do not Drive Post-thymic T cell Maturation

PubMed Central

Houston, Evan G.; Boursalian, Tamar E.; Fink, Pamela J.

2012-01-01

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3-week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, naïve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86. Furthermore, while CCR7/CCL19,21-regulated homing of recent thymic emigrants to the T cell zones within the secondary lymphoid organs is not required for post-thymic T cell maturation, an intact dendritic cell compartment modulates this process. It is thus clear that, unlike T cell development and homeostasis, post-thymic maturation is focused not on interrogating the T cell receptor or the cell’s responsiveness to homeostatic or costimulatory signals, but on some as yet unrecognized property. PMID:22398309

The NLRP3 Inflammasome Promotes Age-related Thymic Demise and Immunosenescence

PubMed Central

Youm, Yun-Hee; Kanneganti, Thirumala-Devi; Vandanmagsar, Bolormaa; Zhu, Xuewei; Ravussin, Anthony; Adijiang, Ayinuer; Owen, John S.; Thomas, Michael J.; Francis, Joseph; Parks, John S.; Dixit, Vishwa Deep

2013-01-01

The collapse of thymic stromal cell microenvironment with age and resultant inability of the thymus to produce naïve T cells contributes to lower immune-surveillance in the elderly. Here we show that age-related increase in ‘lipotoxic danger signals’ such as free cholesterol (FC) and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy and results in an increase in cortical thymic epithelial cells, T cell progenitors and maintenance of T cell repertoire diversity. Using a mouse model of irradiation and hematopoietic stem cell transplantation (HSCT), we show that deletion of the Nlrp3 inflammasome accelerates T cell reconstitution and immune recovery in middle-aged animals. Collectively, these data demonstrate that lowering inflammasome-dependent caspase-1 activation increases thymic lymphopoiesis and suggest that Nlrp3 inflammasome inhibitors may aid the reestablishment of a diverse T cell repertoire in middle-aged or elderly patients undergoing HSCT. PMID:22832107

Genetic Regulation of Development of Thymic Lymphomas Induced by N‐Propyl‐N‐nitrosourea in the Rat

PubMed Central

Fukami, Hiroko; Nishimura, Mayumi; Matsuyama, Mutsushi

1995-01-01

To clarify the linkage between Hbb and Tls‐1 (thymic lymphoma susceptible‐1) loci and to investigate other loci concerned in thymic lymphomagenesis, the BUF/Mna rat, which is highly sensitive to the lymphomagenic activity of N‐propyl‐N‐nitrosourea (PNU), the WKY/NCrj rat, reported to be resistant, and their cross offspring were subjected to genetic analysis. F1 hybrid and backcross generations were raised from the 2 strains, and 6 genetic markers including Hbb were analyzed in individuals of the backcross generation. However, no linkage between Hbb and Tls‐1 loci could be demonstrated since WKY rats also developed a high incidence of thymic lymphomas in response to PNU. Nevertheless, thymic lymphomas developed more rapidly and reached a larger size in the BUF rats. F1 rats expressed a rather rapid and large tumor growth phenotype, while the [(WKY × BUF) × WKY] backcross generation consisted of rats with either rapidly growing or slowly growing tumors. It was thus concluded that rapid development of thymic lymphomas is determined by a gene, provisionally designated Tls‐3. Analysis of the relationship between 6 genetic markers and development of thymic lymphoma in the backcross generation demonstrated that the Tls‐3 locus is loosely linked to the Gc locus, suggesting a possible location on rat chromosome 14. Tls‐3 may not be identical with Tls‐1 and other genes known to be relevant to thymic tumors, but its relationship with Tls‐2 remains obscure. PMID:7559080

Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease.

PubMed

Dudakov, Jarrod A; Mertelsmann, Anna M; O'Connor, Margaret H; Jenq, Robert R; Velardi, Enrico; Young, Lauren F; Smith, Odette M; Boyd, Richard L; van den Brink, Marcel R M; Hanash, Alan M

2017-08-17

Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22-mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22-dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity posttransplant. Manipulation of the ILC-IL-22-TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency. © 2017 by The American Society of Hematology.

Elevated CRP levels predict poor outcome and tumor recurrence in patients with thymic epithelial tumors: A pro- and retrospective analysis

PubMed Central

Janik, Stefan; Bekos, Christine; Hacker, Philipp; Raunegger, Thomas; Ghanim, Bahil; Einwallner, Elisa; Beer, Lucian; Klepetko, Walter; Müllauer, Leonhard; Ankersmit, Hendrik J.; Moser, Bernhard

2017-01-01

Objective Scarce information exists on the pathogenesis of thymic epithelial tumors (TETs), comprising thymomas, thymic carcinomas (TCs) and neuroendocrine tumors. C-reactive protein (CRP) increases during certain malignancies. We aimed to investigate the clinical relevance of CRP in patients with TETs. Results Pretreatment CRP serum concentrations were significantly elevated in patients with TETs, particularly TCs and metastatic TETs. After complete tumor resection CRP serum concentrations were decreased (p = 0.135) but increased significantly in case of tumor recurrence (p = 0.001). High pretreatment CRP was associated with significantly worse 5- and 10-year freedom-from recurrence (FFR) (p = 0.010) and was a negative prognostic factor for FFR (HR 3.30; p = 0.015). IL-6 (not IL-1β) serum concentrations were significantly elevated in patients with TETs but we did not detect CRP tissue expression in TETs. Materials and Methods Pretreatment CRP serum concentrations were retrospectively analyzed from 128 surgical patients (1990–2015). In a subset of 68 patients longitudinal analysis of CRP was performed. Additionally, immunohistochemical tumor CRP expression and serum concentrations of interleukin (IL)-6 and IL-1β were measured. Conclusions Hence, diagnostic measurement of serum CRP might be useful to indicate highly aggressive TETs and to make doctors consider tumor recurrences during oncological follow-up. PMID:28514756

The IASLC/ITMIG thymic malignancies staging project: development of a stage classification for thymic malignancies.

PubMed

Detterbeck, Frank C; Asamura, Hisao; Crowley, John; Falkson, Conrad; Giaccone, Giuseppe; Giroux, Dori; Huang, James; Kim, Jhingook; Kondo, Kazuya; Lucchi, Marco; Marino, Mirella; Marom, Edith M; Nicholson, Andrew; Okumura, Meinoshin; Ruffini, Enrico; van Schil, Paul; Stratton, Kelly

2013-12-01

The lack of an official-stage classification system for thymic malignancies is an issue that hampers progress in this rare disease. A collaborative effort by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group is underway to develop proposals for such a system. A database of more than 10,000 cases worldwide has been assembled to provide a solid basis for analysis. This report outlines the structure of the effort and the process that has been designed.

Neuroticism, coping strategies, and negative well-being among caregivers.

PubMed

Patrick, J H; Hayden, J M

1999-06-01

Neuroticism was incorporated into a model for predicting the well-being of family caregivers. Using data from 596 women with an adult child with a chronic disability, the model hypothesizes direct effects of neuroticism on a caregiver's perceptions of the stressor, on her wishful-escapism and problem-focused coping, and on psychological well-being. Results indicate that neuroticism exerts direct and indirect effects on negative well-being. Results also indicate that stressors have direct effects on both wishful-escapism coping and problem-focused coping. Burden had direct effects on negative psychological well-being. Diagnosis influences the model by having direct effects on stressors and wishful-escapism coping but not on problem-focused coping or burden. Inclusion of individual level variables, such as neuroticism, results in a substantial amount of explained variance in negative well-being.

Diffusion-weighted MR imaging in thymic epithelial tumors: correlation with World Health Organization classification and clinical staging.

PubMed

Abdel Razek, Ahmed Abdel Khalek; Khairy, Mohamed; Nada, Nadia

2014-10-01

To assess thymic epithelial tumors with diffusion-weighted magnetic resonance (MR) imaging. Informed consent from patients and institutional review board approval were obtained. Prospective study was conducted on 30 consecutive patients (21 men and nine women; age range, 35-71 years) with thymic epithelial tumors. They underwent true fast imaging with steady-state precession and single-shot echo-planar diffusion-weighted MR imaging of the mediastinum with b values of 0, 400, and 800 sec/mm(2). Apparent diffusion coefficient (ADC) of the thymic epithelial tumors was calculated by the same observer at two settings and was correlated with World Health Organization classification and clinical staging. There was significant difference in longest diameter (P = .001) and necrotic part of the tumor (P = .014) between low-risk thymoma, high-risk thymoma, and thymic carcinoma. Mean ADC value of both readings of thymic epithelial tumors (n = 30) was 1.24 × 10(-3) mm(2)/sec and 1.22 × 10(-3) mm(2)/sec, with good intraobserver agreement (κ = 0.732). There was significant difference in both readings (P = .01 and .20) of low-risk thymoma (1.30 × 10(-3) mm(2)/sec and 1.29 × 10(-3) mm(2)/sec), high-risk thymoma (1.16 × 10(-3) mm(2)/sec and 1.14 × 10(-3) mm(2)/sec), and thymic carcinoma (1.18 × 10(-3) mm(2)/sec and 1.06 × 10(-3) mm(2)/sec). Cutoff ADC values of both readings used to differentiate low-risk thymoma from high-risk thymoma and thymic carcinoma were 1.25 and 1.22 × 10(-3) mm(2)/sec with area under the curve of 0.804 and 0.851, respectively. There was significant difference in both readings of ADC value of early (stage I, II) and advanced stages (stage III, IV) of thymic epithelial tumors (P = .006 and .005, respectively). ADC value is a noninvasive, reliable, and reproducible imaging parameter that may help to assess and characterize thymic epithelial tumors. © RSNA, 2014.

Specialized proteasome subunits play an essential role in thymic selection of CD8+ T cells

PubMed Central

Kincaid, Eleanor Z.; Murata, Shigeo; Tanaka, Keiji; Rock, Kenneth L.

2016-01-01

The cells that stimulate positive selection express different specialized proteasome β-subunits than all other cells, including those involved in negative selection. Mice that lack all four specialized proteasome β-subunits, and therefore express only constitutive proteasomes in all cells, had a profound defect in the generation of CD8+ T cells. While a defect in positive selection would reflect an inability to generate the appropriate positively selecting peptides, a block at negative selection would point to the potential need to switch peptides between positive and negative selection to avoid the two processes often cancelling each other out. We found that the block in T cell development occurred around the checkpoints of positive and, surprisingly, also negative selection. PMID:27294792

Ectopic Thymic Cyst of the Subglottis: Considerations for Diagnosis and Management.

PubMed

Ahmad, Iram; Kirby, Patricia; Liming, Bryan

2018-03-01

To share the diagnostic and management challenges created by an extremely rare airway lesion-the subglottic ectopic thymic cyst. Case report and literature review. We review the presentation, management, and clinical course of an infant who presented with a subglottic mass that was histologically confirmed as a thymic cyst. A brief literature review supplements the case presentation Results: We present the third described case of an ectopic thymic cyst presenting as a subglottic mass. The differential diagnosis of subglottic masses in neonates consists primarily of subglottic hemangioma and mucous retention cysts. Otolaryngologists must be prepared for unexpected findings when dealing with critical airways. We compare the presentation and management of our patient with the 2 previously described cases. We propose an embryologic theory for the origin of these rare lesions. An ectopic thymic cyst is a rare and unexpected cause of neonatal stridor. Management of pediatric airway lesions must allow for unexpected findings at the time of diagnostic and therapeutic endoscopy. The appropriate management of subglottic thymic cysts is poorly defined, but close surveillance for recurrence is mandatory.

The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence.

PubMed

Youm, Yun-Hee; Kanneganti, Thirumala-Devi; Vandanmagsar, Bolormaa; Zhu, Xuewei; Ravussin, Anthony; Adijiang, Ayinuer; Owen, John S; Thomas, Michael J; Francis, Joseph; Parks, John S; Dixit, Vishwa Deep

2012-01-26

The collapse of thymic stromal cell microenvironment with age and resultant inability of the thymus to produce naive T cells contributes to lower immune-surveillance in the elderly. Here we show that age-related increase in 'lipotoxic danger signals' such as free cholesterol (FC) and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy and results in an increase in cortical thymic epithelial cells, T cell progenitors and maintenance of T cell repertoire diversity. Using a mouse model of irradiation and hematopoietic stem cell transplantation (HSCT), we show that deletion of the Nlrp3 inflammasome accelerates T cell reconstitution and immune recovery in middle-aged animals. Collectively, these data demonstrate that lowering inflammasome-dependent caspase-1 activation increases thymic lymphopoiesis and suggest that Nlrp3 inflammasome inhibitors may aid the re-establishment of a diverse T cell repertoire in middle-aged or elderly patients undergoing HSCT. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Optimal surgical approach to thymic malignancies: New trends challenging old dogmas.

PubMed

Ruffini, Enrico; Filosso, Pier Luigi; Guerrera, Francesco; Lausi, Paolo; Lyberis, Paraskevas; Oliaro, Alberto

2018-04-01

Until recently, the surgical approach to thymic tumors has remained basically unchanged. The collaborative effort led by ITMIG with the collaboration of regional and society-based interest groups (ESTS, JART) produced an enthusiastic surge of interest in testing the new technological advances in thoracic surgery and many historical dogmas in thymic surgery have been questioned and challenged. The present review addresses the new trends in the optimal surgical management of thymic tumors based on the review of the current literature. 1. Minimally-invasive techniques (MIT) including video-assisted thoracic surgery (VATS) and robotic-assisted thoracic Surgery (RATS) are now to be considered the standard of care in early-stage thymic tumors. MIT are no inferior to open approaches in terms of postoperative complications, loco-regional recurrence rates and survival. MIT are associated with a shorter length of stay, reduced intraoperative blood loss and better cosmetic results. 2. The adoption of the ITMIG/IASLC TNM staging system for thymic tumors requires a paradigm shift among thoracic surgeons to include regional lymphadenectomy according to the IASLC/ITMIG nodal map in the surgical management of thymic tumors. 3. A limited thymectomy instead of total thymectomy along with the removal of the thymic tumor in nonmyasthenic Stage I-II tumors has been proposed by some authors, although the results are not uniform. Until more mature data is available, adherence to the current guidelines recommending total thymectomy in addition to thymomectomy is always indicated. 4. In locally-advanced Stage IVa patients with pleural involvement, major pleural resections, including pleurectomy/decortication or extrapleural pneumonectomy are indicated, provided a complete resection of the pleural deposits is anticipated, usually in a multidisciplinary setting, with excellent long-term results. The incorporation of these new concepts and techniques in the surgical armamentarium of the thoracic surgeons dealing with thymic malignancies will certainly be of help in the optimal management of these patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Thymus involvement in myasthenia gravis: Epidemiological and clinical impacts of different self-tolerance breakdown mechanisms.

PubMed

Karni, Arnon; Asmail, Ali; Drory, Vivian E; Kolb, Hadar; Kesler, Anat

2016-09-15

The reasons for the abrogation of self-immunological tolerance in patients with myasthenia gravis (MG) may be different between those with concomitant thymic hyperplasia or thymoma, and those with no evidence of thymic involvement. We conducted a retrospective observational case series study to investigate the epidemiology as well as the clinical, serologic, and electromyographic (EMG) characteristics of individuals diagnosed as having MG. We found that the average age at MG onset of patients with either thymic hyperplasia or thymoma was much younger (by ~20years) than that of MG patients without thymic involvement. Thymic hyperplasia was more common in females than males. There were no differences in the rates of ocular MG vs. generalized MG among those three study groups. There were also no group differences in the rates of neuromuscular junction disfunction, as observed on EMG or by the results of serology tests for acetyl choline receptor antibody. Interestingly, only patients without thymic involvement had other autoimmune diseases, and most of them were females. The patients with other coexisting autoimmune disease had a similar age at MG onset as the other patients with no thymic involvement. These results shed light on the impact of epidemiological and clinical factors that result from different mechanisms of self-immunological tolerance breakdown that occurs in MG. Copyright © 2016 Elsevier B.V. All rights reserved.

FSP1+ fibroblast subpopulation is essential for the maintenance and regeneration of medullary thymic epithelial cells

PubMed Central

Sun, Lina; Sun, Chenming; Liang, Zhanfeng; Li, Hongran; Chen, Lin; Luo, Haiying; Zhang, Hongmei; Ding, Pengbo; Sun, Xiaoning; Qin, Zhihai; Zhao, Yong

2015-01-01

Thymic epithelial cells (TECs) form a 3-dimentional network supporting thymocyte development and maturation. Besides epithelium and thymocytes, heterogeneous fibroblasts are essential components in maintaining thymic microenvironments. However, thymic fibroblast characteristics, development and function remain to be determined. We herein found that thymic non-hematopoietic CD45-FSP1+ cells represent a unique Fibroblast specific protein 1 (FSP1)—fibroblast-derived cell subset. Deletion of these cells in FSP1-TK transgenic mice caused thymus atrophy due to the loss of TECs, especially mature medullary TECs (MHCIIhigh, CD80+ and Aire+). In a cyclophosphamide-induced thymus injury and regeneration model, lack of non-hematopoietic CD45-FSP1+ fibroblast subpopulation significantly delayed thymus regeneration. In fact, thymic FSP1+ fibroblasts released more IL-6, FGF7 and FSP1 in the culture medium than their FSP1- counterparts. Further experiments showed that the FSP1 protein could directly enhance the proliferation and maturation of TECs in the in vitro culture systems. FSP1 knockout mice had significantly smaller thymus size and less TECs than their control. Collectively, our studies reveal that thymic CD45-FSP1+ cells are a subpopulation of fibroblasts, which is crucial for the maintenance and regeneration of TECs especially medullary TECs through providing IL-6, FGF7 and FSP1. PMID:26445893

DOE Office of Scientific and Technical Information (OSTI.GOV)

Defresne, M.P.; Greimers, R.; Lenaerts, P.

A split-dose regimen of whole-body irradiation (4 X 175 rad at weekly intervals) induced thymic lymphomas in C57BL/Ka mice after a latent period of 3-9 months. Meanwhile, preleukemia cells arose in the thymus and bone marrow and persisted until the onset of lymphomas. Simultaneously, thymic lymphopoiesis was impaired; thymocyte numbers were subnormal and thymic nurse cells disappeared in a progressive but irreversible fashion. The depletion of these lymphoepithelial complexes, which are normally involved in the early steps of thymic lymphopoiesis, was related to altered prothymocyte activity in bone marrow and to damaged thymic microenvironment, perhaps as a consequence of themore » presence of preleukemia cells. The grafting of normal bone marrow cells after irradiation prevented the development of lymphomas. However, marrow reconstitution did not inhibit the induction of preleukemia cells. They disappeared from the thymus during the second part of the latent period. At the same time, thymic lymphopoiesis was restored; thymocytes and nurse cell numbers returned to normal as a consequence of the proliferation of grafted marrow-derived cells within the thymus. The results thus demonstrated an intimate relationship between preleukemia cells and an alteration of thymic lymphopoiesis, which particularly involved the nurse cell microenvironment. Some preleukemia cells in marrow-reconstituted, irradiated mice derived from the unirradiated marrow inoculate. Thus these cells acquired neoplastic potential through a factor present in the irradiated tissues. The nature of this indirect mechanism was briefly discussed.« less

The thymoprotective function of leptin is indirectly mediated via suppression of obesity.

PubMed

Sreenivasan, Jayasree; Schlenner, Susan; Franckaert, Dean; Dooley, James; Liston, Adrian

2015-09-01

Leptin is an adipokine that regulates metabolism and plays an important role as a neuroendocrine hormone. Leptin mediates these functions via the leptin receptor, and deficiency in either leptin or its receptor leads to obesity in humans and mice. Leptin has far reaching effects on the immune system, as observed in obese mice, which display decreased thymic function and increased inflammatory responses. With expression of the leptin receptor on T cells and supporting thymic epithelium, aberrant signalling through the leptin receptor has been thought to be the direct cause of thymic involution in obese mice. Here, we demonstrate that the absence of leptin receptor on either thymic epithelial cells or T cells does not lead to the loss of thymic function, demonstrating that the thymoprotective effect of leptin is mediated by obesity suppression rather than direct signalling to the cellular components of the thymus. © 2015 John Wiley & Sons Ltd.

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

PubMed Central

Wertheimer, Tobias; Velardi, Enrico; Tsai, Jennifer; Cooper, Kirsten; Xiao, Shiyun; Kloss, Christopher C.; Ottmüller, Katja J.; Mokhtari, Zeinab; Brede, Christian; deRoos, Paul; Kinsella, Sinéad; Palikuqi, Brisa; Ginsberg, Michael; Young, Lauren F.; Kreines, Fabiana; Lieberman, Sophia R.; Lazrak, Amina; Guo, Peipei; Malard, Florent; Smith, Odette M.; Shono, Yusuke; Jenq, Robert R.; Hanash, Alan M.; Nolan, Daniel J.; Butler, Jason M.; Beilhack, Andreas; Manley, Nancy R.; Rafii, Shahin; Dudakov, Jarrod A; van den Brink, Marcel RM

2018-01-01

The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. Here we show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration, via their production of BMP4. ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signalling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance and regeneration; and its downstream targets such as Dll4, itself a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity. PMID:29330161

The Effects of Variable-Time Delivery of Food Items and Praise on Problem Behavior Reinforced by Escape

ERIC Educational Resources Information Center

Lomas, Joanna E.; Fisher, Wayne W.; Kelley, Michael E.

2010-01-01

Prior research indicates that reinforcement of an appropriate response (e.g., compliance) can produce concomitant reductions in problem behavior reinforced by escape when problem behavior continues to produce negative reinforcement (e.g., Lalli et al., 1999). These effects may be due to a preference for positive over negative reinforcement or to…

Pharmacological modulation of caspase-8 in thymus-related medical conditions.

PubMed

Pozzesi, Nicola; Fierabracci, Alessandra; Thuy, Trinh Thy; Martelli, Maria Paola; Liberati, Anna Marina; Ayroldi, Emira; Riccardi, Carlo; Delfino, Domenico V

2014-10-01

The thymus is a lymphoid organ that governs the development of a diverse T-cell repertoire capable of defending against nonself-antigens and avoiding autoimmunity. However, the thymus can also succumb to different diseases. Hypertrophic diseases, such as thymomas, are typically associated with impairment of negative selection, which leads to autoimmune disease, or disruption of positive selection, which results in immunodeficiency. Hypotrophic diseases of the thymus can manifest during acute infections, cancer, allogeneic bone marrow transplantation, or with aging. This condition leads to decreased immune function and can be treated by either replacing lost thymic tissue or by preventing thymic tissue death. Studies have demonstrated the critical role of caspase-8 in regulating apoptosis in the thymus. In this review, we discuss how pharmacological activation and inhibition of caspase-8 can be used to treat hypertrophic and hypotrophic diseases of the thymus, respectively, to improve its function. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

[Effect of low-intensity electromagnetic fields of industrial frequency on the ultrastructure and proliferative activity of rat's thymus cells].

PubMed

Zhitkevich, T I; Bokut', T B; Netukova, N I

2001-01-01

Effects of two types of low-intensity electromagnetic fields (EMF) of industrial frequency (50 Hz) on the fine structure and proliferative activity of thymic cells in white rats were studied. It was found that a weak EMF with a prevailing electrical component (380-480 V/m, 120-140 nT1) did not affect the DNA synthesis intensity. An EMF with a stronger magnetic induction (10-15 V/m, 800-1500 nT1) diminished the glucose-6-phosphate dehydrogenase activity and proliferative processes in cultured stimulated lymphocytes. Electron microscopic investigation of the thymus after both types of exposure revealed an accumulation of lymphocytes with pyknotic nuclei and electron-dense cytoplasm, as well as hypoplasia of the vascular endothelium. At the same time, EMF with a prevailing magnetic component produced a more marked negative effect on the ultrastructure of thymic cells, which indicated a lowered secretory activity of epitheliocytes.

Intrapericardial primary thymic carcinoma in a 73-year-old man.

PubMed

Calderon, Ana Maria; Merchan, Juan Andres; Rozo, Juan Carlos; Guerrero, Cesar Ivan; Treistman, Bernardo; Sulak, Laura E; Cheong, Benjamin Y C; Rodríguez, German; Mesa, Andrés

2008-01-01

Thymic carcinoma is a rare, highly aggressive type of tumor that typically occurs in the anterior mediastinum. We describe the case of a 73-year-old man who presented with weakness, cough, dyspnea, anorexia, and weight loss. An echocardiogram showed an intrapericardial mass that occupied the space around the lateral walls of the left ventricle and distally compressed the right ventricle. Magnetic resonance imaging and a biopsy confirmed the presence of intrapericardial primary thymic carcinoma. The patient underwent surgical excision of the tumor and died of right ventricular rupture during the procedure. This case highlights the importance of considering thymic carcinoma whenever an otherwise unexplained intrapericardial mass is encountered.

Label retention identifies a multipotent mesenchymal stem cell-like population in the postnatal thymus.

PubMed

Osada, Masako; Singh, Varan J; Wu, Kenmin; Sant'Angelo, Derek B; Pezzano, Mark

2013-01-01

Thymic microenvironments are essential for the proper development and selection of T cells critical for a functional and self-tolerant adaptive immune response. While significant turnover occurs, it is unclear whether populations of adult stem cells contribute to the maintenance of postnatal thymic epithelial microenvironments. Here, the slow cycling characteristic of stem cells and their property of label-retention were used to identify a K5-expressing thymic stromal cell population capable of generating clonal cell lines that retain the capacity to differentiate into a number of mesenchymal lineages including adipocytes, chondrocytes and osteoblasts suggesting a mesenchymal stem cell-like phenotype. Using cell surface analysis both culture expanded LRCs and clonal thymic mesenchymal cell lines were found to express Sca1, PDGFRα, PDGFRβ,CD29, CD44, CD49F, and CD90 similar to MSCs. Sorted GFP-expressing stroma, that give rise to TMSC lines, contribute to thymic architecture when reaggregated with fetal stroma and transplanted under the kidney capsule of nude mice. Together these results show that the postnatal thymus contains a population of mesenchymal stem cells that can be maintained in culture and suggests they may contribute to the maintenance of functional thymic microenvironments.

Treatment of Escape-Maintained Challenging Behavior Using Chained Schedules: An Evaluation of the Effects of Thinning Positive plus Negative Reinforcement During Functional Communication Training.

PubMed

Zangrillo, Amanda N; Fisher, Wayne W; Greer, Brian D; Owen, Todd M; DeSouza, Andresa A

2016-01-01

Previous research has supported functional communication training (FCT) as an effective intervention for reducing challenging behavior. Clinicians often program schedule-thinning procedures to increase the portability of the treatment (i.e., reinforcement is provided less frequently). For individuals with escape-maintained problem behavior, chained schedules have proven effective in increasing task completion and supplemental procedures may ameliorate reemergence of challenging behavior as access to reinforcement is decreased. The present study compared the use of a chained schedule-thinning procedure with and without alternative reinforcement (e.g., toys and activities) embedded in an intervention in which escape from the task is provided contingent on a request for a break. Two individuals with escape-maintained challenging behavior participated. We compared two treatment conditions, escape-only and escape-to-tangibles, using a single-subject, alternating treatments design with each treatment implemented in a distinct academic context. With the escape-to-tangibles treatment, we reached the final schedule in both contexts with both participants (4 successes out of 4 applications). We did not reach the final schedule with either participant with the escape-only intervention (0 successes out of 2 applications). The current results provided preliminary confirmation that providing positive plus negative reinforcement would decrease destructive behavior, increase compliance, and facilitate reinforcer-schedule thinning.

Treatment of Escape-Maintained Challenging Behavior Using Chained Schedules: An Evaluation of the Effects of Thinning Positive plus Negative Reinforcement During Functional Communication Training

PubMed Central

Zangrillo, Amanda N.; Fisher, Wayne W.; Greer, Brian D.; Owen, Todd M.; DeSouza, Andresa A.

2016-01-01

Objective Previous research has supported functional communication training (FCT) as an effective intervention for reducing challenging behavior. Clinicians often program schedule-thinning procedures to increase the portability of the treatment (i.e., reinforcement is provided less frequently). For individuals with escape-maintained problem behavior, chained schedules have proven effective in increasing task completion and supplemental procedures may ameliorate reemergence of challenging behavior as access to reinforcement is decreased. The present study compared the use of a chained schedule-thinning procedure with and without alternative reinforcement (e.g., toys and activities) embedded in an intervention in which escape from the task is provided contingent on a request for a break. Method Two individuals with escape-maintained challenging behavior participated. We compared two treatment conditions, escape-only and escape-to-tangibles, using a single-subject, alternating treatments design with each treatment implemented in a distinct academic context. Results With the escape-to-tangibles treatment, we reached the final schedule in both contexts with both participants (4 successes out of 4 applications). We did not reach the final schedule with either participant with the escape-only intervention (0 successes out of 2 applications). Conclusion The current results provided preliminary confirmation that providing positive plus negative reinforcement would decrease destructive behavior, increase compliance, and facilitate reinforcer-schedule thinning. PMID:28626579

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands.

PubMed

Das, Dibyendu Kumar; Mallis, Robert J; Duke-Cohan, Jonathan S; Hussey, Rebecca E; Tetteh, Paul W; Hilton, Mark; Wagner, Gerhard; Lang, Matthew J; Reinherz, Ellis L

2016-12-02

The pre-T cell receptor (pre-TCR) is a pTα-β heterodimer functioning in early αβ T cell development. Although once thought to be ligand-autonomous, recent studies show that pre-TCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the αβTCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the Cβ FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCRαβ and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic Vβ patch apposition. This patch functions in the pre-TCR as a surrogate Vα domain, fostering ligand promiscuity to favor development of β chains with self-reactivity but is occluded by α subunit replacement of pTα upon αβTCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor αβTCR repertoire tuning via the pre-TCR. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands*♦

PubMed Central

Das, Dibyendu Kumar; Mallis, Robert J.; Duke-Cohan, Jonathan S.; Hussey, Rebecca E.; Tetteh, Paul W.; Hilton, Mark; Wagner, Gerhard; Lang, Matthew J.; Reinherz, Ellis L.

2016-01-01

The pre-T cell receptor (pre-TCR) is a pTα-β heterodimer functioning in early αβ T cell development. Although once thought to be ligand-autonomous, recent studies show that pre-TCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the αβTCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the Cβ FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCRαβ and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic Vβ patch apposition. This patch functions in the pre-TCR as a surrogate Vα domain, fostering ligand promiscuity to favor development of β chains with self-reactivity but is occluded by α subunit replacement of pTα upon αβTCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor αβTCR repertoire tuning via the pre-TCR. PMID:27707880

Histogram analysis of apparent diffusion coefficient maps for assessing thymic epithelial tumours: correlation with world health organization classification and clinical staging.

PubMed

Kong, Ling-Yan; Zhang, Wei; Zhou, Yue; Xu, Hai; Shi, Hai-Bin; Feng, Qing; Xu, Xiao-Quan; Yu, Tong-Fu

2018-04-01

To investigate the value of apparent diffusion coefficients (ADCs) histogram analysis for assessing World Health Organization (WHO) pathological classification and Masaoka clinical stages of thymic epithelial tumours. 37 patients with histologically confirmed thymic epithelial tumours were enrolled. ADC measurements were performed using hot-spot ROI (ADC HS-ROI ) and histogram-based approach. ADC histogram parameters included mean ADC (ADC mean ), median ADC (ADC median ), 10 and 90 percentile of ADC (ADC 10 and ADC 90 ), kurtosis and skewness. One-way ANOVA, independent-sample t-test, and receiver operating characteristic were used for statistical analyses. There were significant differences in ADC mean , ADC median , ADC 10 , ADC 90 and ADC HS-ROI among low-risk thymoma (type A, AB, B1; n = 14), high-risk thymoma (type B2, B3; n = 9) and thymic carcinoma (type C, n = 14) groups (all p-values <0.05), while no significant difference in skewness (p = 0.181) and kurtosis (p = 0.088). ADC 10 showed best differentiating ability (cut-off value, ≤0.689 × 10 -3 mm 2 s -1 ; AUC, 0.957; sensitivity, 95.65%; specificity, 92.86%) for discriminating low-risk thymoma from high-risk thymoma and thymic carcinoma. Advanced Masaoka stages (Stage III and IV; n = 24) tumours showed significant lower ADC parameters and higher kurtosis than early Masaoka stage (Stage I and II; n = 13) tumours (all p-values <0.05), while no significant difference on skewness (p = 0.063). ADC 10 showed best differentiating ability (cut-off value, ≤0.689 × 10 -3 mm 2 s -1 ; AUC, 0.913; sensitivity, 91.30%; specificity, 85.71%) for discriminating advanced and early Masaoka stage epithelial tumours. ADC histogram analysis may assist in assessing the WHO pathological classification and Masaoka clinical stages of thymic epithelial tumours. Advances in knowledge: 1. ADC histogram analysis could help to assess WHO pathological classification of thymic epithelial tumours. 2. ADC histogram analysis could help to evaluate Masaoka clinical stages of thymic epithelial tumours. 3. ADC 10 might be a promising imaging biomarker for assessing and characterizing thymic epithelial tumours.

A comparison of positive and negative reinforcement for compliance to treat problem behavior maintained by escape.

PubMed

Slocum, Sarah K; Vollmer, Timothy R

2015-09-01

Previous research has shown that problem behavior maintained by escape can be treated using positive reinforcement. In the current study, we directly compared functional (escape) and nonfunctional (edible) reinforcers in the treatment of escape-maintained problem behavior for 5 subjects. In the first treatment, compliance produced a break from instructions. In the second treatment, compliance produced a small edible item. Neither treatment included escape extinction. Results suggested that the delivery of a positive reinforcer for compliance was effective for treating escape-maintained problem behavior for all 5 subjects, and the delivery of escape for compliance was ineffective for 3 of the 5 subjects. Implications and future directions related to the use of positive reinforcers in the treatment of escape behavior are discussed. © Society for the Experimental Analysis of Behavior.

An empirical investigation of time-out with and without escape extinction to treat escape-maintained noncompliance.

PubMed

Everett, Gregory E; Joe Olmi, D; Edwards, Ron P; Tingstrom, Daniel H; Sterling-Turner, Heather E; Christ, Theodore J

2007-07-01

The present study evaluates the effectiveness of two time-out (TO) procedures in reducing escape-maintained noncompliance of 4 children. Noncompliant behavioral function was established via a functional assessment (FA), including indirect and direct descriptive procedures and brief confirmatory experimental analyses. Following FA, parents were taught to consequate noncompliance with two different TO procedures, one without and one with escape extinction following TO release. Although results indicate TO without escape extinction is effective in increasing compliance above baseline levels, more optimal levels of compliance were obtained for all 4 children when escape extinction was added to the TO procedures already in place. Results indicate efficacy of TO with escape extinction when applied to escape-maintained noncompliance and are discussed as an initial example of the successful application of TO to behaviors maintained by negative reinforcement.

Post-thymic maturation: young T cells assert their individuality.

PubMed

Fink, Pamela J; Hendricks, Deborah W

2011-07-22

T cell maturation was once thought to occur entirely within the thymus. Now, evidence is mounting that the youngest peripheral T cells in both mice and humans comprise a distinct population from their more mature, yet still naive, counterparts. These cells, termed recent thymic emigrants (RTEs), undergo a process of post-thymic maturation that can be monitored at the levels of cell phenotype and immune function. Understanding this final maturation step in the process of generating useful and safe T cells is of clinical relevance, given that RTEs are over-represented in neonates and in adults recovering from lymphopenia. Post-thymic maturation may function to ensure T cell fitness and self tolerance.

The International Thymic Malignancy Interest Group thymic initiative: a state-of-the-art study of thymic malignancies.

PubMed

Detterbeck, Frank; Korst, Robert

2014-01-01

Thymic malignancies are relatively rare tumors. A general lack of knowledge, misconceptions about benignancy, confusion about the definition of terms, and variability in reporting of outcomes have further hampered progress in these diseases. The International Thymic Malignancy Interest Group has emerged to counter these challenges and has brought together a worldwide multidisciplinary community determined to improve outcomes for these patients. Although the organization is young (initiated in 2010), major early accomplishments have created a foundation and infrastructure for scientific research. These include consensus definitions of terms, an unprecedented global database, development of practical clinical resources and, together with the International Association for the Study of Lung Cancer, development of proposals for the first formal stage classification of these malignant tumors. Many articles have been published or are under way, and a second phase of projects building on the early success is proceeding. The greatest accomplishment of the International Thymic Malignancy Interest Group lies in the establishment of an open culture of collaboration and the engagement of a broad group of individuals united by a common mission. It is a testament to what can be achieved, despite ongoing and inherent challenges, by determination and a collective effort. Copyright © 2014 Elsevier Inc. All rights reserved.

Application values of 99mTc-methoxyisobutylisonitrile imaging for differentiating benign and malignant thymic masses.

PubMed

Lu, Chenghui; Wang, Xufu; Liu, Bin; Liu, Xinfeng; Wang, Guoming; Zhang, Qin

2017-08-01

The aim of the present study was to investigate the application value of 99m Tc-methoxyisobutylisonitrile (MIBI) imaging to differentiate between benign and malignant thymic masses. A total of 32 patients with space-occupying mediastinal masses were enrolled and early and delayed-phase images were collected following injection with the imaging agent. The tumor to background ratio (T/N) values at the different phases were also recorded. The sensitivity of the qualitative analysis to distinguish between benign and malignant thymic masses was 95.24%, with specificity as 90.91%. The T/N values in the early and delayed phases were not significantly different in the group with benign thymic masses, but demonstrated statistical significant differences in the groups with low- and intermediate-grade malignant thymic masses. The T/N values at the above early and delayed phase were significantly different between the benign and low-grade malignancy groups, as well as between low- and moderate-grade malignancy groups. Those between the benign and moderate-grade malignancy groups demonstrated no significant difference. 99m Tc-MIBI imaging was able to differentiate between benign and malignant thymic masses, and the simultaneous semi-quantitative analysis of the T/N values of the tumors may be able to initially determine the degree of malignancy of thymoma.

Acute respiratory failure revealing a multilocular thymic cyst in an infant: a case report.

PubMed

Asma, Bouziri; Ammar, Khaldi; Khaled, Menif; Najoua, Guandoura; Nejla, Ben Jaballah

2009-11-30

Multilocular thymic cysts are rare benign lesions of the neck and mediastinum that can occur at any age. In children, multilocular thymic cysts are usually symptomatic after the age of 2 years and produce few symptoms. We present an unusual case of a multilocular thymic cyst diagnosed in a 3-month-old girl and causing severe respiratory failure. A 3 month-old-girl, with a medical history of dyspnea and wheezing since the age of 20 days, presented in our pediatric intensive care unit for acute respiratory failure requiring mechanical ventilation. The chest radiograph showed thoracic distension without any other abnormalities. The diagnosis of severe asthma was initially suspected and the patient was treated by intravenous corticosteroids and continuous perfusion of salbutamol without any improvement. A chest tomography scan was performed and demonstrated an anterior mediastinal multiseptated cystic mass extending from the inferior face of the thyroid gland to the left cardiophrenic angle. Sternotomy and excision biopsy were planned urgently. The cystic mass was excised completely. The histopathological examination confirmed the diagnosis of a multilocular thymic cyst. The particularities of our observation are the occurrence of a multilocular thymic cyst in a young infant and its presentation by a severe acute respiratory failure mimicking asthma.

Methylation and expression profiles of MGMT gene in thymic epithelial tumors.

PubMed

Mokhtar, Mohamed; Kondo, Kazuya; Namura, Toshiaki; Ali, Abdellah H K; Fujita, Yui; Takai, Chikako; Takizawa, Hiromitsu; Nakagawa, Yasushi; Toba, Hiroaki; Kajiura, Koichiro; Yoshida, Mitsuteru; Kawakami, Gyokei; Sakiyama, Shoji; Tangoku, Akira

2014-02-01

A key challenge in diagnosis and treatment of thymic epithelial tumors (TET) is in improving our understanding of the genetic and epigenetic changes of these relatively rare tumors. Methylation specific PCR (MSP) and immunohistochemistry were applied to 66 TET to profile the methylation status of DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) and its protein expression in TET to clarify the association between MGMT status and clinicopathological features, response to chemotherapy and overall survival. MGMT methylation was significantly more frequent in thymic carcinoma than in thymoma (17/23, 74% versus 13/44, 29%; P<0.001). Loss of expression of MGMT protein was significantly more frequent in thymic carcinoma than in thymoma (20/23, 87% versus 10/44, 23%; P<0.0001). There is a significant correlation between of MGMT methylation and loss of its protein expression (P<0.0003). MGMT methylation and loss of expression were significantly more frequent in advanced thymic epithelial tumors (III/IV) than in early tumors (I/II). MGMT methylation plays a soul role in development of TET, especially in thymic carcinoma. Therefore, translation of our results from basic molecular research to clinical practice may have important implication for considering MGMT methylation as a marker and a target of future therapies in TET. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Histologic patterns of thymic involvement in Langerhans cell proliferations: a clinicopathologic study and review of the literature.

PubMed

Picarsic, Jennifer; Egeler, R Maarten; Chikwava, Kudakwashe; Patterson, Kathleen; Jaffe, Ronald

2015-01-01

Thymic involvement by Langerhans cell histiocytosis (LCH) has been described mainly in isolated case reports. A description of the histopathologic patterns of LCH proliferations in the thymus, together with therapeutic implications, has not, to our knowledge, been previously addressed. The pathology consultation files at Children's Hospital of Pittsburgh of the University of Pennsylvania Medical Center were reviewed for cases of thymic involvement by LCH. Relevant cases in the literature were also reviewed, and the histopathology and clinical course of those cases were collected. Nine consultation cases of thymic involvement were reviewed, together with 23 cases in the literature, which provided adequate pathologic description and ancillary confirmation (n  =  32), revealing 4 distinct pathologic groups. Group 1 showed microscopic collection of hyperplastic LCH-like cells in incidental thymectomies of patients without LCH disease, requiring no further treatment (n  =  7; 22%). Group 2 showed solitary and/or cystic LCH of the thymus with gland disruption, and at least 3 cases resolved without systemic therapy (n  =  10; 31%). Group 3 showed more variable thymic involvement in multisystemic LCH disease, with either a medullary restricted pattern or more diffuse gland involvement, requiring adjuvant therapy and having a higher mortality rate (n  =  13; 41%). Group 4 showed a mixed histiocytic lesion with a concurrent LCH and juvenile xanthogranuloma-like proliferation (n  =  2; 6%). Thymic involvement in LCH is quite rare. Based on our cases and those in the literature, we propose 4 distinct pathologic groups of thymic involvement in Langerhans cell proliferations with relevance for diagnosis and treatment.

Cytomorphology and sonographic features of ectopic thymic tissue diagnosed in paediatric FNA biopsies.

PubMed

Escobar, F A; Pantanowitz, L; Picarsic, J L; Craig, F E; Simons, J P; Viswanathan, P A; Yilmaz, S; Monaco, S E

2018-03-26

Ectopic thymic tissue can arise as an asymptomatic neck mass, which may be detected on imaging studies. The aim of this study was to determine the incidence of ectopic thymic tissue in paediatric FNAs and to the correlate clinical, radiological and cytomorphological findings. FNAs in children with neck and mediastinal lesions performed between January 2012 and July 2016 were reviewed for cases of ectopic thymus. These were then evaluated and correlated with the cytology findings. Of 739 FNAs, 13 (1.8%) cases from 11 patients showed ectopic thymic tissue. The targeted lesions were in the thyroid (n = 7), submandibular region (n = 1), superior mediastinum (n = 1) and paratracheal region (n = 1). The most common indication was for microcalcifications concerning for papillary thyroid carcinoma on ultrasound (n = 6). Imaging findings included fusiform lesions with linear and punctuate bright echoes. The cytology evaluation showed small lymphocytes with discohesive epithelioid cells in most cases, and proteinaceous fluid in the cystic case. There were rare macrophages and Hassall's corpuscles. Flow cytometry and/or immunostains were performed in all cases, supporting thymic origin. Ectopic thymic tissue is rarely present as a neck mass or thyroid nodule on FNA biopsy. The ultrasound imaging findings reveal a well-defined fusiform lesion with punctate bright echoes that could be misinterpreted as papillary thyroid carcinoma. The aspirates show a small lymphoid population, immunophenotypically compatible with thymic T-cells, in addition to scattered epithelial cells. Therefore, knowledge of the typical ultrasonographic and cytopathological features can help make a definitive diagnosis and avoid more invasive procedures in paediatric patients. © 2018 John Wiley & Sons Ltd.

Evaluation of the proposed International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) staging revisions in thymic well-differentiated neuroendocrine carcinoma patients.

PubMed

Zhao, Yang; Shi, Jianxin; Fan, Limin; Yang, Jun; Hu, Dingzhong; Zhao, Heng

2016-02-01

In 2014, the International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) launched a worldwide Tumor Node Metastasis (TNM) staging proposal for the next edition of thymic tumours. The objective of the current study was to evaluate the proposed new staging system specific to the thymic well-differentiated neuroendocrine carcinoma (TWDNC). From November 2003 to July 2014, 61 consecutive patients were enrolled in this study with pathologically confirmed TWDNC in Shanghai Chest Hospital. Clinical and pathological data were retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier and log-rank tests. Validity evaluation was addressed by Cox proportional hazards regression model, after adjusting for potential confounders and visually assessing the distinction of curves generated based on the staging system of Masaoka-Koga and the proposed TNM ones. Thymic carcinoids made up 4% of total thymic tumours in our institution. The 5-year overall survival (OS) rate and the disease-free survival (DFS) rate were 72 and 41%, respectively. Neither Masaoka-Koga staging system nor the proposed TNM system showed ordered appropriateness visually in survival curves and the prognostic demarcation between stages was poor on both OS and DFS. The IASLC/ITMIG suggested that the TNM and Masaoka-Koga staging systems fail to predict the clinical course of TWDNC patients. Collaborative effort is needed in the future staging validation as ITMIG recommended. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

CD52, CD22, CD26, EG5 and IGF-1R expression in thymic malignancies.

PubMed

Remon, J; Abedallaa, N; Taranchon-Clermont, E; Bluthgen, V; Lindsay, C R; Besse, B; Thomas de Montpréville, V

2017-06-01

Thymic epithelial tumours are rare cancers for which new treatment options are required. Identification of putative predictive markers is important for developing clinical trials. We studied the expression of five putative predictive biomarkers, potentially actionable by approved experimental drugs. CD52, CD22, CD26, EG5, and IGF-1R expression were investigated by immunohistochemistry in formalin-fixed surgical samples of thymic epithelial tumour patients. All samples containing 10% positive epithelial tumour cells, independent of tumour cell intensity, were considered as positive. Correlation with histological subtype was performed. 106 surgical samples (89 thymomas, 12 thymic carcinoma, and 5 thymic neuroendocrine tumours) were evaluated. Overall, CD52, CD22, CD26, EG5 and IGF-1R expression was observed in 7%, 42%, 25%, 42% and 77% of samples, respectively. CD52 expression was more frequent in B2 and B3 thymoma. All TET subtypes stained for CD22, mainly AB thymoma (68%). CD26 expression also correlated with AB thymoma (68%), and A thymoma (50%) subtype, while IGFR1 was the most common marker expressed by thymic carcinoma samples (92%), followed by EG5 (60%). Only EG5 expression was significantly higher in thymic carcinomas than in thymomas (75% vs. 38%, p=0.026). Our data were consistent with a previous study of IGF-1R expression. Based on their expression, activity of agents targeting CD52, CD 22, CD26 and EG5 could be further explored in TET patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Micronodular thymic neoplasms: case series and literature review with emphasis on the spectrum of differentiation.

PubMed

Mneimneh, Wadad S; Gökmen-Polar, Yesim; Kesler, Kenneth A; Loehrer, Patrick J; Badve, Sunil

2015-11-01

We report nine cases of micronodular thymoma with lymphoid B-cell hyperplasia and one case of micronodular thymic carcinoma with lymphoid hyperplasia from our institution. For a better understanding of these rare tumors, clinical records, and histological features of these cases were reviewed, with detailed review of additional 64 literature cases of micronodular thymic neoplasms. The joint analysis identified 64 cases of micronodular thymoma with lymphoid B-cell hyperplasia and 9 cases of micronodular thymic carcinoma with lymphoid hyperplasia. Both groups revealed slight male predilection, with male:female ratio of 1.3:1 and 5:4, and occurred at >40 years of age, with a mean of 64 (41-83) and 62 (42-78) years, respectively. Myasthenia gravis was noted in 3/64 (5%) and 1/9 (11%) patients, respectively. Other systemic, disimmune, or hematologic disorders were noted in 6/64 (9%) and 1/9 (11%) patients, respectively. Components of conventional thymoma were reported in 11/64 (17%) micronodular thymomas with lymphoid B-cell hyperplasia, with transitional morphology between the two components in most of them. Cellular morphology was predominantly spindle in micronodular thymoma with lymphoid B-cell hyperplasia when specified (30/43), and epithelioid in micronodular thymic carcinoma with lymphoid hyperplasia (6/9), and cytological atypia was more encountered in the latter. Dedifferentiation/transformation from micronodular thymoma with lymphoid B-cell hyperplasia to micronodular thymic carcinoma with lymphoid hyperplasia seems to occur in a small subset of cases. Three cases of micronodular thymomas with lymphoid B-cell hyperplasia were described with co-existent low-grade B-cell lymphomas. Follow-up data were available for 30 micronodular thymomas with lymphoid B-cell hyperplasia and 6 micronodular thymic carcinomas with lymphoid hyperplasia, with a mean of 47 (0.2-180) months and 23 (3-39) months, respectively. Patients were alive without disease, except for five micronodular thymoma with lymphoid B-cell hyperplasia patients (dead from unrelated causes), and one micronodular thymic carcinoma with lymphoid hyperplasia patient (dead of disease).

Imaging Characteristics of Pathologically Proven Thymic Hyperplasia: Identifying Features That Can Differentiate True From Lymphoid Hyperplasia

PubMed Central

Araki, Tetsuro; Sholl, Lynette M.; Gerbaudo, Victor H.; Hatabu, Hiroto; Nishino, Mizuki

2014-01-01

OBJECTIVE The purpose of this article is to investigate the imaging characteristics of pathologically proven thymic hyperplasia and to identify features that can differentiate true hyperplasia from lymphoid hyperplasia. MATERIALS AND METHODS Thirty-one patients (nine men and 22 women; age range, 20–68 years) with pathologically confirmed thymic hyperplasia (18 true and 13 lymphoid) who underwent preoperative CT (n = 27), PET/CT (n = 5), or MRI (n = 6) were studied. The length and thickness of each thymic lobe and the transverse and anterior-posterior diameters and attenuation of the thymus were measured on CT. Thymic morphologic features and heterogeneity on CT and chemical shift on MRI were evaluated. Maximum standardized uptake values were measured on PET. Imaging features between true and lymphoid hyperplasia were compared. RESULTS No significant differences were observed between true and lymphoid hyperplasia in terms of thymic length, thickness, diameters, morphologic features, and other qualitative features (p > 0.16). The length, thickness, and diameters of thymic hyperplasia were significantly larger than the mean values of normal glands in the corresponding age group (p < 0.001). CT attenuation of lymphoid hyperplasia was significantly higher than that of true hyperplasia among 15 patients with contrast-enhanced CT (median, 47.9 vs 31.4 HU; Wilcoxon p = 0.03). The receiver operating characteristic analysis yielded greater than 41.2 HU as the optimal threshold for differentiating lymphoid hyperplasia from true hyperplasia, with 83% sensitivity and 89% specificity. A decrease of signal intensity on opposed-phase images was present in all four cases with in- and opposed-phase imaging. The mean maximum standardized uptake value was 2.66. CONCLUSION CT attenuation of the thymus was significantly higher in lymphoid hyperplasia than in true hyperplasia, with an optimal threshold of greater than 41.2 HU in this cohort of patients with pathologically confirmed thymic hyperplasia. PMID:24555583

DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration.

PubMed

Osada, Masako; Jardine, Logan; Misir, Ruth; Andl, Thomas; Millar, Sarah E; Pezzano, Mark

2010-02-08

Thymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus. Here we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of DeltaNP63(+) Foxn1(+) and Aire(+) TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments. Taken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated with cancer therapy and bone marrow transplants.

Update on Aire and thymic negative selection.

PubMed

Passos, Geraldo A; Speck-Hernandez, Cesar A; Assis, Amanda F; Mendes-da-Cruz, Daniella A

2018-01-01

Twenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological - i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases. © 2017 John Wiley & Sons Ltd.

Structural basis of human β-cell killing by CD8+ T cells in Type 1 diabetes

PubMed Central

Bulek, Anna M.; Cole, David K.; Skowera, Ania; Dolton, Garry; Gras, Stephanie; Madura, Florian; Fuller, Anna; Miles, John J.; Gostick, Emma; Price, David A.; Drijfhout, Jan W.; Knight, Robin R.; Huang, Guo C.; Lissin, Nikolai; Molloy, Peter E.; Wooldridge, Linda; Jakobsen, Bent K.; Rossjohn, Jamie; Peakman, Mark; Rizkallah, Pierre J.; Sewell, Andrew K.

2011-01-01

The structural characteristics of autoreactive-T cell receptor (TCR) engagement of major histocompatability (MHC) class II-restricted self-antigens is established, but how autoimmune-TCRs interact with self-MHC class I has been unclear. We examined how CD8+ T cells kill human islet β-cells, in Type-1 diabetes, via autoreactive-TCR (1E6) recognition of an HLA-A*0201-restricted glucose-sensitive preproinsulin peptide. Rigid ‘lock-and-key’ binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHCI-restricted TCRs. However, this interaction was extraordinarily weak, due to limited contacts with MHCI. TCR binding was highly peptide-centric, dominated by two CDR3-loop-encoded residues, acting as an ‘aromatic-cap’, over the peptide MHCI (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8+ T cell-mediated autoreactivity. PMID:22245737

On the relative contributions of positive reinforcement and escape extinction in the treatment of food refusal.

PubMed

Piazza, Cathleen C; Patel, Meeta R; Gulotta, Charles S; Sevin, Bari M; Layer, Stacy A

2003-01-01

We compared the effects of positive reinforcement alone, escape extinction alone, and positive reinforcement with escape extinction in the treatment of the food and fluid refusal of 4 children who had been diagnosed with a pediatric feeding disorder. Consumption did not increase when positive reinforcement was implemented alone. By contrast, consumption increased for all participants when escape extinction was implemented, independent of the presence or absence of positive reinforcement. However, the addition of positive reinforcement to escape extinction was associated with beneficial effects (e.g., greater decreases in negative vocalizations and inappropriate behavior) for some participants.

A thymic neuroendocrine tumour in a young female: a rare cause of relapsing and remitting Cushing's syndrome.

PubMed

Trott, M J; Farah, G; Stokes, V J; Wang, L M; Grossman, A B

2016-01-01

We present a case of a young female patient with a rare cause of relapsing and remitting Cushing's syndrome due to ectopic ACTH secretion from a thymic neuroendocrine tumour. A 34-year-old female presented with a constellation of symptoms of Cushing's syndrome, including facial swelling, muscle weakness and cognitive impairment. We use the terms 'relapsing and remitting' in this case report, given the unpredictable time course of symptoms, which led to a delay of 2 years before the correct diagnosis of hypercortisolaemia. Diagnostic workup confirmed ectopic ACTH secretion, and a thymic mass was seen on mediastinal imaging. The patient subsequently underwent thymectomy with complete resolution of her symptoms. Several case series have documented the association of Cushing's syndrome with thymic neuroendocrine tumours (NETs), although to our knowledge there are a few published cases of patients with relapsing and remitting symptoms. This case is also notable for the absence of features of the MEN-1 syndrome, along with the female gender of our patient and her history of non-smoking. Ectopic corticotrophin (ACTH) secretion should always be considered in the diagnostic workup of young patients with Cushing's syndromeThere is a small but growing body of literature describing the correlation between ectopic ACTH secretion and thymic neuroendocrine tumours (NETs)The possibility of a MEN-1 syndrome should be considered in all patients with thymic NETs, and we note the observational association with male gender and cigarette smoking in this cohortAn exception to these associations is the finding of relatively high incidence of thymic NETs among female non-smoking MEN-1 patients in the Japanese compared with Western populationsThe relapsing and remitting course of our patient's symptoms is noteworthy, given the paucity of this finding among other published cases.

Provirus Integration at the 3 Region of N‐myc in Cell Lines Established from Thymic Lymphomas Spontaneously Formed in AKR Mice and a [(BALB/c × B6)F1AKR] Bone Marrow Chimera

PubMed Central

Yano, Yoko; Kobayashi, Seiichi; Yasumizu, Ryoji; Tamaki, Junko; Kubo, Mitsumasa; Sasaki, Akio; Hasan, Shahid; Okuyama, Harue; Inaba, Muneo; Ikehara, Susumu; Hiai, Hiroshi; Kakinuma, Mitsuaki

1991-01-01

Among 18 thymic leukemia cell lines which have been established from spontaneous thymic lym‐phomas in AKR mice as well as in bone marrow chimeras which were constructed by transplanting allogeneic bone marrow cells into irradiated AKR mice, three proviral integration sites were identified; near c‐myc, N‐myc and pim‐l loci. No integration site specific for chimeric leukemia cell lines was found. In three thymic leukemia cell lines which contained rearranged N‐myc, genes, insertions of long terminal repeats (LTRs) of murine leukemia viruses were detected at 18 or 20 bp downstream of the translational termination codon. These results demonstrate that the 3’region of the N‐myc gene is one of the integration targets for murine leukemia viruses in spontaneous thymic lymphomas. In these three cell lines, N‐myc mRNA was stably transcribed and transcription of c‐myc mRNA was down‐regulated. The integrated murine leukemia viruses in AKR thymic leukemia were most likely AKV, though the DNA sequence of the LTR inserted in the genome of a leukemic cell line from [(BALB/c × B6)F1‐AKR], CAK20, was different from LTRs of murine leukemia viruses so far reported. PMID:1900822

Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCRβ Repertoire

PubMed Central

Li, Kun-Po; Fahnrich, Anke; Roy, Eron; Cuda, Carla M.; Grimes, H. Leighton; Perlman, Harris R.; Kalies, Kathrin; Hildeman, David A.

2017-01-01

CD8αα TCRαβ+ intestinal intraepithelial lymphocytes play a critical role in promoting intestinal homeostasis, although mechanisms controlling their development and peripheral homeostasis remain unclear. In this study, we examined the spatiotemporal role of Bim in the thymic selection of CD8αα precursors and the fate of these cells in the periphery. We found that T cell–specific expression of Bim during early/cortical, but not late/medullary, thymic development controls the agonist selection of CD8αα precursors and limits their private TCRβ repertoire. During this process, agonist-selected double-positive cells lose CD4/8 coreceptor expression and masquerade as double-negative (DN) TCRαβhi thymocytes. Although these DN thymocytes fail to re-express coreceptors after OP9-DL1 culture, they eventually mature and accumulate in the spleen where TCR and IL-15/STAT5 signaling promotes their conversion to CD8αα cells and their expression of gut-homing receptors. Adoptive transfer of splenic DN cells gives rise to CD8αα cells in the gut, establishing their precursor relationship in vivo. Interestingly, Bim does not restrict the IL-15–driven maturation of CD8αα cells that is critical for intestinal homeostasis. Thus, we found a temporal and tissue-specific role for Bim in limiting thymic agonist selection of CD8αα precursors and their TCRβ repertoire, but not in the maintenance of CD8αα intraepithelial lymphocytes in the intestine. PMID:27852740

Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Newsom-Davis, J.; Willcox, N.; Calder, L.

1981-11-26

We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlatedmore » with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.« less

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration.

PubMed

Wertheimer, Tobias; Velardi, Enrico; Tsai, Jennifer; Cooper, Kirsten; Xiao, Shiyun; Kloss, Christopher C; Ottmüller, Katja J; Mokhtari, Zeinab; Brede, Christian; deRoos, Paul; Kinsella, Sinéad; Palikuqi, Brisa; Ginsberg, Michael; Young, Lauren F; Kreines, Fabiana; Lieberman, Sophia R; Lazrak, Amina; Guo, Peipei; Malard, Florent; Smith, Odette M; Shono, Yusuke; Jenq, Robert R; Hanash, Alan M; Nolan, Daniel J; Butler, Jason M; Beilhack, Andreas; Manley, Nancy R; Rafii, Shahin; Dudakov, Jarrod A; van den Brink, Marcel R M

2018-01-12

The thymus is not only extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood, and this capacity diminishes considerably with age. We show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration via their production of bone morphogenetic protein 4 (BMP4) ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signaling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1 , a key transcription factor involved in TEC development, maintenance, and regeneration, and its downstream targets such as Dll4 , a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells

PubMed Central

Sojka, Dorothy K; Plougastel-Douglas, Beatrice; Yang, Liping; Pak-Wittel, Melissa A; Artyomov, Maxim N; Ivanova, Yulia; Zhong, Chao; Chase, Julie M; Rothman, Paul B; Yu, Jenny; Riley, Joan K; Zhu, Jinfang; Tian, Zhigang; Yokoyama, Wayne M

2014-01-01

Natural killer (NK) cells belong to the innate immune system; they can control virus infections and developing tumors by cytotoxicity and producing inflammatory cytokines. Most studies of mouse NK cells, however, have focused on conventional NK (cNK) cells in the spleen. Recently, we described two populations of liver NK cells, tissue-resident NK (trNK) cells and those resembling splenic cNK cells. However, their lineage relationship was unclear; trNK cells could be developing cNK cells, related to thymic NK cells, or a lineage distinct from both cNK and thymic NK cells. Herein we used detailed transcriptomic, flow cytometric, and functional analysis and transcription factor-deficient mice to determine that liver trNK cells form a distinct lineage from cNK and thymic NK cells. Taken together with analysis of trNK cells in other tissues, there are at least four distinct lineages of NK cells: cNK, thymic, liver (and skin) trNK, and uterine trNK cells. DOI: http://dx.doi.org/10.7554/eLife.01659.001 PMID:24714492

Anomalous barrier escape: The roles of noise distribution and correlation.

PubMed

Hu, Meng; Zhang, Jia-Ming; Bao, Jing-Dong

2017-05-28

We study numerically and analytically the barrier escape dynamics of a particle driven by an underlying correlated Lévy noise for a smooth metastable potential. A "quasi-monochrome-color" Lévy noise, i.e., the first-order derivative variable of a linear second-order differential equation subjected to a symmetric α-stable white Lévy noise, also called the harmonic velocity Lévy noise, is proposed. Note that the time-integral of the noise Green function of this kind is equal to zero. This leads to the existence of underlying negative time correlation and implies that a step in one direction is likely followed by a step in the other direction. By using the noise of this kind as a driving source, we discuss the competition between long flights and underlying negative correlations in the metastable dynamics. The quite rich behaviors in the parameter space including an optimum α for the stationary escape rate have been found. Remarkably, slow diffusion does not decrease the stationary rate while a negative correlation increases net escape. An approximate expression for the Lévy-Kramers rate is obtained to support the numerically observed dependencies.

Anomalous barrier escape: The roles of noise distribution and correlation

NASA Astrophysics Data System (ADS)

Hu, Meng; Zhang, Jia-Ming; Bao, Jing-Dong

2017-05-01

We study numerically and analytically the barrier escape dynamics of a particle driven by an underlying correlated Lévy noise for a smooth metastable potential. A "quasi-monochrome-color" Lévy noise, i.e., the first-order derivative variable of a linear second-order differential equation subjected to a symmetric α-stable white Lévy noise, also called the harmonic velocity Lévy noise, is proposed. Note that the time-integral of the noise Green function of this kind is equal to zero. This leads to the existence of underlying negative time correlation and implies that a step in one direction is likely followed by a step in the other direction. By using the noise of this kind as a driving source, we discuss the competition between long flights and underlying negative correlations in the metastable dynamics. The quite rich behaviors in the parameter space including an optimum α for the stationary escape rate have been found. Remarkably, slow diffusion does not decrease the stationary rate while a negative correlation increases net escape. An approximate expression for the Lévy-Kramers rate is obtained to support the numerically observed dependencies.

Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling.

PubMed

Hassler, Melanie R; Pulverer, Walter; Lakshminarasimhan, Ranjani; Redl, Elisa; Hacker, Julia; Garland, Gavin D; Merkel, Olaf; Schiefer, Ana-Iris; Simonitsch-Klupp, Ingrid; Kenner, Lukas; Weisenberger, Daniel J; Weinhaeusel, Andreas; Turner, Suzanne D; Egger, Gerda

2016-10-04

Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK-) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK- ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

The conveyor belt hypothesis for thymocyte migration: participation of adhesion and de-adhesion molecules.

PubMed

Villa-Verde, D M; Calado, T C; Ocampo, J S; Silva-Monteiro, E; Savino, W

1999-05-01

Thymocyte differentiation is the process by which bone marrow-derived precursors enter the thymus, proliferate, rearrange the genes and express the corresponding T cell receptors, and undergo positive and/or negative selection, ultimately yielding mature T cells that will represent the so-called T cell repertoire. This process occurs in the context of cell migration, whose cellular and molecular basis is still poorly understood. Kinetic studies favor the idea that these cells leave the organ in an ordered pattern, as if they were moving on a conveyor belt. We have recently proposed that extracellular matrix glycoproteins, such as fibronectin, laminin and type IV collagen, among others, produced by non-lymphoid cells both in the cortex and in the medulla, would constitute a macromolecular arrangement allowing differentiating thymocytes to migrate. Here we discuss the participation of both molecules with adhesive and de-adhesive properties in the intrathymic T cell migration. Functional experiments demonstrated that galectin-3, a soluble beta-galactoside-binding lectin secreted by thymic microenvironmental cells, is a likely candidate for de-adhesion proteins by decreasing thymocyte interaction with the thymic microenvironment.

Positive and Negative Regulatory Mechanisms for Fine-Tuning Cellularity and Functions of Medullary Thymic Epithelial Cells.

PubMed

Akiyama, Taishin; Tateishi, Ryosuke; Akiyama, Nobuko; Yoshinaga, Riko; Kobayashi, Tetsuya J

2015-01-01

Self-tolerant T cells and regulatory T cells develop in the thymus. A wide variety of cell-cell interactions in the thymus is required for the differentiation, proliferation, and repertoire selection of T cells. Various secreted and cell surface molecules expressed in thymic epithelial cells (TECs) mediate these processes. Moreover, cytokines expressed by cells of hematopoietic origin regulate the cellularity of TECs. Tumor necrosis factor (TNF) family RANK ligand, lymphotoxin, and CD40 ligand, expressed in T cells and innate lymphoid cells (ILCs), promote the differentiation and proliferation of medullary TECs (mTECs) that play critical roles in the induction of immune tolerance. A recent study suggests that interleukin-22 (IL-22) produced by ILCs promotes regeneration of TECs after irradiation. Intriguingly, tumor growth factor-β and osteoprotegerin limit cellularity of mTECs, thereby attenuating regulatory T cell generation. We will review recent insights into the molecular basis for cell-cell interactions regulating differentiation and proliferation of mTECs and also discuss about a perspective on use of mathematical models for understanding this complicated system.

Bioprocessing feasibility analysis. [thymic hormone bioassay and electrophoresis

NASA Technical Reports Server (NTRS)

1978-01-01

The biology and pathophysiology of the thymus gland is discussed and a clinical procedure for thymic hormone assay is described. The separation of null lymphocytes from mice spleens and the functional characteristics of the cells after storage and transportation were investigated to develop a clinical procedure for thymic hormone assay, and to determine whether a ground-based approach will provide the desired end-product in sufficient quantities, or whether the microgravity of space should be exploited for more economical preparation of the hormone.

A Prospective Phase II Study of Cisplatin and Cremophor EL-Free Paclitaxel (Genexol-PM) in Patients with Unresectable Thymic Epithelial Tumors.

PubMed

Kim, Hae Su; Lee, Ji Yun; Lim, Sung Hee; Sun, Jong-Mu; Lee, Se Hoon; Ahn, Jin Seok; Park, Keunchil; Moon, Seung Hwan; Ahn, Myung-Ju

2015-12-01

We conducted a prospective phase II study of cisplatin plus cremophor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors to determine the efficacy and tolerability of the combination therapy. Patients were treated with cisplatin (70 mg/m) and Genexol-PM (230 mg/m) on day 1 of a 3-week cycle as first-line palliative chemotherapy. The primary end point of this study was objective response rate, and the secondary end points included toxicity, progression-free survival (PFS), overall survival, correlation between early 18F-fluorodeoxyglucose positron emission tomography/computed tomography response and PFS, and correlation between baseline flurododeoxyglucose uptake and histology. Forty-two patients with unresectable thymoma (n = 14) or thymic carcinoma (n = 28) were enrolled between May 2012 and October 2014. The median age was 59 years (range: 25-77) and 30 patients (71%) were male, and 39 patients (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range: 1-6). For 40 assessable patients, the objective response rate was 62.5% (95% confidence interval [CI]: 47.6-77.4) with rates of 46% (95% CI: 23.3-76.9) for advanced thymoma (n = 13) and 70% (95% CI: 52.0-82.1) for thymic carcinoma (n = 27). With a median follow-up of 15.5 months, the median PFS for all 42 patients was 9.8 months (11.4 months for thymoma versus 8.1 months for thymic carcinoma). The 2-year overall survival was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Eight patients (19%) experienced grade 2 hypersensitivity reactions. There was no correlation between early positron emission tomography response and PFS, but tumor histology (thymoma versus thymic carcinoma) was correlated with SUVmax before chemotherapy. These data suggest that combination of cisplatin and Genexol-PM is highly effective and tolerable for the treatment of unresectable thymic epithelial tumors.

Does oral polio vaccine at birth affect the size of the thymus? Observations within a randomized trial.

PubMed

Eriksen, Helle Brander; Lund, Najaaraq; Biering-Sørensen, Sofie; Correia, Cizete; Barbosa, Amarildo; Andersen, Andreas; Aaby, Peter; Jeppesen, Dorthe L; Benn, Christine Stabell

2014-05-30

There is increasing evidence that vaccines have an effect on general mortality which goes beyond specific disease protection. Oral polio vaccine (OPV) is widely used in low-income countries, but in observational studies in Guinea-Bissau we observed that not receiving OPV at birth was associated with reduced overall male infant mortality and enhanced immune response to BCG vaccine. We therefore initiated a randomized trial to test the overall effect of OPV at birth (OPV0). A small thymic gland is a predictor of mortality in high-mortality settings. Within the trial we aimed to test whether no-OPV0 was associated with increased thymic size. In 511 normal birth weight infants who were randomized to receive or not receive OPV0, thymic index and thymus/weight index were measured before randomization and after 2 weeks (N=49), 4 weeks (N=308) or 6 weeks (N=27). The association between OPV0 and the log transformed thymic size indicators were analyzed in ANCOVA models with thymic size at follow-up as the outcome and adjusting for thymic size at enrollment and age at follow-up. Estimates were reported as geometric mean ratios (GMR) with 95% confidence intervals, comparing no-OPV0 to OPV0. No-OPV0 was not associated with thymic index after 2 weeks (GMR: 1.14 (0.99-1.30)), after 4 weeks (GMR: 0.98 (0.93-1.05)) or after 6 weeks (GMR: 1.00 (0.81-1.23)). However, no-OPV0 was associated with increased thymus/weight index after 2 weeks (GMR: 1.22 (1.06-1.40)), but the effect was not seen after 4 weeks (GMR: 0.97 (0.92-1.03)) and 6 weeks (GMR: 0.99 (0.82-1.19)). There were no strong sex-differences. Overall there was no effect on thymic size of OPV0 when administered with BCG. The results could indicate that if an effect occurs, it is only within the first weeks after vaccination. Copyright © 2014 Elsevier Ltd. All rights reserved.

ESCAPE AS REINFORCEMENT AND ESCAPE EXTINCTION IN THE TREATMENT OF FEEDING PROBLEMS

PubMed Central

LaRue, Robert H; Stewart, Victoria; Piazza, Cathleen C; Volkert, Valerie M; Patel, Meeta R; Zeleny, Jason

2011-01-01

Given the effectiveness of putative escape extinction as treatment for feeding problems, it is surprising that little is known about the effects of escape as reinforcement for appropriate eating during treatment. In the current investigation, we examined the effectiveness of escape as reinforcement for mouth clean (a product measure of swallowing), escape as reinforcement for mouth clean plus escape extinction (EE), and EE alone as treatment for the food refusal of 5 children. Results were similar to those of previous studies, in that reinforcement alone did not result in increases in mouth clean or decreases in inappropriate behavior (e.g., Piazza, Patel, Gulotta, Sevin, & Layer, 2003). Increases in mouth clean and decreases in inappropriate behavior occurred when the therapist implemented EE independent of the presence or absence of reinforcement. Results are discussed in terms of the role of negative reinforcement in the etiology and treatment of feeding problems. PMID:22219525

[Absent or hypoplastic thymus: A marker for 22q11.2 microdeletion syndrome in case of polyhydramnios].

PubMed

Lamouroux, A; Mousty, E; Prodhomme, O; Bigi, N; Le Gac, M-P; Letouzey, V; De Tayrac, R; Mares, P

2016-04-01

In prenatal diagnosis of 22q11.2 microdeletion syndrome, without cardiac malformation or multiple associated congenital anomalies, we study the presence of polyhydramnios and its association with thymic dysgenesis. This was a multicenter retrospective observational study. It was performed in two multidisciplinary centers for prenatal diagnosis in the south of France between January 1, 2010 and June 30, 2013. Inclusion criteria were prenatal diagnosis of 22q11.2 deletion syndrome. We excluded from the study any fetus with cardiac malformation or multiple associated congenital anomalies. During the inclusion period, eleven antenatal diagnoses of 22q11.2 microdeletion syndrome have been made. Six cases were excluded: 5 fetuses with cardiac malformation and one with multiple associated congenital anomalies. Therefore, five cases of isolated polyhydramnios were included. All 5 fetuses had a thymic dysgenesis: 3 had a thymic agenesis and 1 thymic hypoplasia diagnosed by sonography and 1 had a thymic agenesis diagnosed by retrospective reading of fetal MRI. When faced with a polyhydramnios, the presence of a thymic dysgenesis should be search for by ultrasound screening and would alert to the possibility of a 22q11.2 microdeletion syndrome. The confirmation of this is diagnosis by amniocentesis would enable improved antenatal support for parents and would enable early implementation of the multidisciplinary neonatal care that is required to avoid serious complications of this syndrome. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Utility of Electrocardiography (ECG)-Gated Computed Tomography (CT) for Preoperative Evaluations of Thymic Epithelial Tumors.

PubMed

Ozawa, Yoshiyuki; Hara, Masaki; Nakagawa, Motoo; Shibamoto, Yuta

2016-01-01

Preoperative evaluation of invasion to the adjacent organs is important for the thymic epithelial tumors on CT. The purpose of our study was to evaluate the utility of electrocardiography (ECG)-gated CT for assessing thymic epithelial tumors with regard to the motion artifacts produced and the preoperative diagnostic accuracy of the technique. Forty thymic epithelial tumors (36 thymomas and 4 thymic carcinomas) were examined with ECG-gated contrast-enhanced CT using a dual source scanner. The scan delay after the contrast media injection was 30 s for the non-ECG-gated CT and 100 s for the ECG-gated CT. Two radiologists blindly evaluated both the non-ECG-gated and ECG-gated CT images for motion artifacts and determined whether the tumors had invaded adjacent structures (mediastinal fat, superior vena cava, brachiocephalic veins, aorta, pulmonary artery, pericardium, or lungs) on each image. Motion artifacts were evaluated using a 3-grade scale. Surgical and pathological findings were used as a reference standard for tumor invasion. Motion artifacts were significantly reduced for all structures by ECG gating ( p =0.0089 for the lungs and p <0.0001 for the other structures). Non-ECG-gated CT and ECG-gated CT demonstrated 79% and 95% accuracy, respectively, during assessments of pericardial invasion ( p =0.03). ECG-gated CT reduced the severity of motion artifacts and might be useful for preoperative assessment whether thymic epithelial tumors have invaded adjacent structures.

Utility of Electrocardiography (ECG)-Gated Computed Tomography (CT) for Preoperative Evaluations of Thymic Epithelial Tumors

PubMed Central

Ozawa, Yoshiyuki; Hara, Masaki; Nakagawa, Motoo; Shibamoto, Yuta

2016-01-01

Summary Background Preoperative evaluation of invasion to the adjacent organs is important for the thymic epithelial tumors on CT. The purpose of our study was to evaluate the utility of electrocardiography (ECG)-gated CT for assessing thymic epithelial tumors with regard to the motion artifacts produced and the preoperative diagnostic accuracy of the technique. Material/Methods Forty thymic epithelial tumors (36 thymomas and 4 thymic carcinomas) were examined with ECG-gated contrast-enhanced CT using a dual source scanner. The scan delay after the contrast media injection was 30 s for the non-ECG-gated CT and 100 s for the ECG-gated CT. Two radiologists blindly evaluated both the non-ECG-gated and ECG-gated CT images for motion artifacts and determined whether the tumors had invaded adjacent structures (mediastinal fat, superior vena cava, brachiocephalic veins, aorta, pulmonary artery, pericardium, or lungs) on each image. Motion artifacts were evaluated using a 3-grade scale. Surgical and pathological findings were used as a reference standard for tumor invasion. Results Motion artifacts were significantly reduced for all structures by ECG gating (p=0.0089 for the lungs and p<0.0001 for the other structures). Non-ECG-gated CT and ECG-gated CT demonstrated 79% and 95% accuracy, respectively, during assessments of pericardial invasion (p=0.03). Conclusions ECG-gated CT reduced the severity of motion artifacts and might be useful for preoperative assessment whether thymic epithelial tumors have invaded adjacent structures. PMID:27920842

Effect of Ion Escape Velocity and Conversion Surface Material on H- Production

NASA Astrophysics Data System (ADS)

Tarvainen, O.; Kalvas, T.; Komppula, J.; Koivisto, H.; Geros, E.; Stelzer, J.; Rouleau, G.; Johnson, K. F.; Carmichael, J.

2011-09-01

According to generally accepted models surface production of negative ions depends on ion escape velocity and work function of the surface. We have conducted an experimental study addressing the role of the ion escape velocity on H- production. A converter-type ion source at Los Alamos Neutron Science Center was employed for the experiment. The ion escape velocity was affected by varying the bias voltage of the converter electrode. It was observed that due to enhanced stripping of H- no direct gain of extracted beam current can be achieved by increasing the converter voltage. The conversion efficiency of H- was observed to vary with converter voltage and follow the existing theories in qualitative manner. We present calculations predicting relative H- yields from different cesiated surfaces with comparison to experimental observations from different types of H- ion sources. Utilizing materials exhibiting negative electron affinity and exposed to UV-light is considered for Cesium-free H-/D- production.

Negative regulators in homeostasis of naïve peripheral T cells.

PubMed

Modiano, Jaime F; Johnson, Lisa D S; Bellgrau, Donald

2008-01-01

It is now apparent that naïve peripheral T cells are a dynamic population where active processes prevent inappropriate activation while supporting survival. The process of thymic education makes naïve peripheral T cells dependent on interactions with self-MHC for survival. However, as these signals can potentially result in inappropriate activation, various non-redundant, intrinsic negative regulatory molecules including Tob, Nfatc2, and Smad3 actively enforce T cell quiescence. Interactions among these pathways are only now coming to light and may include positive or negative crosstalk. In the case of positive crosstalk, self-MHC initiated signals and intrinsic negative regulatory factors may cooperate to dampen T cell activation and sustain peripheral tolerance in a binary fashion (on-off). In the case of negative crosstalk, self-MHC signals may promote survival through partial activation while intrinsic negative regulatory factors act as rheostats to restrain cell cycle entry and prevent T cells from crossing a threshold that would break tolerance.

RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice.

PubMed

Song, Yurong; Sullivan, Teresa; Klarmann, Kimberly; Gilbert, Debra; O'Sullivan, T Norene; Lu, Lucy; Wang, Sophie; Haines, Diana C; Van Dyke, Terry; Keller, Jonathan R

2017-01-01

Thymic epithelial cells (TEC), as part of thymic stroma, provide essential growth factors/cytokines and self-antigens to support T cell development and selection. Deletion of Rb family proteins in adult thymic stroma leads to T cell hyperplasia in vivo. To determine whether deletion of Rb specifically in keratin (K) 18 positive TEC was sufficient for thymocyte hyperplasia, we conditionally inactivated Rb and its family members p107 and p130 in K18+ TEC in genetically engineered mice (TgK18GT121; K18 mice). We found that thymocyte hyperproliferation was induced in mice with Rb inactivation in K18+ TEC, while normal T cell development was maintained; suggesting that inactivation of Rb specifically in K18+ TEC was sufficient and responsible for the phenotype. Transplantation of wild type bone marrow cells into mice with Rb inactivation in K18+ TEC resulted in donor T lymphocyte hyperplasia confirming the non-cell autonomous requirement for Rb proteins in K18+ TEC in regulating T cell proliferation. Our data suggests that thymic epithelial cells play an important role in regulating lymphoid proliferation and thymus size.

The value of computed tomography in myasthenia gravis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, L.R.; Muhm, J.R.; Sheedy, P.F. II

1983-01-01

In a 5 year study, 19 patients with myasthenia gravis were studied by computed tomography (CT) and underwent thymectomy. CT was accurate in detecting the nine true thymic masses but could not differentiate thymomas from nonthymomatous masses, including thymic cysts. No thymoma was found in a patient under 25 years of age. In one case, the 18 sec scanner could not differentiate a large gland from a thymoma. In eight cases, glands with histologic thymic hyperplasia and histologically normal thymus appeared to be similar and could not be differentiated by CT.

Imaging of thymic disorders

PubMed Central

Bogot, Naama R; Quint, Leslie E

2005-01-01

Evaluation of the thymus poses a challenge to the radiologist. In addition to age-related changes in thymic size, shape, and tissue composition, there is considerable variability in the normal adult thymic appearance within any age group. Many different types of disorders may affect the thymus, including hyperplasia, cysts, and benign and malignant neoplasms, both primary and secondary; clinical and imaging findings typical for each disease process are described in this article. Whereas computed tomography is the mainstay for imaging the thymus, other imaging modalities may occasionally provide additional structural or functional information. PMID:16361143

Internet Game Addiction, Depression, and Escape From Negative Emotions in Adulthood: A Nationwide Community Sample of Korea.

PubMed

Kim, Dong Jun; Kim, Kiwon; Lee, Hae-Woo; Hong, Jin-Pyo; Cho, Maeng Je; Fava, Maurizio; Mischoulon, David; Heo, Jung-Yoon; Jeon, Hong Jin

2017-07-01

The aim of this study was to investigate the association between adult Internet game addiction (IGA) and mental disorders. A total of 1401 adults aged between 18 and 74 years participated in this study. The IGA group had significantly younger patients, and it showed a higher proportion of unmarried and unemployed adults, and higher rates of suicidal ideation, plan, and attempt than the non-IGA group. Multivariate logistic regression indicated that IGA was significantly associated with major depressive disorder, dysthymia, and depressive disorders adjusting for all variables. The Patient Health Questionnaire-9 score was significantly higher in the IGA group than in the non-IGA group for both young adults and middle groups. "Escape from negative emotions like nervousness, sadness, and anger" was the only significant item associated with depression among symptoms of IGA. This study suggests that adults with IGA and depression may use Internet games to escape from negative emotions.

Thymocyte emigration is mediated by active movement away from stroma-derived factors

PubMed Central

Poznansky, Mark C.; Olszak, Ivona T.; Evans, Richard H.; Wang, Zhengyu; Foxall, Russell B.; Olson, Douglas P.; Weibrecht, Kathryn; Luster, Andrew D.; Scadden, David T.

2002-01-01

T cells leave the thymus at a specific time during differentiation and do not return despite elaboration of known T cell chemoattractants by thymic stroma. We observed differentiation stage–restricted egress of thymocytes from an artificial thymus in which vascular structures or hemodynamics could not have been playing a role. Hypothesizing that active movement of cells away from a thymic product may be responsible, we demonstrated selective reduction in emigration from primary thymus by inhibitors of active movement down a concentration gradient (chemofugetaxis). Immature intrathymic precursors were insensitive to an emigration signal, whereas mature thymocytes and peripheral blood T cells were sensitive. Thymic stroma was noted to elaborate at least two proteins capable of inducing emigration, one of which was stromal cell–derived factor-1. Thymic emigration is mediated, at least in part, by specific fugetaxis-inducing factors to which only mature cells respond. PMID:11956248

Apatinib treatment in extensive metastatic advanced thymic carcinoma.

PubMed

He, Y; Liu, S; E, M; Wang, C; Shi, M; Liu, G; Abiyasi, N

2018-01-01

Apatinib is a novel oral, anti-tumor, angiogenic-targeting drug that can selectively target vascular endothelial growth factor receptor-2 (VEGFR-2). In clinical trials, this new tyrosine kinase inhibitor (TKI) has been shown to be an effective and safe treatment for a variety of malignancies. Currently, there is a lack of studies of patients with thymic carcinoma; therefore, we present a case of advanced thymic carcinoma treated with apatinib after chemotherapy failure with multiple lung metastases. This patient has been taking a dose of 500 mg of apatinib per day, and his efficacy has achieved partial response (PR), according to the RECIST 1.1 standard, and progression-free survival (PFS) is 6.3 months at this point. Apatinib will continue as his maintenance treatment. During the treatment, drug-related toxicity and side effects were tolerable. Thus, apatinib may be a meaningful option for the treatment of advanced metastatic thymic carcinoma after chemotherapy failure.

A Comparison of Two Models of Risky Sexual Behavior During Late Adolescence.

PubMed

Braje, Sopagna Eap; Eddy, J Mark; Hall, Gordon C N

2016-01-01

Two models of risky sexual behavior (RSB) were compared in a community sample of late adolescents (N = 223). For the traumagenic model, early negative sexual experiences were posited to lead to an association between negative affect with sexual relationships. For the cognitive escape model, depressive affect was posited to lead to engagement in RSB as a way to avoid negative emotions. The current study examined whether depression explained the relationship between sexual trauma and RSB, supporting the cognitive escape model, or whether it was sexual trauma that led specifically to RSB, supporting the traumagenic model. Physical trauma experiences were also examined to disentangle the effects of sexual trauma compared to other emotionally distressing events. The study examined whether the results would be moderated by participant sex. For males, support was found for the cognitive escape model but not the traumagenic model. Among males, physical trauma and depression predicted engagement in RSB but sexual trauma did not. For females, support was found for the traumagenic and cognitive escape model. Among females, depression and sexual trauma both uniquely predicted RSB. There was an additional suppressor effect of socioeconomic status in predicting RSB among females. Results suggest that the association of trauma type with RSB depends on participant sex. Implications of the current study for RSB prevention efforts are discussed.

Critical role for invariant chain in CD1d-mediated selection and maturation of Vα14-invariant NKT cells.

PubMed

Sillé, Fenna C M; Martin, Constance; Jayaraman, Pushpa; Rothchild, Alissa; Besra, Gurdyal S; Behar, Samuel M; Boes, Marianne

2011-09-30

The development and maturation of Vα14 invariant (i)NKT cells in mice requires CD1d-mediated lipid antigen presentation in the thymus and the periphery. Cortical thymocytes mediate positive selection, while professional APCs are involved in thymic negative selection and in terminal maturation of iNKT cells in the periphery. CD1d requires entry in the endosomal pathway to allow antigen acquisition for assembly as lipid/CD1d complexes for display to iNKT cells. This process involves tyrosine-based sorting motifs in the CD1d cytoplasmic tail and invariant chain (Ii) that CD1d associates with in the endoplasmic reticulum. The function of Ii in iNKT cell thymic development and peripheral maturation had not been fully understood. Using mice deficient in Ii and the Ii-processing enzyme cathepsin S (catS), we addressed this question. Ii(-/-) mice but not catS(-/-) mice developed significantly fewer iNKT cells in thymus, that were less mature as measured by CD44 and NK1.1 expression. Ii(-/-) mice but not catS(-/-) mice developed fewer Vβ7(+) cells in their iNKT TCR repertoire than WT counterparts, indicative of a change in endogenous glycolipid antigen/CD1d-mediated iNKT cell selection. Finally, using a Mycobacterium tuberculosis infection model in macrophages, we show that iNKT developed in Ii(-/-) but not catS(-/-) mice have defective effector function. Our data support a role for professional APCs expressing Ii, but no role for catS in the thymic development and peripheral terminal maturation of iNKT cells. Copyright © 2011 Elsevier B.V. All rights reserved.

Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies.

PubMed

Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

2016-01-01

Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. PubMed, Cochrane's Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55-1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors.

Intestinal lymphangiectasia and thymic hypoplasia.

PubMed Central

Sorensen, R U; Halpin, T C; Abramowsky, C R; Hornick, D L; Miller, K M; Naylor, P; Incefy, G S

1985-01-01

We have evaluated the immunological abnormalities present in a 6 year old patient with primary intestinal and generalized lymphangiectasia confirmed by intestinal, lung and lymph node biopsies. Lymphocyte loss through the gut was confirmed by the detection of lymphocytes in her stool. An increased enteric protein loss was suggested by hypoproteinaemia, peripheral oedema, and a very short half-life for i.v. immune serum globulin (3 days). Lymphocyte subpopulation analysis revealed a selective loss of T lymphocytes, with a proportionally increased loss of the OKT4 positive helper/inducer subpopulation. Functionally, there was a decrease in proliferative responses to some mitogens and to allogeneic cells, and a lack of T cell help for in vitro B lymphocyte differentiation into immunoglobulin secreting cells. Natural killer function was normal. In this patient, a concomitant thymic deficiency was documented by failure to identify thymic tissue on a thymus biopsy and by an absence or decrease of the serum thymic factor (thymulin) and thymosin alpha 1. No compensatory lymphopoiesis was detected in the bone marrow. In an attempt to increase T lymphocyte development, the patient was treated with thymosin fraction 5. Daily treatment with this preparation resulted in a transient clinical improvement which could not be sustained on a weekly thymosin treatment schedule. However, lymphocyte numbers did not increase during this treatment. The findings in this patient support the notion that T lymphocytes are needed to stimulate thymic epithelium. In situations of excessive loss of long lived T lymphocytes a secondary thymic atrophy may occur and further contribute to the development of a deficiency in cell-mediated immunity. Images Fig. 1 Fig. 2 PMID:3971596

Histogenesis of the epithelial component of rat thymus: an ultrastructural and immunohistological analysis.

PubMed

Vicente, A; Varas, A; Sacedón, R; Zapata, A G

1996-04-01

Despite the assumed importance of thymic cell microenvironments for governing T-cell maturation, little is known about the ontogeny of their cell components. A few studies have analyzed previously the ontogenetical development of rat thymic epithelium (Bogojevic et al. 1990. Period. Biol., 92:126; Kampinga and Aspinall 1990 Harwood Acad. Pub., London, pp. 149-186; Micic et al., 1991 Dev. Comp. Immunol., 15:443-450) and recently we have reported the development of both interdigitating/dendritic cells and macrophages (Vicente et al., 1994 Immunology, 82:75-81, 1995 Immunology, 85:99-105). In the present work we analyze in situ ultrastructural, immunohistochemical, and histoenzymatically the appearance and development of the thymic epithelial cell component in both embryonic and neonatal Wistar rats with special emphasis on the origin of the different epithelial cell types, the occurrence or absence of a common precursor for these, and the expression of MHC molecules. The thymic primordium of 13-day-old embryos is formed by a homogeneous population of primitive epithelial cells differentiating gradually into various epithelial cell subtypes of both the cortex and the medulla. In the cortex, subcapsular and stroma-supporting epithelial cells appear at days 14-15 as two structurally different cell entities. At the same time, stroma-supporting, keratinized, and vacuolated epithelial cells occur in the thymic medulla. These last two cell types differentiate subsequently into Hassall's bodies and hypertrophied cells. Lympho-epithelial cell complexes are identified in the deep cortex around birth, when the cortical parenchyma houses a transitional erythropoiesis. mAbs (His-39, RMC-20) which recognize medullary epithelial cells in the adult thymus stain positively cells of the thymic primordium as early as day 16 of embryonic life. Cortical epithelial cell markers (His-37, RMC-17) appear, however, slightly later and the subcapsulary region is not established until postnatal life. MHC class I and class II molecules can be identified on epithelial cells in the thymus of 15-day-old embryonic rats although they reach the highest expression around birth. Our results confirm the heterogeneity of the thymic epithelial component, the persistence of primitive, non-differentiated epithelial cells morphologically similar to those occurring in the early thymic primordium in adult thymus, and the mutual relevance of epithelial cells and thymocytes for an adequate development of rat thymus gland.

Longitudinal investigation on learned helplessness tested under negative and positive reinforcement involving stimulus control.

PubMed

Oliveira, Emileane C; Hunziker, Maria Helena

2014-07-01

In this study, we investigated whether (a) animals demonstrating the learned helplessness effect during an escape contingency also show learning deficits under positive reinforcement contingencies involving stimulus control and (b) the exposure to positive reinforcement contingencies eliminates the learned helplessness effect under an escape contingency. Rats were initially exposed to controllable (C), uncontrollable (U) or no (N) shocks. After 24h, they were exposed to 60 escapable shocks delivered in a shuttlebox. In the following phase, we selected from each group the four subjects that presented the most typical group pattern: no escape learning (learned helplessness effect) in Group U and escape learning in Groups C and N. All subjects were then exposed to two phases, the (1) positive reinforcement for lever pressing under a multiple FR/Extinction schedule and (2) a re-test under negative reinforcement (escape). A fourth group (n=4) was exposed only to the positive reinforcement sessions. All subjects showed discrimination learning under multiple schedule. In the escape re-test, the learned helplessness effect was maintained for three of the animals in Group U. These results suggest that the learned helplessness effect did not extend to discriminative behavior that is positively reinforced and that the learned helplessness effect did not revert for most subjects after exposure to positive reinforcement. We discuss some theoretical implications as related to learned helplessness as an effect restricted to aversive contingencies and to the absence of reversion after positive reinforcement. This article is part of a Special Issue entitled: insert SI title. Copyright © 2014. Published by Elsevier B.V.

Quantification of simian immunodeficiency virus cytotoxic T lymphocyte escape mutant viruses.

PubMed

Loh, Liyen; Kent, Stephen J

2008-08-01

Escape from cytotoxic T-lymphocyte (CTL) pressure is common in HIV-1 infection of humans and simian immunodeficiency virus (SIV) infections of macaques. CTL escape typically incurs a fitness cost as reversion back to wild-type can occur upon transmission. We utilized sequence-specific primers and DNA probes with real-time polymerase chain reaction (PCR) to sensitively and specifically track wild-type and escape mutant viremia at the Mane-A*17-restricted SIV Gag(371379) epitope AF9 in pigtail macaques. The generation of minor escape mutant populations is detected by the real-time PCR 2 weeks earlier than observed using standard sequencing techniques. We passaged the AF9 CTL escape mutant virus into two naïve Mane-A*17-negative pigtail macaques and showed that reversion to wild-type was rapid during acute infection and then slowed considerably at later stages of the infection. These data help refine our understanding of how CTL escape mutant viruses evolve.

Thymic hyperplasia in a patient with Grave's disease.

PubMed

Hamzaoui, Amira A; Klii, Rim R; Salem, Randa R; Kochtali, Ines I; Golli, Mondher M; Mahjoub, Silvia S

2012-02-09

Hyperplastic changes of the thymus may be found in patients with Graves' disease. However, this rarely presents as an anterior mediastinal mass, particularly among adults. In this report, we describe a 46-year old woman with Graves' disease and thymic hyperplasia.

Effects of highly active antiretroviral therapy on thymical reconstitution of CD4 T lymphocytes in vertically HIV-infected children.

PubMed

Correa, Rafael; Muñoz-Fernández, Angeles

2002-05-24

CD4 T-cell percentages, viral load and thymic function measured as T-cell receptor rearrangement excision circle (TREC) levels were determined every 2-3 months in six treated HIV-infected children for 4 years. All children experienced a marked increase in CD4 cell count after therapy, accompanied by a concomitantly marked increase in TREC levels. In children, the decrease in viral load caused by antiviral therapy leads to an increase in CD4 T cells, mainly because of a recovery in the thymic production of new T cells.

A Comparative Analysis of the Murine Thymic Microenvironment in Normal, Autoimmune, and Immunodeficiency States

PubMed Central

Takeoka, Yuichi; Chen, Shao-Yuan; Boyd, Richard L.; Tsuneyama, Koichi; Taguchi, Nobuhisa; Morita, Shinji; Yago, Hisashi; Suehiro, Seishi; Ansari, Aftab A.; Shultz, Leonard D.

1997-01-01

It is widely accepted that the thymic microenvironment regulates normal thymopoiesis through a highly coordinated and complex series of cellular and cytokine interactions. A direct corollary of this is that abnormalities within the microenvironment could be of etiologic significance in T-cell-based diseases. Our laboratory has developed a large panel of monoclonal antibodies (mAbs) that react specifically with epithelial or nonepithelial markers in the thymus. We have taken advantage of these reagents to characterize the thymic microenvironment of several genetic strains of mice, including BALB/cJ, C57BL/6J, NZB/BlnJ, SM/J, NOD/Ltz, NOD/Ltz-scid/sz, C57BL/6J-Hcph me/Hcph me, and ALY/NscJcl-aly/aly mice, and littermate control animals. We report herein that control mice, including strains of several backgrounds, have a very consistent phenotypic profile with this panel of monoclonal antibodies, including reactivity with thymic epithelial cells in the cortex, the medulla and the corticomedullary junction, and the extracellular matrix. In contrast, the disease-prone strains studied have unique, abnormal staining of thymic cortex and medulla at both the structural and cellular levels. These phenotypic data suggest that abnormalities in interactions between developing thymocytes and stromal cells characterize disease-prone mice. PMID:9587708

Tuberculosis, the Disrupted Immune-Endocrine Response and the Potential Thymic Repercussion As a Contributing Factor to Disease Physiopathology.

PubMed

D'Attilio, Luciano; Santucci, Natalia; Bongiovanni, Bettina; Bay, María L; Bottasso, Oscar

2018-01-01

Upon the pathogen encounter, the host seeks to ensure an adequate inflammatory reaction to combat infection but at the same time tries to prevent collateral damage, through several regulatory mechanisms, like an endocrine response involving the production of adrenal steroid hormones. Our studies show that active tuberculosis (TB) patients present an immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro-inflammatory cytokines, and decreased amounts of dehydroepiandrosterone. Studies in patients undergoing specific treatment revealed that cortisol levels remained increased even after several months of initiating therapy. In addition to the well-known metabolic and immunological effects, glucocorticoids are involved in thymic cortical depletion with immature thymocytes being quite sensitive to such an effect. The thymus is a central lymphoid organ supporting thymocyte T-cell development, i.e., lineage commitment, selection events and thymic emigration. While thymic TB is an infrequent manifestation of the disease, several pieces of experimental and clinical evidence point out that the thymus can be infected by mycobacteria. Beyond this, the thymic microenvironment during TB may be also altered because of the immune-hormonal alterations. The thymus may be then an additional target of organ involvement further contributing to a deficient control of infection and disease immunopathology.

Decreased expression of thymus-specific proteasome subunit β5t in Down syndrome patients.

PubMed

Tomaru, Utano; Tsuji, Takahiro; Kiuchi, Shizuka; Ishizu, Akihiro; Suzuki, Akira; Otsuka, Noriyuki; Ito, Tomoki; Ikeda, Hitoshi; Fukasawa, Yuichiro; Kasahara, Masanori

2015-08-01

The majority of patients with Down syndrome (DS), trisomy 21, have morphologically abnormal thymuses and present with intrinsic immunological abnormalities affecting mainly the cellular immune response. The aim of this study was to examine whether the expression of functionally important molecules is altered in thymic stromal cells in patients with DS. We analysed thymic tissues from patients with trisomy 13 (n = 4), trisomy 18 (n = 14) and trisomy 21 (n = 13) for histological alterations, and for the expression of functionally important molecules such as β5t, a thymoproteasome subunit, and cathepsins L and S. In patients with trisomy 13 and trisomy 18, the thymus was morphologically normal or showed only mild depletion of cortical thymocytes. In contrast, the thymus showed variable histological changes in patients with trisomy 21; six of 13 cases showed severe depletion of thymocytes accompanied by the disappearance of thymic lobular architecture. In such thymuses, spindle-shaped keratin-positive cells were densely distributed, and expression of β5t, but not of cathepsin L, was markedly decreased. The present study suggests that abnormal thymic architecture and decreased expression of functionally important molecules in thymic stromal cells may be involved in immunological abnormalities in DS patients. © 2015 John Wiley & Sons Ltd.

Association of murine lupus and thymic full-length endogenous retroviral expression maps to a bone marrow stem cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krieg, A.M.; Gourley, M.F.; Steinberg, A.D.

1991-05-01

Recent studies of thymic gene expression in murine lupus have demonstrated 8.4-kb (full-length size) modified polytropic (Mpmv) endogenous retroviral RNA. In contrast, normal control mouse strains do not produce detectable amounts of such RNA in their thymuses. Prior studies have attributed a defect in experimental tolerance in murine lupus to a bone marrow stem cell rather than to the thymic epithelium; in contrast, infectious retroviral expression has been associated with the thymic epithelium, rather than with the bone marrow stem cell. The present study was designed to determine whether the abnormal Mpmv expression associated with murine lupus mapped to thymicmore » epithelium or to a marrow precursor. Lethally irradiated control and lupus-prone mice were reconstituted with T cell depleted bone marrow; one month later their thymuses were studied for endogenous retroviral RNA and protein expression. Recipients of bone marrow from nonautoimmune donors expressed neither 8.4-kb Mpmv RNA nor surface MCF gp70 in their thymuses. In contrast, recipients of bone marrow from autoimmune NZB or BXSB donors expressed thymic 8.4-kb Mpmv RNA and mink cell focus-forming gp70. These studies demonstrate that lupus-associated 8.4-kb Mpmv endogenous retroviral expression is determined by bone marrow stem cells.« less

AIRE: a missing link to explain female susceptibility to autoimmune diseases.

PubMed

Berrih-Aknin, Sonia; Panse, Rozen Le; Dragin, Nadine

2018-01-01

Women are more susceptible to autoimmune diseases than men. Autoimmunity results from tolerance breakdown toward self-components. Recently, three transcription modulators were identified in medullary thymic epithelial cells that orchestrate immune central tolerance processes: the autoimmune regulator (AIRE), FEZ family zinc finger 2 (FEZF2 or FEZ1), and PR domain zinc finger protein 1 (PRDM1). Interestingly, these three transcription modulators regulate nonredundant tissue-specific antigen subsets and thus cover broad antigen diversity. Recent data from different groups demonstrated that sex hormones (estrogen and testosterone) are involved in the regulation of thymic AIRE expression in humans and mice through direct transcriptional modulation and epigenetic changes. As a consequence, AIRE displays gender-biased thymic expression, with females showing a lower expression compared with males, a finding that could explain the female susceptibility to autoimmune diseases. So far, FEZF2 has not been related to an increased gender bias in autoimmune disease. PRDM1 expression has not been shown to display gender-differential thymic expression, but its expression level and its gene polymorphisms are associated with female-dependent autoimmune disease risk. Altogether, various studies have demonstrated that increased female susceptibility to autoimmune diseases is in part a consequence of hormone-driven reduced thymic AIRE expression. © 2017 New York Academy of Sciences.

[Etiology and therapy in anorexia nervosa (author's transl)].

PubMed

Wurst, E

1976-01-01

ASPERGER (1963) mentioned as a very important etiological aspect of anorexia nervosa a desintegration of intellectual and thymical functions causing the fact, that these patients are not able to accept the role of an adult, especially that one of a woman. We discuss that statment in connexion with ERIKSON'S (1974) concept about "ego-identity" ("Ich-Identitat") and "negative-identity" ("negative Identitat"). The pathological family-structure seems to reinforce the situation and the existence of inadequate behavior of patients with anorexia nervosa, who are often introverted and predestinated for conditioning. The therapy of these patients should focuse on the development of ego-identity, including the treatment of the family members, the modification of the inadapted behavior and a special endocrinological therapy.

Thymic hyperplasia in a patient with Grave's disease

PubMed Central

2012-01-01

Hyperplastic changes of the thymus may be found in patients with Graves' disease. However, this rarely presents as an anterior mediastinal mass, particularly among adults. In this report, we describe a 46-year old woman with Graves' disease and thymic hyperplasia. PMID:22321290

Psychological Escapism: Predicting the Amount of Television Viewing by Need for Cognition.

ERIC Educational Resources Information Center

Henning, Bernd; Vorderer, Peter

2001-01-01

Investigates differences observed among German students regarding amount of television viewing. Finds a significant negative effect of need for cognition on viewing amount. Interprets this as a manifestation of individual-psychological escapism in which the lower viewers' need for cognition is, the less pleasant they feel when they have nothing to…

V beta-specific deletion of mature thymocytes induced by the plant superantigen Urtica dioica agglutinin.

PubMed

Delcourt, M; Peumans, W J; Wagner, M C; Truffa-Bachi, P

1996-03-15

Urtica dioica agglutinin (UDA), a plant protein, is a superantigen activating in a MHC class II-restricted manner the V beta 8. 3-bearing T-cells (Galelli and Truffa-Bachi, J. Immunol. 151, 1821, 1993). Administration of UDA to adult mice provokes the clonal expansion of the responding cells which is followed by the deletion of the major fraction of the UDA-sensitive cells, whereas the remaining cells become anergic (Galelli et al., J. Immunol. 154, 2600, 1995). We have analyzed the effect of UDA on thymocytes. Injection of UDA resulted in a rapid, but transient, deletion of a large fraction of the V beta 8.3-bearing mature T-cells. In contrast to other exogenous superantigens, this deletion was not preceded by the clonal expansion of the UDA-responding thymocytes. Moreover, the V beta 8.3-bearing mature T-cells escaping the deletion were not anergic to an in vitro UDA restimulation. UDA and the other superantigens also differ as the general, V beta-unrestricted, thymic atrophy induced by classical superantigens was not observed with UDA.

MiR-21 plays an Important Role in Radiation Induced Carcinogenesis in BALB/c Mice by Directly Targeting the Tumor Suppressor Gene Big-h3

PubMed Central

Liu, Cong; Li, Bailong; Cheng, Ying; Lin, Jing; Hao, Jun; Zhang, Shuyu; Mitchel, R.E.J.; Sun, Ding; Ni, Jin; Zhao, Luqian; Gao, Fu; Cai, Jianming

2011-01-01

Dysregulation of certain microRNAs (miRNAs) in cancer can promote tumorigenesis, metastasis and invasion. However, the functions and targets of only a few mammalian miRNAs are known. In particular, the miRNAs that participates in radiation induced carcinogenesis and the miRNAs that target the tumor suppressor gene Big-h3 remain undefined. Here in this study, using a radiation induced thymic lymphoma model in BALB/c mice, we found that the tumor suppressor gene Big-h3 is down-regulated and miR-21 is up-regulated in radiation induced thymic lymphoma tissue samples. We also found inverse correlations between Big-h3 protein and miR-21 expression level among different tissue samples. Furthermore, our data indicated that miR-21 could directly target Big-h3 in a 3′UTR dependent manner. Finally, we found that miR-21 could be induced by TGFβ, and miR-21 has both positive and negative effects in regulating TGFβ signaling. We conclude that miR-21 participates in radiation induced carcinogenesis and it regulates TGFβ signaling. PMID:21494432

GATA-3 is required for early T lineage progenitor development

PubMed Central

Hosoya, Tomonori; Kuroha, Takashi; Moriguchi, Takashi; Cummings, Dustin; Maillard, Ivan; Lim, Kim-Chew

2009-01-01

Most T lymphocytes appear to arise from very rare early T lineage progenitors (ETPs) in the thymus, but the transcriptional programs that specify ETP generation are not completely known. The transcription factor GATA-3 is required for the development of T lymphocytes at multiple late differentiation steps as well as for the development of thymic natural killer cells. However, a role for GATA-3 before the double-negative (DN) 3 stage of T cell development has to date been obscured both by the developmental heterogeneity of DN1 thymocytes and the paucity of ETPs. We provide multiple lines of in vivo evidence through the analysis of T cell development in Gata3 hypomorphic mutant embryos, in irradiated mice reconstituted with Gata3 mutant hematopoietic cells, and in mice conditionally ablated for the Gata3 gene to show that GATA-3 is required for ETP generation. We further show that Gata3 loss does not affect hematopoietic stem cells or multipotent hematopoietic progenitors. Finally, we demonstrate that Gata3 mutant lymphoid progenitors exhibit neither increased apoptosis nor diminished cell-cycle progression. Thus, GATA-3 is required for the cell-autonomous development of the earliest characterized thymic T cell progenitors. PMID:19934022

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice.

PubMed

Huo, Xueyun; Li, Zhenkun; Zhang, Shuangyue; Li, Changlong; Guo, Meng; Lu, Jing; Lv, Jianyi; Du, Xiaoyan; Chen, Zhenwen

2017-10-01

Tumorigenesis is often caused by somatic mutation or epigenetic changes in genes that regulate aspects of cell death, proliferation and survival. Although the functions of multiple tumor suppressor genes have been well studied in isolation, how these genes cooperate during the progression of a single tumor remains unclear in numerous cases. The present study used N-methyl-N-nitrosourea (MNU), one of the most potent mutagenic nitrosourea compounds, to induce thymic lymphoma in C57BL/6J mice. Subsequently, the protein expression levels of phosphatase and tensin homolog (PTEN), transformation protein 53 and mutS homolog 2 (MSH2) were evaluated concomitantly in the thymus, liver, kidney and spleen of MNU-treated mice by western blotting. To determine whether changes in expression level were due to aberrant epigenetic regulation, the present study further examined the methylation status of each gene by MassARRAY analysis. During the tumorigenesis process of an MNU-induced single thymic lymphoma, the expression level of PTEN was revealed to be reduced in thymic lymphoma samples but not in normal or non-tumor thymus tissue samples. Furthermore, a marked reduction of P53 expression levels were demonstrated in thymic lymphomas and spleens with a metastatic tumor. Conversely, MSH2 upregulation was identified only in liver, kidney, and spleen samples that were infiltrated by thymic lymphoma cells. Furthermore, the present study revealed that a number of 5'-C-phosphate-G-3' sites located in the promoter of aberrantly expressed genes had significantly altered methylation statuses. These results improve the understanding of the course of mutagen-induced cancer, and highlight that epigenetic regulation may serve an important function in cancer.

A Whole-Tumor Histogram Analysis of Apparent Diffusion Coefficient Maps for Differentiating Thymic Carcinoma from Lymphoma.

PubMed

Zhang, Wei; Zhou, Yue; Xu, Xiao-Quan; Kong, Ling-Yan; Xu, Hai; Yu, Tong-Fu; Shi, Hai-Bin; Feng, Qing

2018-01-01

To assess the performance of a whole-tumor histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating thymic carcinoma from lymphoma, and compare it with that of a commonly used hot-spot region-of-interest (ROI)-based ADC measurement. Diffusion weighted imaging data of 15 patients with thymic carcinoma and 13 patients with lymphoma were retrospectively collected and processed with a mono-exponential model. ADC measurements were performed by using a histogram-based and hot-spot-ROI-based approach. In the histogram-based approach, the following parameters were generated: mean ADC (ADC mean ), median ADC (ADC median ), 10th and 90th percentile of ADC (ADC 10 and ADC 90 ), kurtosis, and skewness. The difference in ADCs between thymic carcinoma and lymphoma was compared using a t test. Receiver operating characteristic analyses were conducted to determine and compare the differentiating performance of ADCs. Lymphoma demonstrated significantly lower ADC mean , ADC median , ADC 10 , ADC 90 , and hot-spot-ROI-based mean ADC than those found in thymic carcinoma (all p values < 0.05). There were no differences found in the kurtosis ( p = 0.412) and skewness ( p = 0.273). The ADC 10 demonstrated optimal differentiating performance (cut-off value, 0.403 × 10 -3 mm 2 /s; area under the receiver operating characteristic curve [AUC], 0.977; sensitivity, 92.3%; specificity, 93.3%), followed by the ADC mean , ADC median , ADC 90 , and hot-spot-ROI-based mean ADC. The AUC of ADC 10 was significantly higher than that of the hot spot ROI based ADC (0.977 vs. 0.797, p = 0.036). Compared with the commonly used hot spot ROI based ADC measurement, a histogram analysis of ADC maps can improve the differentiating performance between thymic carcinoma and lymphoma.

Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies

PubMed Central

Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

2016-01-01

Background Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. Methods PubMed, Cochrane’s Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Results Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55–1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Conclusion Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors. PMID:27524907

Thymic Dendritic Cells Are Primary Targets for the Oncogenic Virus SL3-3

PubMed Central

Uittenbogaart, Christel H.; Law, Wendy; Leenen, Pieter J. M.; Bristol, Gregory; van Ewijk, Willem; Hays, Esther F.

1998-01-01

The murine retrovirus SL3-3 causes malignant transformation of thymocytes and thymic lymphoma in mice of the AKR and NFS strains when they are inoculated neonatally. The objective of the present study was to identify the primary target cells for the virus in the thymuses of these mice. Immunohistochemical studies of the thymus after neonatal inoculation of the SL3-3 virus showed that cells expressing the viral envelope glycoprotein (gp70+ cells) were first seen at 2 weeks of age. These virus-expressing cells were found in the cortex and at the corticomedullary junction in both mouse strains. The gp70+ cells had the morphology and immunophenotype of dendritic cells. They lacked macrophage-specific antigens. Cell separation studies showed that bright gp70+ cells were detected in a fraction enriched for dendritic cells. At 3 weeks of age, macrophages also expressed gp70. At that time, both gp70+ dendritic cells and macrophages were found at the corticomedullary junction and in foci in the thymic cortex. At no time during this 3-week period was the virus expressed in cortical and medullary epithelial cells or in thymic lymphoid cells. Infectious cell center assays indicated that cells expressing infectious virus were present in small numbers at 2 weeks after inoculation but increased at 5 weeks of age by several orders of magnitude, indicating virus spread to the thymic lymphoid cells. Thus, at 2 weeks after neonatal inoculation of SL3-3, thymic dendritic cells are the first cells to express the virus. At 3 weeks of age, macrophages also express the virus. In subsequent weeks, the virus spreads to the thymocytes. This pathway of virus expression in the thymus allows the inevitable provirus integration in a thymocyte that results in a clonal lymphoma. PMID:9811752

Copanlisib and Nivolumab in Treating Participants With Recurrent or Refractory Diffuse Large B-cell Lymphoma or Primary Mediastinal Large B-cell Lymphoma

ClinicalTrials.gov

2018-06-11

Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma

Thymic involution in the suspended rat model for weightlessness - Decreased glucocorticoid receptor concentration

NASA Technical Reports Server (NTRS)

Steffen, J. M.; Musacchia, X. J.

1984-01-01

Hindlimb muscle atrophy, thymic involution and adrenal hypertrophy in rats during spaceflight can be simulated using suspension models. Skeletal muscle and thymus are sensitive to gluco-corticoids (GC), and previous studies have demonstrated that muscle atrophy in suspended rats is associated with increased GC receptor concentration. The objectives were to confirm thymic involution during suspension, and determine if involution correlated with increased GC receptor concentration. Seven days of antiorthostatic (AO) suspension of rats produced a significant (P less than 0.001) reduction in thymic wet weight not associated with an alteration of percent water content. GC receptor concentration (pmol/mg protein) decreased 20 percent (P less than 0.025) in thymus glands from 7 day AO suspended rats. Suspension, therefore, is associated with involution of the thymus, but this is not dependent upon AO positioning. Thymus GC receptor concentrations were depressed in 7-day suspended rats, in contrast with previous observations on skeletal muscle, suggesting that different mechanisms may underlie these responses.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuang, Xianghong; Shen, Jianjun; Wong, Paul K.Y.

Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/-more » mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.« less

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

PubMed Central

Siddiqui, Sana; Lustig, Ana; Carter, Arnell; Sankar, Mathavi; Daimon, Caitlin M.; Premont, Richard T.; Etienne, Harmonie; van Gastel, Jaana; Azmi, Abdelkrim; Janssens, Jonathan; Becker, Kevin G.; Zhang, Yongqing; Wood, William; Lehrmann, Elin; Martin, James G.; Martin, Bronwen; Taub, Dennis D.; Maudsley, Stuart

2017-01-01

Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of ‘neurometabolic’ integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2−/− mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2−/− (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical ‘organ’, i.e. ‘parathymic lobes’. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe – suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature ‘aging’ phenotype of GIT2KO mice. PMID:28260693

Titan's plasma interaction: photoelectrons and negative ions

NASA Astrophysics Data System (ADS)

Coates, Coates; Welbrock, Anne; Desai, Ravi; Waite, Hunter

2016-06-01

We present a review of some of the most important results from the CAPS electron spectrometer.These include the role of photoelectrons and polar wind escape processes, and remarkable negative ion observations.

[Self-evaluation of physical, cognitive and mood symptoms in a cohort of traumatic and vascular brain injury patients participating in social and neuropsychological remediation programmes].

PubMed

Thomas-Antérion, C; Truche, A; Sciéssère, K; Guyot, E; Hibert, O; Paris, N

2005-01-01

We studied 23 vascular or traumatic head injury subjects, five years after their injury. Neuropsychological testing included language tests, memory performance, frontal lobe tests and standard tests of intelligence (QI). Behavior was evaluated with the neuropsychiatric interview (NPI). Using an analogic visual scale, subjects performed a self-evaluation of their memory, language, attention, physical and thymic complaints. Neuropsychological assessment was heterogeneous but seemed to show severe impairment. Mean NPI score was 31.4: 91 percent of patients showed depression or anxiety and 78 percent of them showed irritability. Mean memory and thymic complaints were scored 6 on the analogic visual scale. Thymic complaint was not correlated with neuropsychological tests but with physical complaints. Thymic complaint was correlated with NPI score. Language complaint was correlated with VIQ, attentional complaint was correlated with PIQ, memory complaint with memory tests. In a second part, we studied 21 patients again 6 months later and 14 patients 1 year later. Mean complaints were scored over 5 after 6 months and over 4 after 1 year. With neuropsychological remediation and social activities, memory complaints improved significantly after 6 months and attentional and thymic complaints after 1 year. Using of analogical visual scales appears to be feasible: patients were able to evaluate their difficulties. This could be useful to elaborate remediation programs and evaluate outcome.

HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications.

PubMed

Janik, S; Schiefer, A I; Bekos, C; Hacker, P; Haider, T; Moser, J; Klepetko, W; Müllauer, L; Ankersmit, H J; Moser, B

2016-04-21

Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated.

HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications

PubMed Central

Janik, S.; Schiefer, A. I.; Bekos, C.; Hacker, P.; Haider, T.; Moser, J.; Klepetko, W.; Müllauer, L.; Ankersmit, H. J.; Moser, B.

2016-01-01

Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated. PMID:27097982

Thymic pathogenicity of an HIV-1 envelope is associated with increased CXCR4 binding efficiency and V5-gp41-dependent activity, but not V1/V2-associated CD4 binding efficiency and viral entry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meissner, Eric G.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599; Coffield, Vernon M.

2005-06-05

We previously described a thymus-tropic HIV-1 envelope (R3A Env) from a rapid progressor obtained at the time of transmission. An HIV-1 molecular recombinant with the R3A Env supported extensive replication and pathogenesis in the thymus and did not require Nef. Another Env from the same patient did not display the same thymus-tropic pathogenesis (R3B Env). Here, we show that relative to R3B Env, R3A Env enhances viral entry of T cells, increases fusion-induced cytopathicity, and shows elevated binding efficiency for both CD4 and CXCR4, but not CCR5, in vitro. We created chimeric envelopes to determine the region(s) responsible for eachmore » in vitro phenotype and for thymic pathogenesis. Surprisingly, while V1/V2 contributed to enhanced viral entry, CD4 binding efficiency, and cytopathicity in vitro, it made no contribution to thymic pathogenesis. Rather, CXCR4 binding efficiency and V5-gp41-associated activity appear to independently contribute to thymic pathogenesis of the R3A Env. These data highlight the contribution of unique HIV pathogenic factors in the thymic microenvironment and suggest that novel mechanisms may be involved in Env pathogenic activity in vivo.« less

Assessing Preferences for Positive and Negative Reinforcement during Treatment of Destructive Behavior with Functional Communication Training

ERIC Educational Resources Information Center

Fisher, Wayne W.; Adelinis, John D.; Volkert, Valerie M.; Keeney, Kris M.; Neidert, Pamela L.; Hovanetz, Alyson

2005-01-01

Results of prior studies (e.g. [J. Appl. Behav. Anal. 32 (1999) 285]) showing that participants chose alternative behavior (compliance) over escape-reinforced destructive behavior when this latter response produced escape and the former response produced positive reinforcement may have been due to (a) the value of the positive reinforcer…

Regulation of theta-antigen expression by agents altering cyclic AMP level and by thymic factor.

PubMed

Bach, M A; Fournier, C; Bach, J F

1975-02-28

Thymic factor, cyclic AMP, and products increasing its cellular level, such as Prostaglandin E1, induce the appearance of the theta-antigen on T-cell precursors whether assessed by a rossette-inhibition assay or a cytotoxic assay after cell fractionation on BSA discontinuous gradiet. Synergism has been demonstrated between cyclic AMPT and TF for that effect. Conversely, decrease of theta expression has been obtained by altering cyclic AMP level in theta-positive cells either increasing it by dibutyryl cAMP treatment or decreasing it by indomethacin treatment. Finally, these data suggest the involvement of cyclic AMP in the regulation of theta expression under thymic hormone control.

Anti-Apoptotic Signature in Thymic Squamous Cell Carcinomas - Functional Relevance of Anti-Apoptotic BIRC3 Expression in the Thymic Carcinoma Cell Line 1889c.

PubMed

Huang, Bei; Belharazem, Djeda; Li, Li; Kneitz, Susanne; Schnabel, Philipp A; Rieker, Ralf J; Körner, Daniel; Nix, Wilfred; Schalke, Berthold; Müller-Hermelink, Hans Konrad; Ott, German; Rosenwald, Andreas; Ströbel, Philipp; Marx, Alexander

2013-01-01

The molecular pathogenesis of thymomas and thymic carcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.

Intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation; comparison with thymic lymphoepithelioma-like carcinoma and a possibility of development from a multipotential stem cell.

PubMed

Hirokawa, Mitsuyoshi; Miyauchi, Akira; Minato, Hiroshi; Yokoyama, Shigeo; Kuma, Seiji; Kojima, Masaru

2013-06-01

The purpose of our article is to describe the immunohistochemical findings of intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation (ITET/CASTLE) of the thyroid in detail, to clarify the difference between ITET/CASTLE and thymic lymphoepithelioma-like carcinoma (LELC), and to discuss the pathogenesis of ITET/CASTLE. We immunohistochemically examined five ITET/CASTLE and eight LELC cases. All of ITET/CASTLE cases were strongly positive for CD5, P63, high-molecular-weight cytokeratin and B-cell CLL/lymphoma-2. Carcinoembryonic antigen-positive carcinoma cells were found in four ITET/CASTLE cases. Neuroendocrine marker-positive carcinoma cells were scattered in all cases. Immunohistochemical findings in thymic LELC were essentially similar to those in ITET/CASTLE, but the sensitivity was different. There is a possibility that ITET/CASTLE and thymic LELC are not the quite same disease entity. We think that ITET/CASTLE is derived from ectopic thymus, but not related to solid cell nests. © 2012 APMIS Published by John Wiley & Sons Ltd.

T-cell receptor excision circles (TREC) in CD4+ and CD8+ T-cell subpopulations in atopic dermatitis and psoriasis show major differences in the emission of recent thymic emigrants.

PubMed

Just, Helle L; Deleuran, Mette; Vestergaard, Christian; Deleuran, Bent; Thestrup-Pedersen, Kristian

2008-01-01

We used T-cell receptor excision circles (TREC) to evaluate thymic function in adult patients with atopic dermatitis and psoriasis. We observed that men, but not women, with atopic dermatitis had a significantly faster decline in TREC content with increasing age compared with healthy men. In contrast, both men and women with psoriasis had significantly reduced TREC levels, which were, on average, only 30% of that of healthy persons. In atopic dermatitis the levels of TREC declined with increasing levels of IgE, disease intensity and extent of eczema. Furthermore, patients with atopic dermatitis showed signs of altered thymus function, as they had a significantly greater variation in TREC content measured over time than healthy controls, especially within the CD8+ T-cell subpopulation. Because both atopic dermatitis and psoriasis patients have an increased number of T-cells, this indicates that atopic dermatitis patients can have compensatory emissions of thymic emigrants, whereas psoriatic patients do not, thus supporting different thymic function in these two diseases.

Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms.

PubMed

Feyerabend, Thorsten B; Terszowski, Grzegorz; Tietz, Annette; Blum, Carmen; Luche, Hervé; Gossler, Achim; Gale, Nicholas W; Radtke, Freddy; Fehling, Hans Jörg; Rodewald, Hans-Reimer

2009-01-16

Notch1 signaling is required for T cell development and has been implicated in fate decisions in the thymus. We showed that Notch1 deletion in progenitor T cells (pro-T cells) revealed their latent developmental potential toward becoming conventional and plasmacytoid dendritic cells. In addition, Notch1 deletion in pro-T cells resulted in large numbers of thymic B cells, previously explained by T-to-B cell fate conversion. Single-cell genotyping showed, however, that the majority of these thymic B cells arose from Notch1-sufficient cells by a cell-extrinsic pathway. Fate switching nevertheless exists for a subset of thymic B cells originating from Notch1-deleted pro-T cells. Chimeric mice lacking the Notch ligand delta-like 4 (Dll4) in thymus epithelium revealed an essential role for Dll4 in T cell development. Thus, Notch1-Dll4 signaling fortifies T cell commitment by suppressing non-T cell lineage potential in pro-T cells, and normal Notch1-driven T cell development repels excessive B cells in the thymus.

Thymic minimally invasive surgery: state of the art across the world: Central-South America

PubMed Central

2017-01-01

Literature suggests that, for thymectomy in myasthenia or resection of thymic tumors, minimally invasive surgery is equivalent to open surgery with regard to long-term outcomes. However, it could bring some benefits in the immediate results as complication rate or length-of-stay. There are doubts about the worldwide adoption of the method, though. In Latin America, the implementation of video-assisted thoracic surgery (VATS) started in the 1990s, but it progressed slowly. The main barriers were associated costs and training. Thymic surgery poses a bigger challenge due to its rarity, so just a few reports mention the use of the method in the region. Nonetheless, in recent years we observe a faster dissemination of the method both in number and in complexity of the procedures performed. Confirming this fact, half of the patients registered in the Brazilian Society of Thoracic Surgery database in the last 2 years as undergoing resection of thymic tumors, underwent a minimally invasive procedure. Although promising, robotic surgery is still in its early days in Latin America. PMID:29078684

Addiction Motivation Reformulated: An Affective Processing Model of Negative Reinforcement

ERIC Educational Resources Information Center

Baker, Timothy B.; Piper, Megan E.; McCarthy, Danielle E.; Majeskie, Matthew R.; Fiore, Michael C.

2004-01-01

This article offers a reformulation of the negative reinforcement model of drug addiction and proposes that the escape and avoidance of negative affect is the prepotent motive for addictive drug use. The authors posit that negative affect is the motivational core of the withdrawal syndrome and argue that, through repeated cycles of drug use and…

Updates in MRI characterization of the thymus in myasthenic patients.

PubMed

Popa, G A; Preda, E M; Scheau, C; Vilciu, C; Lupescu, I G

2012-06-12

To evaluate the imaging appearance of the thymus in the myasthenic patients by using chemical shift magnetic resonance imaging, and, to correlate the chemical shift ratio (CSR) with pathologic findings after surgical excision. In the past year, a total of 11 myasthenic patients (4 males, 7 females; age range of 26-65 years), have been investigated by MRI centered at the thymic lodge. Our protocol included a Dual-Echo technique, T1-weighted In-phase/Opposed-phase MR images in all patients. A chemical shift ratio (CSR) was calculated by comparing the signal intensity of the thymus gland with that of the chest wall muscle for quantitative analysis. For this purpose, we have used standard region-of-interest electronic cursors at a slice level of the maximum axial surface of the thymus. We have identified two patients groups: a thymic hyperplasia group and a thymic tumoral group. With the decrease in the signal intensity of the thymus gland at chemical shift, the MR imaging was evident only in the hyperplasia group. The mean CSR in the hyperplasia group was considerably lower than that in the tumor group, 0,4964 ± 0,1841, compared with 1,0398 ± 0,0244. The difference in CSR between the hyperplasia and tumor groups was statistically significant (P=0,0028). MR imaging using T1-weighted In-phase/Opposed-phase images could be a useful diagnostic tool in the preoperative assessment of the thymic lodge and may help differentiate thymic hyperplasia from tumors of the thymus gland.

Mathematical Model of Naive T Cell Division and Survival IL-7 Thresholds.

PubMed

Reynolds, Joseph; Coles, Mark; Lythe, Grant; Molina-París, Carmen

2013-01-01

We develop a mathematical model of the peripheral naive T cell population to study the change in human naive T cell numbers from birth to adulthood, incorporating thymic output and the availability of interleukin-7 (IL-7). The model is formulated as three ordinary differential equations: two describe T cell numbers, in a resting state and progressing through the cell cycle. The third is introduced to describe changes in IL-7 availability. Thymic output is a decreasing function of time, representative of the thymic atrophy observed in aging humans. Each T cell is assumed to possess two interleukin-7 receptor (IL-7R) signaling thresholds: a survival threshold and a second, higher, proliferation threshold. If the IL-7R signaling strength is below its survival threshold, a cell may undergo apoptosis. When the signaling strength is above the survival threshold, but below the proliferation threshold, the cell survives but does not divide. Signaling strength above the proliferation threshold enables entry into cell cycle. Assuming that individual cell thresholds are log-normally distributed, we derive population-average rates for apoptosis and entry into cell cycle. We have analyzed the adiabatic change in homeostasis as thymic output decreases. With a parameter set representative of a healthy individual, the model predicts a unique equilibrium number of T cells. In a parameter range representative of persistent viral or bacterial infection, where naive T cell cycle progression is impaired, a decrease in thymic output may result in the collapse of the naive T cell repertoire.

The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla.

PubMed

Stephen, Tom Li; Tikhonova, Anastasia; Riberdy, Janice M; Laufer, Terri M

2009-11-01

Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.

Elevation of oleate-activated phospholipase D activity during thymic atrophy

PubMed Central

Lee, Youngkyun; Song, Soo-Mee; Park, Heung Soon; Kim, Sungyeol; Koh, Eun-Hee; Choi, Myung Sun; Choi, Myung-Un

2002-01-01

Various phospholipases are thought to be associated with the in vitro apoptosis of thymocytes. In the present study, the in vivo phospholipase D (PLD) activity of rat thymus was studied after whole-body X-irradiation or injection of dexamethasone (DEX). Using exogenous [14C]dipalmitoyl phosphatidylcholine (PC) as the substrate, an elevation of oleate-activated PLD activity was observed during thymic atrophy. The activity increases were sevenfold at 48 hr after 5-Gy irradiation and fourfold at 72 hr after injection of 5 mg/kg DEX. The elevation of PLD activity appeared to parallel extensive thymus shrinkage. An increased level of thymic phosphatidic acid (PA), the presumed physiological product of PLD action on PC, was also detected. By comparing the acyl chains of PA with those of other phospholipids, PA appeared to originate from PC. To assess the role of PLD during thymic atrophy, thymocytes and stromal cells were isolated. Although thymocytes themselves exhibited significant PLD activation, the major elevation in PLD activity (greater than fourfold) was found in isolated stromal cells. PLD was also activated during in vitro phagocytosis of apoptotic thymocytes by the macrophage-like cell line P388D1. This in vitro phagocytosis was significantly inhibited by PLD action blockers, such as 2,3-diphosphoglycerate and 1-butanol. These observations strongly suggest that the alteration of oleate-activated PLD activity is part of an in vivo event in the progression of thymic atrophy, including phagocytic clearance of apoptotic thymocytes. PMID:12460188

Computer Simulation of Rocket/Missile Safing and Arming Mechanism (Containing Pin Pallet Runaway Escapement, Three-Pass Involute Gear Train and Acceleration Driven Rotor)

DTIC Science & Technology

1986-03-01

pin is along the escape wheel tooth, and is a measure of the distance along the plane of the tooth to its end. [Again, parameter g has a negative...Reference 2, appendix C gives the details of how thes." parameters are evaluated.) The parameter f is a measure of the distance between the pallet pin... measures the distance from the pallet pin center tO the escape wheel tooth tip along the plane of the tooth. First the parameter f is monitored. If f

Comparison of surgical approach and extent of resection for Masaoka-Koga Stage I and II thymic tumours in Europe, North America and Asia: an International Thymic Malignancy Interest Group retrospective database analysis.

PubMed

Fang, Wentao; Yao, Xiaopan; Antonicelli, Alberto; Gu, Zhitao; Detterbeck, Frank; Vallières, Eric; Aye, Ralph W; Farivar, Alexander S; Huang, James; Shang, Yue; Louie, Brian E

2017-07-01

Surgeons at different institutions worldwide choose different types of operations for thymic tumours. It is not known whether these differences affect the outcomes of the patients. A total of 1430 patients with Masaoka-Koga pathological Stage I-II thymic tumours without myasthenia gravis or pre-treatment were identified from the International Thymic Malignancy Interest Group retrospective database. Outcomes of patients from 3 major continents (Europe, North America and Asia) were compared. Patients from the 3 continents were comparable in gender and performance status. More European patients had more paraneoplastic syndromes; North American patients had the smallest tumour sizes and less adjuvant therapy; and Asian patients were younger and had more Stage I disease but higher grade tumours. Partial thymectomy was performed more often in Asian patients (31.7%) than in European (2.4%) and North American (5.4%; P  < 0.001) patients. The median approach (sternotomy/clamshell) was the major approach in Europe (75.3%) and North America (76.6%). In contrast, the median approach was applied significantly less frequently in Asia (45.6%, P  < 0.001); unilateral open (thoracotomy/hemi-clamshell, 23.3%) and minimally invasive approaches (video-assisted thoracoscopic surgery/robot, 31.1%) were used more often with similar rates of complete resection. The 10-year overall survival rate was 82% for Europe, 78% for North America and 90% for Asia ( P  = 0.005), respectively. The 10-year cumulative recurrence rates were similar among the geographic groups (European 0.08, North American 0.07, and Asian 0.06, P  = 0.61). Age was the only independent predictive factor for overall survival ( P  < 0.001, HR = 1.089, 95% CI 1.056-1.123) in multivariable analysis. Types B3 and thymic carcinoma ( P  = 0.003, HR = 3.932, 95% CI 1.615-9.576) were independent risk factors for increased recurrence. This study shows that the selection of the surgical approach and the extent of resection for Stage I and II thymic tumours differ by geographic region. However, these differences seem to have little impact on outcomes. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.

PubMed

Giaccone, Giuseppe; Kim, Chul; Thompson, Jillian; McGuire, Colleen; Kallakury, Bhaskar; Chahine, Joeffrey J; Manning, Maria; Mogg, Robin; Blumenschein, Wendy M; Tan, Ming T; Subramaniam, Deepa S; Liu, Stephen V; Kaplan, Ian M; McCutcheon, Justine N

2018-03-01

Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. Merck & Co. Copyright © 2018 Elsevier Ltd. All rights reserved.

Negative ion generator

DOEpatents

Stinnett, R.W.

1984-05-08

A negative ion generator is formed from a magnetically insulated transmission line having a coating of graphite on the cathode for producing negative ions and a plurality of apertures on the opposed anode for the release of negative ions. Magnetic insulation keeps electrons from flowing from the cathode to the anode. A transverse magnetic field removes electrons which do escape through the apertures from the trajectory of the negative ions. 8 figs.

Negative ion generator

DOEpatents

Stinnett, Regan W.

1984-01-01

A negative ion generator is formed from a magnetically insulated transmission line having a coating of graphite on the cathode for producing negative ions and a plurality of apertures on the opposed anode for the release of negative ions. Magnetic insulation keeps electrons from flowing from the cathode to the anode. A transverse magnetic field removes electrons which do escape through the apertures from the trajectory of the negative ions.

R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

ClinicalTrials.gov

2018-06-25

CD20 Positive; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

Thymic Nurse Cells Participate in Heterotypic Internalization and Repertoire Selection of Immature Thymocytes; Their Removal from the Thymus of Autoimmune Animals May be Important to Disease Etiology.

PubMed

Guyden, J C; Martinez, M; Chilukuri, R V E; Reid, V; Kelly, F; Samms, M-O D

2015-01-01

Thymic nurse cells (TNCs) are specialized epithelial cells that reside in the thymic cortex. The initial report of their discovery in 1980 showed TNCs to contain up to 200 thymocytes within specialized vacuoles in their cytoplasm. Much has been reported since that time to determine the function of this heterotypic internalization event that exists between TNCs and developing thymocytes. In this review, we discuss the literature reported that describes the internalization event and the role TNCs play during T cell development in the thymus as well as why these multicellular complexes may be important in inhibiting the development of autoimmune diseases.

The biology of recent thymic emigrants.

PubMed

Fink, Pamela J

2013-01-01

The generation of the TCRαβ lineage of T cells occurs in the thymus through a series of orchestrated developmental events that result in a carefully selected population of CD4 or CD8 lineage-committed TCR(+) thymocytes capable of recognizing foreign antigen in the context of self MHC. T cells first exit the thymus in a phenotypically and functionally immature state and require an approximately 3-week period of post-thymic maturation before transitioning into the mature T cell compartment. A greater understanding of recent thymic emigrant biology has come with the development of methods to exclusively identify and isolate this population for further characterization. I now review current knowledge about the phenotype and function of this key but understudied population of peripheral T cells.

A major role for Bim in regulatory T cell homeostasis.

PubMed

Chougnet, Claire A; Tripathi, Pulak; Lages, Celine S; Raynor, Jana; Sholl, Allyson; Fink, Pamela; Plas, David R; Hildeman, David A

2011-01-01

We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanisms underlying the age-dependent accrual of Treg remain unclear. In this study, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, or from enhanced peripheral conversion. Instead, we found that Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7Rα, we found that IL-7R signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the proapoptotic molecule Bim compared with Treg from young mice. Furthermore, in the absence of Bim, Treg accumulate rapidly, accounting for >25% of the CD4(+) T cell compartment by 6 mo of age. Additionally, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bim(lo) Treg. Collectively, our data suggest that chronic stimulation by IL-2 leads to preferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts.

A major role for Bim in regulatory T cell homeostasis1

PubMed Central

Chougnet, Claire A.; Tripathi, Pulak; Lages, Celine S.; Raynor, Jana; Sholl, Allyson; Fink, Pamela; Plas, David R.; Hildeman, David A.

2011-01-01

We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanism(s) underlying the age-dependent accrual of Treg remain unclear. Here, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, nor from enhanced peripheral conversion. Instead, we found that Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7Rα, we found that IL-7R-signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the pro-apoptotic molecule Bim compared to Treg from young mice. Further, in the absence of Bim, Treg accumulate rapidly, accounting for more than 25% of the CD4+ T cell compartment by 6 months of age. In addition, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bimlo Treg. Combined, our data suggest that chronic stimulation by IL-2 leads to preferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts. PMID:21098226

AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liiv, Ingrid, E-mail: ingrid.liiv@ut.ee; Haljasorg, Uku; Kisand, Kai

2012-06-22

Highlights: Black-Right-Pointing-Pointer AIRE induces apoptosis in epithelial cells. Black-Right-Pointing-Pointer CARD domain of AIRE is sufficient for apoptosis induction. Black-Right-Pointing-Pointer AIRE induced apoptosis involves GAPDH translocation to the nuclei. Black-Right-Pointing-Pointer Deprenyl inhibits AIRE induced apoptosis. -- Abstract: AIRE (Autoimmune Regulator) has a central role in the transcriptional regulation of self-antigens in medullary thymic epithelial cells, which is necessary for negative selection of autoreactive T cells. Recent data have shown that AIRE can also induce apoptosis, which may be linked to cross-presentation of these self-antigens. Here we studied AIRE-induced apoptosis using AIRE over-expression in a thymic epithelial cell line as well asmore » doxycycline-inducible HEK293 cells. We show that the HSR/CARD domain in AIRE together with a nuclear localization signal is sufficient to induce apoptosis. In the nuclei of AIRE-positive cells, we also found an increased accumulation of a glycolytic enzyme, glyceraldehyde-3-phosphate (GAPDH) reflecting cellular stress and apoptosis. Additionally, AIRE-induced apoptosis was inhibited with an anti-apoptotic agent deprenyl that blocks GAPDH nitrosylation and nuclear translocation. We propose that the AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells.« less

PD-1 regulates extrathymic regulatory T-cell differentiation

PubMed Central

Chen, Xiufen; Fosco, Dominick; Kline, Douglas E.; Meng, Liping; Nishi, Saki; Savage, Peter A.; Kline, Justin

2014-01-01

Regulatory T (Treg) cells and the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway are both critical for maintaining peripheral tolerance to self antigens. A significant subset of Treg cells constitutively expresses PD-1, which prompted an investigation into the role of PD-1/PD-L1 interactions in Treg-cell development, function and induction in vivo. The phenotype and abundance of Treg cells was not significantly altered in PD-1-deficient mice. The thymic development of polyclonal and monospecific Treg cells was not negatively impacted by PD-1 deficiency. The suppressive function of PD-1−/− Treg cells was similar to their PD-1+/+ counterparts both in vitro and in vivo. However, in three different in vivo experimental settings, PD-1−/− conventional CD4+ T cells demonstrated a strikingly diminished tendency toward differentiation into peripherally induced Treg (pTreg) cells. Our results demonstrate that PD-1 is dispensable for thymic (tTreg) Treg-cell development and suppressive function, but is critical for the extrathymic differentiation of pTreg cells in vivo. These data suggest that antibody blockade of the PD-1/PD-L1 pathway may augment T-cell responses by acting directly on conventional T cells, and also by suppressing the differentiation of pTreg cells. PMID:24975127

Ocean Acidification and Increased Temperature Have Both Positive and Negative Effects on Early Ontogenetic Traits of a Rocky Shore Keystone Predator Species

PubMed Central

Manríquez, Patricio H.; Jara, María Elisa; Seguel, Mylene E.; Torres, Rodrigo; Alarcon, Emilio; Lee, Matthew R.

2016-01-01

The combined effect of ocean acidification and warming is expected to have significant effects on several traits of marine organisms. The gastropod Concholepas concholepas is a rocky shore keystone predator characteristic of the south-eastern Pacific coast of South America and an important natural resource exploited by small-scale artisanal fishermen along the coast of Chile and Peru. In this study, we used small juveniles of C. concholepas collected from the rocky intertidal habitats of southern Chile (39°S) to evaluate under laboratory conditions the potential consequences of projected near-future levels of ocean acidification and warming for important early ontogenetic traits. The individuals were exposed long-term (5.8 months) to contrasting pCO2 (ca. 500 and 1400 μatm) and temperature (15 and 19°C) levels. After this period we compared body growth traits, dislodgement resistance, predator-escape response, self-righting and metabolic rates. With respect to these traits there was no evidence of a synergistic interaction between pCO2 and temperature. Shell growth was negatively affected by high pCO2 levels only at 15°C. High pCO2 levels also had a negative effect on the predator-escape response. Conversely, dislodgement resistance and self-righting were positively affected by high pCO2 levels at both temperatures. High tenacity and fast self-righting would reduce predation risk in nature and might compensate for the negative effects of high pCO2 levels on other important defensive traits such as shell size and escape behaviour. We conclude that climate change might produce in C. concholepas positive and negative effects in physiology and behaviour. In fact, some of the behavioural responses might be a consequence of physiological effects, such as changes in chemosensory capacity (e.g. predator-escape response) or secretion of adhesive mucous (e.g. dislodgement resistance). Moreover, we conclude that positive behavioural responses may assist in the adaptation to negative physiological impacts, and that this may also be the case for other benthic organisms. PMID:27028118

Ocean Acidification and Increased Temperature Have Both Positive and Negative Effects on Early Ontogenetic Traits of a Rocky Shore Keystone Predator Species.

PubMed

Manríquez, Patricio H; Jara, María Elisa; Seguel, Mylene E; Torres, Rodrigo; Alarcon, Emilio; Lee, Matthew R

2016-01-01

The combined effect of ocean acidification and warming is expected to have significant effects on several traits of marine organisms. The gastropod Concholepas concholepas is a rocky shore keystone predator characteristic of the south-eastern Pacific coast of South America and an important natural resource exploited by small-scale artisanal fishermen along the coast of Chile and Peru. In this study, we used small juveniles of C. concholepas collected from the rocky intertidal habitats of southern Chile (39 °S) to evaluate under laboratory conditions the potential consequences of projected near-future levels of ocean acidification and warming for important early ontogenetic traits. The individuals were exposed long-term (5.8 months) to contrasting pCO2 (ca. 500 and 1400 μatm) and temperature (15 and 19 °C) levels. After this period we compared body growth traits, dislodgement resistance, predator-escape response, self-righting and metabolic rates. With respect to these traits there was no evidence of a synergistic interaction between pCO2 and temperature. Shell growth was negatively affected by high pCO2 levels only at 15 °C. High pCO2 levels also had a negative effect on the predator-escape response. Conversely, dislodgement resistance and self-righting were positively affected by high pCO2 levels at both temperatures. High tenacity and fast self-righting would reduce predation risk in nature and might compensate for the negative effects of high pCO2 levels on other important defensive traits such as shell size and escape behaviour. We conclude that climate change might produce in C. concholepas positive and negative effects in physiology and behaviour. In fact, some of the behavioural responses might be a consequence of physiological effects, such as changes in chemosensory capacity (e.g. predator-escape response) or secretion of adhesive mucous (e.g. dislodgement resistance). Moreover, we conclude that positive behavioural responses may assist in the adaptation to negative physiological impacts, and that this may also be the case for other benthic organisms.

Acquisition of cup drinking using previously refused foods as positive and negative reinforcement.

PubMed

Kelley, Michael E; Piazza, Cathleen C; Fisher, Wayne W; Oberdorff, Amanda J

2003-01-01

We used previously refused foods as positive and negative reinforcement in the acquisition of cup drinking. Cup drinking increased with positive and negative reinforcement, both alone and in combination (without escape extinction), indicating that treatment of food refusal can establish some foods as appetitive stimuli whereas others remain aversive.

Evaluating the Separate and Combined Effects of Positive and Negative Reinforcement on Task Compliance

ERIC Educational Resources Information Center

Bouxsein, Kelly J.; Roane, Henry S.; Harper, Tara

2011-01-01

Positive and negative reinforcement are effective for treating escape-maintained destructive behavior. The current study evaluated the separate and combined effects of these contingencies to increase task compliance. Results showed that a combination of positive and negative reinforcement was most effective for increasing compliance. (Contains 1…

Genotoxicity induced by monomethylarsonous acid (MMA+3) in mouse thymic developing T cells.

PubMed

Xu, Huan; Medina, Sebastian; Lauer, Fredine T; Douillet, Christelle; Liu, Ke Jian; Stýblo, Miroslav; Burchiel, Scott W

2017-09-05

Drinking water exposure to arsenic is known to cause immunotoxicity. Our previous studies demonstrated that monomethylarsonous acid (MMA +3 ) was the major arsenical species presented in mouse thymus cells after a 30 d drinking water exposure to arsenite (As +3 ). MMA +3 was also showed to be ten times more toxic than As +3 on the suppression of IL-7/STAT5 signaling in the double negative (DN) thymic T cells. In order to examine the genotoxicity induced by low to moderate doses of MMA +3 , isolated mouse thymus cells were treated with 5, 50 and 500nMMMA +3 for 18h in vitro. MMA +3 suppressed the proliferation of thymus cells in a dose dependent manner. MMA +3 at 5nM induced DNA damage in DN not double positive (DP) cells. Differential sensitivity to double strand breaks and reactive oxygen species generation was noticed between DN and DP cells at 50nM, but the effects were not seen at the high dose (500nM). A stronger apoptotic effect induced by MMA +3 was noticed in DN cells than DP cells at low doses (5 and 50nM), which was negated by the strong apoptosis induction at the high dose (500nM). Analysis of intracellular MMA +3 concentrations in DN and DP cells, revealed that more MMA +3 accumulated in the DN cells after the in vitro treatment. Collectively, these results suggested that MMA +3 could directly induce strong genotoxicity in the early developing T cells in the thymus. The DN cells were much more sensitive to MMA +3 induced genotoxicity and apoptosis than DP cells, probably due to the higher intracellular levels of MMA +3 . Copyright © 2017 Elsevier B.V. All rights reserved.

Advanced and recurring thymic carcinoma is target of new clinical trial | Center for Cancer Research

Cancer.gov

Adults diagnosed with thymic carcinoma who overexpress the protein mesothelin may be eligible to participate in a new clinical trial at the NIH Clinical Center. The study will look at the safety and effectiveness of an investigational drug, anetumab ravtansine, developed by Bayer HealthCare Pharmaceuticals. The drug works by binding to mesothelin, therefore overexpression of

Expression of preprotachykinin-A and neuropeptide-Y messenger RNA in the thymus.

PubMed

Ericsson, A; Geenen, V; Robert, F; Legros, J J; Vrindts-Gevaert, Y; Franchimont, P; Brene, S; Persson, H

1990-08-01

The preprotachykinin-A gene, the common gene of mRNAs encoding both substance-P (SP) and neurokinin-A (NKA), was shown to be expressed in Sprague-Dawley rat thymus by detection of specific mRNA in gel-blot analyses. In situ hybridization revealed dispersed PPT-A-labeled cells in sections from rat thymus, with a concentration of grains over a subpopulation of cells in the thymic medulla. Also, neuropeptide-Y mRNA-expressing cells were found in the rat thymus, primarily in the thymic medulla. Rat thymic extracts contained SP-like immunoreactivity (SP-LI), and the major part of the immunoreactivity coeluted with authentic SP and SP sulfoxide standards. SP-LI was also detected in human thymus, which contained between 0.09-0.88 ng SP-LI/g wet wt. Evidence for translation of preprotachykinin-A mRNA in the rat thymus was obtained from the demonstration of NKA-LI in thymic cells with an epithelial-like cell morphology. Combined with previous observations on the immunoregulatory roles of tachykinin peptides and the existence of specific receptors on immunocompetent cells, the demonstration of intrathymic synthesis of NKA suggests a role for NKA-LI peptides in T-cell differentiation in the thymus.

Anti-Apoptotic Signature in Thymic Squamous Cell Carcinomas – Functional Relevance of Anti-Apoptotic BIRC3 Expression in the Thymic Carcinoma Cell Line 1889c

PubMed Central

Huang, Bei; Belharazem, Djeda; Li, Li; Kneitz, Susanne; Schnabel, Philipp A.; Rieker, Ralf J.; Körner, Daniel; Nix, Wilfred; Schalke, Berthold; Müller-Hermelink, Hans Konrad; Ott, German; Rosenwald, Andreas; Ströbel, Philipp; Marx, Alexander

2013-01-01

The molecular pathogenesis of thymomas and thymic carcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC. PMID:24427739

Orchitis reveals an extragonadal primary mediastinal thymic seminoma: a coincidence or not?

PubMed

Tampakis, Athanasios; Tampaki, Ekaterini Christina; Damaskos, Christos; Feretis, Themistoklis; Thymara, Irene; Kontzoglou, Konstantinos; Tomos, Periklis; Kouraklis, Gregory

2017-04-13

Mediastinal thymic seminomas are rare male germ cell tumors with extragonadal origin that appear predominately with a cystic appearance. A 22-year-old male was referred to our department for further investigation of a mediastinal mass discovered incidentally during routine chest X-ray. The patient has denied any symptoms including dyspnea, chest pain, cough, fever, dysphagia, hemoptysis, weight loss, and weakness. His past medical history was remarkable for orchitis, for which he had undergone a bilateral testicular biopsy, without the latter however, indicating the presence of a germ cell tumor or a premalignant lesion. Contrast-enhanced chest computed tomography revealed a lobulated and well-marginated cystic lesion in the anterior mediastinum. Differential diagnosis included mostly a multilocular thymic cyst, a lymphoma, a seminoma, or a soft tissue tumor. Resection of the mass revealed a primary thymic seminoma. A surgical approach for the management of these tumors might be reasonable considering that an extensive sampling is mandatory to gain an appropriate biopsy preoperatively in order to securely confirm or refute the presence of a mediastinal extragonadal tumor. Orchitis might be a sign of a general disorder of the germ cells which might transform in time.

Hormonal Regulation of Dendritic Cell Differentiation in the Thymus.

PubMed

Shirshev, S V; Orlova, E G; Loginova, O A; Nekrasova, I V; Gorbunova, O L; Maslennikova, I L

2018-06-19

We studied the effect of hormones estriol, ghrelin, kisspeptin, and chorionic gonadotropin in concentrations corresponding to their content in the peripheral blood in each trimester of pregnancy on the expression of membrane molecules on myeloid and plasmacytoid dendritic cells of the thymus. It was found that thymic myeloid dendritic cells are sensitive to the action of estriol and kisspeptin. Estriol in a concentration of the first trimester of pregnancy reduces the number of myeloid dendritic cells expressing receptor for thymic stromal lymphopoietin (CD11c+TSLP-R + ) and inhibitory molecule B7-H3 (CD11c + CD276 + ). In contrast to estriol, kisspeptin regulates the processes of differentiation of thymic myeloid dendritic cells in concentrations typical of the second-third trimesters and reduced their total number (CD11c + ) and the number of cells expressing TSLP-R (CD11c + TSLP-R + ). Estriol and kisspeptin do not affect the total number of plasmacytoid dendritic cells (CD303 + ) and expression of TSLP-R and CD276 by these cells. Ghrelin and chorionic gonadotropin in the studied concentrations had no significant effect on the total number of thymic myeloid and plasmacytoid dendritic cells and on the expression of membrane molecules of TSLP-R and CD276.

Immunolocalization of thymosin alpha 1, thymopoietin and thymulin in mouse thymic epithelial cells at different stages of culture: a light and electron microscopic study.

PubMed Central

Fabien, N; Auger, C; Monier, J C

1988-01-01

The secretory evolution of the thymic hormones (thymulin, thymosin alpha 1 and thymopoietin) in cultured thymic reticuloepithelial cells (TREC) was studied by immunocytochemical techniques using monoclonal anti-thymulin or anti-thymosin alpha 1 and polyclonal anti-thymopoietin antibodies (Ab). The culture of TREC was performed with a medium where L-valine was replaced by D-valine, thus ensuring rapid and selective development of these cells. The number of thymulin, thymosin alpha 1 or thymopoietin-containing cells increased progressively from Day 6 to Day 12 of the culture. The localization of the three thymic hormones within the TREC also varied according to the age of the culture. By light microscopy the staining of the three hormones was localized in some cytoplasmic granules at the beginning of the culture and at Day 90, while at Day 12 it was throughout the cytoplasm. In electron microscopy these localizations corresponded respectively to vacuoles of different sizes and to cytosol. All these results show that the synthesis and excretion of thymulin, thymosin alpha 1 and thymopoietin evolve during the development of TREC in culture. Images Figure 1 Figure 2 PMID:3284819

[Impact of thymic function in age-related immune deterioration].

PubMed

Ferrando-Martínez, Sara; de la Fuente, Mónica; Guerrero, Juan Miguel; Leal, Manuel; Muñoz-Fernández, M Ángeles

2013-01-01

Age-related biological deterioration also includes immune system deterioration and, in consequence, a rise in the incidence and prevalence of infections and cancers, as well as low responses to vaccination strategies. Out of all immune cell subsets, T-lymphocytes seem to be involved in most of the age-related defects. Since T-lymphocytes mature during their passage through the thymus, and the thymus shows an age-related process of atrophy, thymic regression has been proposed as the triggering event of this immune deterioration in elderly people. Historically, it has been accepted that the young thymus sets the T-lymphocyte repertoire during the childhood, whereupon atrophy begins until the elderly thymus is a non-functional evolutionary trace. However, a rising body of knowledge points toward the thymus functioning during adulthood. In the elderly, higher thymic function is associated with a younger immune system, while thymic function failure is associated with all-cause mortality. Therefore, any new strategy focused on the improvement of the elderly quality of life, especially those trying to influence the immune system, should take into account, together with peripheral homeostasis, thymus function as a key element in slowing down age-related decline. Copyright © 2012 SEGG. Published by Elsevier Espana. All rights reserved.

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

PubMed Central

Lopomo, Angela; Ricciardi, Roberta; Maestri, Michelangelo; De Rosa, Anna; Melfi, Franca; Lucchi, Marco; Mussi, Alfredo; Coppedè, Fabio; Migliore, Lucia

2016-01-01

Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood. PMID:27999265

Pathophysiology and immunological profile of myasthenia gravis and its subgroups.

PubMed

Romi, Fredrik; Hong, Yu; Gilhus, Nils Erik

2017-12-01

Myasthenia gravis (MG) is an autoimmune antibody-mediated disease characterized by muscle weakness and fatigability. It is believed that the initial steps triggering humoral immunity in MG take place inside thymic tissue and thymoma. The immune response against one or several epitopes expressed on thymic tissue cells spills over to neuromuscular junction components sharing the same epitope causing humoral autoimmunity and antibody production. The main cause of MG is acetylcholine receptor antibodies. However, many other neuromuscular junction membrane protein targets, intracellular and extracellular proteins are suggested to participate in MG pathophysiology. MG should be divided into subgroups based on clinical presentation and immunology. This includes onset age, clinical characteristics, thymic pathology and antibody profile. The immunological profile of these subgroups is determined by the antibodies present. Copyright © 2017. Published by Elsevier Ltd.

Thymic MIS: state of the art across the world (Russian Federation).

PubMed

Yablonskii, Piotr; Kudriashov, Grigorii; Pischik, Vadim; Sigal, Evgenii; Nuraliev, Sabriddin

2017-01-01

First VATS thymectomy was performed 25 years ago (Landreneau et al ., 1992). After that, minimally invasive approaches for surgical procedures have rapidly increased in the world. The aim of this paper was study of current problems and the status of surgery for thymus diseases in Russia. This is first global survey of all thoracic centers, which had experience in thymic surgery.

Thymic MIS: state of the art across the world (Russian Federation)

PubMed Central

Yablonskii, Piotr; Pischik, Vadim; Sigal, Evgenii; Nuraliev, Sabriddin

2017-01-01

First VATS thymectomy was performed 25 years ago (Landreneau et al., 1992). After that, minimally invasive approaches for surgical procedures have rapidly increased in the world. The aim of this paper was study of current problems and the status of surgery for thymus diseases in Russia. This is first global survey of all thoracic centers, which had experience in thymic surgery. PMID:29078679

Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling.

PubMed

Daniels, Mark A; Teixeiro, Emma; Gill, Jason; Hausmann, Barbara; Roubaty, Dominique; Holmberg, Kaisa; Werlen, Guy; Holländer, Georg A; Gascoigne, Nicholas R J; Palmer, Ed

2006-12-07

A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the basis for establishing central tolerance.

Isoflavones: Anti-Inflammatory Benefit and Possible Caveats

PubMed Central

Yu, Jie; Bi, Xiaojuan; Yu, Bing; Chen, Daiwen

2016-01-01

Inflammation, a biological response of body tissues to harmful stimuli, is also known to be involved in a host of diseases, such as obesity, atherosclerosis, rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Increasing evidence has highlighted the potential for isoflavones to prevent the chronic diseases in which inflammation plays a key role, though the underlying mechanisms remain unclear. Recently, some studies have raised concerns about isoflavones induced negative effects like carcinogenesis, thymic involution, and immunosuppression. Therefore, this review aims to summarize the anti-inflammatory effects of isoflavones, unravel the underlying mechanisms, and present the potential health risks. PMID:27294954

Isoflavones: Anti-Inflammatory Benefit and Possible Caveats.

PubMed

Yu, Jie; Bi, Xiaojuan; Yu, Bing; Chen, Daiwen

2016-06-10

Inflammation, a biological response of body tissues to harmful stimuli, is also known to be involved in a host of diseases, such as obesity, atherosclerosis, rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Increasing evidence has highlighted the potential for isoflavones to prevent the chronic diseases in which inflammation plays a key role, though the underlying mechanisms remain unclear. Recently, some studies have raised concerns about isoflavones induced negative effects like carcinogenesis, thymic involution, and immunosuppression. Therefore, this review aims to summarize the anti-inflammatory effects of isoflavones, unravel the underlying mechanisms, and present the potential health risks.

[Department of the molecular bases of semiotics].

PubMed

Ternovyĭ, K S

1995-01-01

Department of molecular basis of semiotics was organized in 1986. The main task of the department was to work out new approaches in estimation of the state of immune and blood system at the tissue, cell and molecular levels, using biochemical, biophysical and molecular biology techniques. There are several main directions of scientific investigations at the department. Most informational methods were collected in "immunological portrait" for differential diagnostic and complex investigation of the immune system of autoimmune patients. This group of techniques was used to study changes in the immune system of Kievites after the Chernobyl disaster. A decrease of complement and thymic serum activity was detected. Antibodies against nuclear components appeared in 20% of donors. And a higher of circulating immune complex of low molecular weight was observed. Low level of thymic serum activity in blood of autoimmune patients with rheumatoid arthritis, lupus erythematosus, diabetes, herpes and other depends on the appearance of zinc-independent timuline inhibitor less then 2000 D. Another kind of thymic hormone inhibitors was detected in thymectomized adult mice. Its effect disappears when zinc added in blood rather due to competition for lymphocyte surface receptors timuline and its inactive analogue than other mechanism. Therapeutic effect of UV irradiation of patients' blood was shown to be closely connected with the changes in thymic serum activity in respect to stabilization of thymic hormone/inhibitor ratio. The immunochemical techniques were used to detect and investigate tumor-associated chromatin antigens in human and animal tumor cells. Antigens not found in normal tissues were detected when using rabbit antibodies against chromatin of rat hepatocarcinoma and human colon and carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired thymic selection in mice expressing altered levels of the SLP-76 adaptor protein.

PubMed

Ramsey, Kimberley; Luckashenak, Nancy; Koretzky, Gary A; Clements, James L

2008-02-01

Intracellular signaling initiated by ligation of the TCR influences cell fate at multiple points during the lifespan of a T cell. This is especially evident during thymic selection, where the nature of TCR-dependent signaling helps to establish a MHC-restricted, self-tolerant T cell repertoire. The Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) adaptor protein is a required intermediate in multiple signaling pathways triggered by TCR engagement, several of which have been implicated in dictating the outcome of thymic selection (e.g., intracellular calcium flux and activation of ERK family MAPKs). To determine if thymocyte maturation and selection at later stages of development are sensitive to perturbations in SLP-76 levels, we analyzed these crucial events using several transgenic (Tg) lines of mice expressing altered levels of SLP-76 in the thymus. In Tg mice expressing low levels of SLP-76 in preselection thymocytes, the CD4:CD8 ratio in the thymus and spleen was skewed in a manner consistent with impaired selection and/or maturation of CD4+ thymocytes. Low SLP-76 expression also correlated with reduced CD5 expression on immature thymocytes, consistent with reduced TCR signaling potential. In contrast, reconstitution of SLP-76 at higher levels resulted in normal thymic CD5 expression and CD4:CD8 ratios in the thymus and periphery. It is curious that thymic deletion of TCR-Tg (HY) thymocytes was markedly impaired in both lines of Tg-reconstituted SLP-76-/- mice. Studies using chimeric mice indicate that the defect in deletion of HY+ thymocytes is intrinsic to the developing thymocyte, suggesting that maintenance of sufficient SLP-76 expression from the endogenous locus is a key element in the selection process.

IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity.

PubMed

Silva, Susana L; Albuquerque, Adriana S; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T; Victorino, Rui M M; Sousa, Ana E

2017-01-01

Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31 - subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31 + naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6 , a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31 - naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31 + naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.

Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors

PubMed Central

Steele, Keith E.; Ni, Ai; Moreira, Andre L.; Rekhtman, Natasha; Robbins, Paul B.; Karakunnel, Joyson; Rimner, Andreas; Huang, James; Riely, Gregory J.; Hellmann, Matthew D.

2017-01-01

Introduction The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs. Methods Tumor tissues from 23 patients with WHO Type B2/B3 thymoma (n = 12) and thymic carcinoma (n = 11) were identified and clinical outcomes were annotated. The expression of membranous PD-L1 on tumor cells, CD3+ and CD8+ tumor infiltrating lymphocytes (TILs), co-stimulatory (CD137, GITR, ICOS), and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) were assessed semi-quantitatively using immunohistochemistry. Results PD-L1 positivity (≥ 25% of tumor membrane expression) was frequent in TETs (15/23, 65%), more common in thymomas compared to thymic carcinomas (p<0.01), and was associated with longer overall survival (p = 0.02). TIM-3 and GITR were expressed in all TETs, including 18/23 and 12/23 with at least moderate/high expression, respectively. Moderate/high CD137 expression correlated with CD8+ (p = 0.01) and moderate/high GITR expression co-associated with PD-1 (p = 0.043). Conclusions TETs are characterized by frequent PD-L1 expression and PD-L1 is associated with improved survival, suggesting PD-L1 signaling may be biologically important in TETs. Robust expression of markers of immune activation and immunotherapeutic target molecules in TETs emphasizes the potential for development of anti-PD-1/PD-L1 therapies. PMID:28771603

Pretransplant thymic function predicts acute rejection in antithymocyte globulin-treated renal transplant recipients.

PubMed

Bamoulid, Jamal; Courivaud, Cécile; Crepin, Thomas; Carron, Clémence; Gaiffe, Emilie; Roubiou, Caroline; Laheurte, Caroline; Moulin, Bruno; Frimat, Luc; Rieu, Philippe; Mousson, Christiane; Durrbach, Antoine; Heng, Anne-Elisabeth; Rebibou, Jean-Michel; Saas, Philippe; Ducloux, Didier

2016-05-01

Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA(+)CD31(+)CD4(+) T cell (recent thymic emigrant [RTE]) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4(+) T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08) for each increased percent in RTE/CD4(+) T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm(3) (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody-treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09-5.74) and RTE/mm(3) (>200/mm(3), hazard ratio, 3.71; 95% confidence interval, 1.59-8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Fatty acid-binding protein 4 (FABP4) and FABP5 modulate cytokine production in the mouse thymic epithelial cells.

PubMed

Adachi, Yasuhiro; Hiramatsu, Sumie; Tokuda, Nobuko; Sharifi, Kazem; Ebrahimi, Majid; Islam, Ariful; Kagawa, Yoshiteru; Koshy Vaidyan, Linda; Sawada, Tomoo; Hamano, Kimikazu; Owada, Yuji

2012-09-01

Thymic stromal cells, including cortical thymic epithelial cells (cTEC) produce many humoral factors, such as cytokines and eicosanoids to modulate thymocyte homeostasis, thereby regulating the peripheral immune responses. In this study, we identified fatty acid-binding protein (FABP4), an intracellular fatty acid chaperone, in the mouse thymus, and examined its role in the control of cytokine production in comparison with FABP5. By immunofluorescent staining, FABP4(+) cells enclosing the thymocytes were scattered throughout the thymic cortex with a spatial difference from the FABP5(+) cell that were distributed widely throughout the cTEC. The FABP4(+) cells were immunopositive for MHC class II, NLDC145 and cytokeratin 8, and were identified as part of cTEC. The FABP4(+) cells were identified as thymic nurse cells (TNC), a subpopulation of cTEC, by their active phagocytosis of apoptotic thymocytes. Furthermore, FABP4 expression was confirmed in the isolated TNC at the gene and protein levels. To explore the function of FABP in TNC, TSt-4/DLL1 cells stably expressing either FABP4 or FABP5 were established and the gene expressions of various cytokines were examined. The gene expression of interleukin (IL)-7 and IL-18 was increased both in FABP4 and FABP5 over-expressing cells compared with controls, and moreover, the increase in their expressions by adding of stearic acids was significantly enhanced in the FABP4 over-expressing cells. These data suggest that both FABPs are involved in the maintenance of T lymphocyte homeostasis through the modulation of cytokine production, which is possibly regulated by cellular fatty acid-mediated signaling in TEC, including TNC.

Reinterpreting recent thymic emigrant function: defective or adaptive?

PubMed

Cunningham, Cody A; Helm, Eric Y; Fink, Pamela J

2018-04-01

Recent thymic emigrants (RTEs) are those peripheral T cells that have most recently completed thymic development and egress. Over the past decade, significant advances have been made in understanding the cell-extrinsic and cell-intrinsic requirements for RTE maturation to mature naïve (MN) T cells and in detailing the functional differences that characterize these two T cell populations. Much of this work has suggested that RTEs are hypo-functional versions of more mature T cells. However, recent evidence has indicated that rather than being defective T cells, RTEs are exquisitely adapted to their cellular niche. In this review, we argue that RTEs are not flawed mature T cells but are adapted to fill an underpopulated T cell compartment, while maintaining self tolerance and possessing the capacity to mount robust immune responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation

PubMed Central

Bowers, Cyril Y.

2011-01-01

Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E2 (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 ≤ P ≤ 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E2/T administration potentiated both pulsatile (P = 0.006) and entropic (P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode (P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass (P = 0.005). The composite of gender, body mass index, E2, IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans. PMID:21795635

The impact of escaped farmed Atlantic salmon (Salmo salar L.) on catch statistics in Scotland.

PubMed

Green, Darren M; Penman, David J; Migaud, Herve; Bron, James E; Taggart, John B; McAndrew, Brendan J

2012-01-01

In Scotland and elsewhere, there are concerns that escaped farmed Atlantic salmon (Salmo salar L.) may impact on wild salmon stocks. Potential detrimental effects could arise through disease spread, competition, or inter-breeding. We investigated whether there is evidence of a direct effect of recorded salmon escape events on wild stocks in Scotland using anglers' counts of caught salmon (classified as wild or farmed) and sea trout (Salmo trutta L.). This tests specifically whether documented escape events can be associated with reduced or elevated escapes detected in the catch over a five-year time window, after accounting for overall variation between areas and years. Alternate model frameworks were somewhat inconsistent, however no robust association was found between documented escape events and higher proportion of farm-origin salmon in anglers' catch, nor with overall catch size. A weak positive correlation was found between local escapes and subsequent sea trout catch. This is in the opposite direction to what would be expected if salmon escapes negatively affected wild fish numbers. Our approach specifically investigated documented escape events, contrasting with earlier studies examining potentially wider effects of salmon farming on wild catch size. This approach is more conservative, but alleviates some potential sources of confounding, which are always of concern in observational studies. Successful analysis of anglers' reports of escaped farmed salmon requires high data quality, particularly since reports of farmed salmon are a relatively rare event in the Scottish data. Therefore, as part of our analysis, we reviewed studies of potential sensitivity and specificity of determination of farmed origin. Specificity estimates are generally high in the literature, making an analysis of the form we have performed feasible.

The Impact of Escaped Farmed Atlantic Salmon (Salmo salar L.) on Catch Statistics in Scotland

PubMed Central

Green, Darren M.; Penman, David J.; Migaud, Herve; Bron, James E.; Taggart, John B.; McAndrew, Brendan J.

2012-01-01

In Scotland and elsewhere, there are concerns that escaped farmed Atlantic salmon (Salmo salar L.) may impact on wild salmon stocks. Potential detrimental effects could arise through disease spread, competition, or inter-breeding. We investigated whether there is evidence of a direct effect of recorded salmon escape events on wild stocks in Scotland using anglers' counts of caught salmon (classified as wild or farmed) and sea trout (Salmo trutta L.). This tests specifically whether documented escape events can be associated with reduced or elevated escapes detected in the catch over a five-year time window, after accounting for overall variation between areas and years. Alternate model frameworks were somewhat inconsistent, however no robust association was found between documented escape events and higher proportion of farm-origin salmon in anglers' catch, nor with overall catch size. A weak positive correlation was found between local escapes and subsequent sea trout catch. This is in the opposite direction to what would be expected if salmon escapes negatively affected wild fish numbers. Our approach specifically investigated documented escape events, contrasting with earlier studies examining potentially wider effects of salmon farming on wild catch size. This approach is more conservative, but alleviates some potential sources of confounding, which are always of concern in observational studies. Successful analysis of anglers' reports of escaped farmed salmon requires high data quality, particularly since reports of farmed salmon are a relatively rare event in the Scottish data. Therefore, as part of our analysis, we reviewed studies of potential sensitivity and specificity of determination of farmed origin. Specificity estimates are generally high in the literature, making an analysis of the form we have performed feasible. PMID:22970132

JCAR014 and Durvalumab in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

ClinicalTrials.gov

2018-04-02

BCL2 Gene Rearrangement; BCL6 Gene Rearrangement; CD19 Positive; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; High-Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements; MYC Gene Rearrangement; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma

Analysis of TNF-related apoptosis-inducing ligand and receptors and implications in thymus biology and myasthenia gravis.

PubMed

Kanatli, Irem; Akkaya, Bahar; Uysal, Hilmi; Kahraman, Sevim; Sanlioglu, Ahter Dilsad

2017-02-01

Myasthenia Gravis is an autoantibody-mediated, neuromuscular junction disease, and is usually associated with thymic abnormalities presented as thymic tumors (~10%) or hyperplastic thymus (~65%). The exact role of thymus in Myasthenia Gravis development is not clear, yet many patients benefit from thymectomy. The apoptotic ligand TNF-Related Apoptosis-Inducing Ligand is thought to be involved in the regulation of thymocyte counts, although conflicting results are reported. We investigated differential expression profiles of TNF-Related Apoptosis-Inducing Ligand and its transmembrane receptors, Nuclear Factor-kB activation status, and apoptotic cell counts in healthy thymic tissue and pathological thymus from Myasthenia Gravis patients. All tissues expressed TNF-Related Apoptosis-Inducing Ligand and its receptors, with hyperplastic tissue having the highest expression levels of death receptors DR4 and DR5. No detectable Nuclear Factor-kB activation, at least via the canonical Protein Kinase A-mediated p65 Ser276 phosphorylation, was evident in any of the tissues studied. Apoptotic cell counts were higher in MG-associated tissue compared to the normal thymus. Possible use of the TNF-Related Apoptosis-Inducing Ligand within the concept of an apoptotic ligand-mediated medical thymectomy in thymoma- or thymic hyperplasia-associated Myasthenia Gravis is also discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Dataset for reporting of thymic epithelial tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR).

PubMed

Nicholson, Andrew G; Detterbeck, Frank; Marx, Alexander; Roden, Anja C; Marchevsky, Alberto M; Mukai, Kiyoshi; Chen, Gang; Marino, Mirella; den Bakker, Michael A; Yang, Woo-Ick; Judge, Meagan; Hirschowitz, Lynn

2017-03-01

The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organization formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists-Association Canadienne des Pathologists in association with the Canadian Partnership Against Cancer, and the European Society of Pathology. Its goal is to produce standardized, internationally agreed, evidence-based datasets for use throughout the world. This article describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of thymic epithelial tumours. The dataset includes 'required' (mandatory) and 'recommended' (non-mandatory) elements, which are validated by a review of current evidence and supported by explanatory text. Seven required elements and 12 recommended elements were agreed by the international dataset authoring committee to represent the essential information for the reporting of thymic epithelial tumours. The use of an internationally agreed, structured pathology dataset for reporting thymic tumours provides all of the necessary information for optimal patient management, facilitates consistent and accurate data collection, and provides valuable data for research and international benchmarking. The dataset also provides a valuable resource for those countries and institutions that are not in a position to develop their own datasets. © 2016 John Wiley & Sons Ltd.

Opposite actions of transforming growth factor-beta 1 on the gene expression of atrial natriuretic peptide biological and clearance receptors in a murine thymic stromal cell line.

PubMed

Agui, T; Xin, X; Cai, Y; Shim, G; Muramatsu, Y; Yamada, T; Fujiwara, H; Matsumoto, K

1995-09-01

The regulation of the gene expression of the atrial natriuretic peptide receptor (ANPR) subtypes, ANPR-A, ANPR-B, and ANPR-C, was investigated in a murine thymic stromal cell line, MRL 104.8a. When MRL 104.8a cells were cultured with transforming growth factor (TGF)-beta1, [125I]ANP binding sites increased with increasing dose of TGF-beta1. These binding sites were identified as ANPR-C by a displacement experiment with ANPR-C-specific ligand, C-ANF, and by the affinity cross-linking of the [125I]ANP binding sites with a chemical cross-linker to determine the molecular weight of the ANPR. This augmentation of the ANPR-C expression was elucidated to occur at the transcriptional level by Northern blot experiment, comparison of the relative amounts of mRNA by reverse transcription (RT)-PCR, and in vitro nuclear transcription assay. Conversely, the expression of the ANP biological receptors, ANPR-A and ANPR-B, was shown to be down-regulated by TGF-beta1. These data suggest that TGF-beta1 regulates the gene expression of ANPRs in the thymic stromal cells and that ANP and TGF-beta1 might affect the thymic stromal cell functions.

Association between thymic function and allogeneic hematopoietic stem cell transplantation outcome: results of a pediatric study.

PubMed

Saglio, Francesco; Cena, Silvia; Berger, Massimo; Quarello, Paola; Boccasavia, Viola; Ferrando, Federica; Pittana, Laura; Bruno, Benedetto; Fagioli, Franca

2015-06-01

Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Thymic pathologies in myasthenia gravis: a preoperative assessment of CAT scan and nuclear based imaging.

PubMed

Jordan, Berit; Kellner, Juliane; Jordan, Karin; Bähre, Manfred; Behrmann, Curd; Zierz, Stephan

2016-04-01

Precise diagnostic work up of a suspected thymic pathology in patients with myasthenia gravis (MG) is very important for potential surgical implications and further disease course. In this study the diagnostic value of combined preoperative radiological (CAT scan) and nuclear based imaging (octreotide and thallium scintigraphy) in patients with MG was evaluated. Twenty four patients were included. Histopathology revealed thymoma in nine patients, thymic carcinoma (TC) in one patient, lymphofollicular hyperplasia in seven patients, and involuted thymus in another seven patients. Diagnostic sensitivity for detecting thymoma/TC was 80 % in CAT scan as well as in somatostatin scintigraphy; the combination of both procedures reached 90 %. However, the diagnostic specifity to exclude thymoma in CAT scan was 100 % and in octreotide scintigraphy 85.7 %. Semiquantitative octreotide uptake significantly correlated with histological grading of thymoma/TC (r = 0.764) and histological proliferation rate Ki67 (r = 0.894). Thallium scintigraphy was positive only in one out of four thymoma cases. In this study, somatostatin scintigraphy has been shown to be a useful additional diagnostic technique in detecting thymic malignancies in patients with MG. These results might be especially helpful in patients with late onset MG as these patients are in general no candidates for thymectomy.

Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging.

PubMed

Paltsev, Michael A; Polyakova, Victoria O; Kvetnoy, Igor M; Anderson, George; Kvetnaia, Tatiana V; Linkova, Natalia S; Paltseva, Ekaterina M; Rubino, Rosa; De Cosmo, Salvatore; De Cata, Angelo; Mazzoccoli, Gianluigi

2016-03-15

Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin А); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T-cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing-associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing.

The 2015 WHO Classification of Tumors of the Thymus: Continuity and Changes

PubMed Central

Marx, Alexander; Chan, John K.C.; Coindre, Jean-Michel; Detterbeck, Frank; Girard, Nicolas; Harris, Nancy L.; Jaffe, Elaine S.; Kurrer, Michael O.; Marom, Edith M.; Moreira, Andre L.; Mukai, Kiyoshi; Orazi, Attilio; Ströbel, Philipp

2015-01-01

This overview of the 4th edition of the WHO Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumour entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1–B3 thymomas and thymic squamous cell carcinoma are given and will hopefully improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery and oncology; by incorporating state-of-the-art PET/CT images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed. PMID:26295375

Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging

PubMed Central

Paltsev, Michael A.; Polyakova, Victoria O.; Kvetnoy, Igor M.; Anderson, George; Kvetnaia, Tatiana V.; Linkova, Natalia S.; Paltseva, Ekaterina M.; Rubino, Rosa; De Cosmo, Salvatore; De Cata, Angelo; Mazzoccoli, Gianluigi

2016-01-01

Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin A); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T-cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing-associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing. PMID:26943046

T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation.

PubMed

Vago, Luca; Oliveira, Giacomo; Bondanza, Attilio; Noviello, Maddalena; Soldati, Corrado; Ghio, Domenico; Brigida, Immacolata; Greco, Raffaella; Lupo Stanghellini, Maria Teresa; Peccatori, Jacopo; Fracchia, Sergio; Del Fiacco, Matteo; Traversari, Catia; Aiuti, Alessandro; Del Maschio, Alessandro; Bordignon, Claudio; Ciceri, Fabio; Bonini, Chiara

2012-08-30

The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell-depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK+ cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK+ -cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.

Inhibitory effects of a polypeptide thymic factor on the development of 7,12-dimethylbenz(a)anthragene-induced mammary adenocarcinoma in female rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anisimov, V.N.; Danetskaya, E.V.; Morozov, V.G.

1980-01-01

It has come to be recognized that tumor growth is accompanied by inhibition of cellular immunity and the function of the T lymphocytes. Restitution of T lymphocyte function by means of several pharmacologic agents such as levamisole, phenformin, or epithalamin (an epiphyseal factor) has, in a number of cases, been accompanied by growth inhibition of both spontaneous and induced tumors. In addition, the importance of the thymus in the regulation of T lymphocytes and in antitumor immunity has been recognized. Several indicators point to the fact that the thymus contains physiologically active substances which stimulate T cell-dependent immunity and preventmore » the occurrence of neoplasms. These considerations have led to attempts at isolation of active thymic factors and studies on their effects on the appearance and growth of tumors. Previously, a thymic factor - thymarin - had been isolated which imparted immunocompetence to the T lymphocytes. This factor differs from other thymic preparations, including thymosine, in terms of a number of physicochemical characteristics and is a polypeptide with a molecular weight of 5000. This study is concerned with its effects on tumor development - mammary gland adenocarcinoma induced in animals with a chemical carcinogen.« less

Surgical outcome in thymic tumors with myasthenia gravis after plasmapheresis--a comparative study.

PubMed

Sarkar, Binay Krishna; Sengupta, Pratim; Sarkar, Uday Narayan

2008-12-01

Plasmapheresis has been used widely in the treatment of myasthenia gravis and also in symptomatic thymectomized patients with short-term clinical improvement. But the utility of preoperative plasmapheresis in the outcome has not been widely studied. The authors analyzed its impact in the surgical outcome of thymic tumors with myasthenia gravis. We studied a total of 19 patients, who were operated on in the period from January 2000 to July 2006 for thymic tumors with myasthenia gravis. Of these 19 patients, preoperative plasmapheresis was performed in 10 patients (group B) and the remaining nine patients (group A) had no preoperative plasmapheresis based on risk factors for requirement of postoperative ventilation. Outcome in the form of requirement of ventilation, symptomatic improvement, hospital stay and requirement of drugs were assessed at the end of one year and compared between the two groups. Six out of nine patients (67%) in group A required ventilatory support in the immediate postoperative period, whereas two out of ten patients (20%) in group B required it. Significant and sustained symptomatic improvement was noted in group B as compared with group A (P<0.01). Preoperative plasmapheresis in the patients of thymic tumors with myasthenia gravis is beneficial and can cause a significant difference in the postoperative outcome.

Personality, Coping, and Well-Being for People Living with Chronic Hepatitis C.

PubMed

Cellar, Douglas F; Voster, Devon; Fetters, Rachel; Twitchell, Emily; Harper, Gary W; Scott, Cotler

2016-04-01

The present study examined the relationships between personality, coping strategies, and health ratings to extend past research to people living with chronic hepatitis C (HCV). Participants were 35 people (11 men, 24 women; M age = 49.6 yr., SD = 10.6) living with chronic hepatitis C for an average of 9.0 yr. (SD = 6.0) since diagnosis. Participants provided descriptions of stressful situations and responded to a personality inventory, Ways of Coping Questionnaire scales (planful problem solving and escape-avoidance) and SF36 Health Survey scales measuring physical functioning and mental health. The stressful situations were judgmentally clustered into seven dimensions (diagnosis/mortality, disclosure, stigma, social and work role functioning, compounding problems, and no stress). Correlational analyses indicated strong negative relationships between escape-avoidance coping and health measures. Emotional Stability and Extraversion were positively related to both health variables, and Extraversion was negatively related to escape-avoidance coping. The results suggest that research from other contexts that has examined these relationships tended to generalize to people living with HCV. © The Author(s) 2016.

Sleep Deprivation, Allergy Symptoms, and Negatively Reinforced Problem Behavior.

ERIC Educational Resources Information Center

Kennedy, Craig H.; Meyer, Kim A.

1996-01-01

A study of the relationship between presence or absence of sleep deprivation, allergy symptoms, and the rate and function of problem behavior in three adolescents with moderate to profound mental retardation found that problem behavior was negatively reinforced by escape from instruction, and both allergy symptoms and sleep deprivation influenced…

DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes.

PubMed

Guha, Mithu; Saare, Mario; Maslovskaja, Julia; Kisand, Kai; Liiv, Ingrid; Haljasorg, Uku; Tasa, Tõnis; Metspalu, Andres; Milani, Lili; Peterson, Pärt

2017-04-21

The autoimmune regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by the TOP1 inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage.

PubMed

Hendricks, Deborah W; Fink, Pamela J

2011-01-27

After intrathymic development, T cells exit the thymus and join the peripheral T-cell pool. Such recent thymic emigrants (RTEs) undergo both phenotypic and functional maturation during the first 3 weeks they reside in the periphery. Using a well-controlled in vitro polarization scheme, we now show that CD4(+) RTEs are defective in T-helper (Th) type 0 (Th0), Th1, Th17, and regulatory T-cell lineage commitment, with dampened cytokine production and transcription factor expression. In contrast, CD4(+) RTES are biased toward the Th2 lineage both in vitro and in vivo, with more robust interleukin-4, interleukin-5, and interleukin-13 production than their mature naive counterparts. Coculture experiments demonstrate that mature naive T cells influence neighboring RTEs in their Th responses. In adoptive hosts, CD4(+) RTEs drive production of the Th2-associated antibody isotype immunoglobulin G1 and mediate airway inflammatory disease. This bias in RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4(+) RTEs thus represent a transitional population with a distinct interpretation of, and response to, immunologic cues. These characteristics may be beneficial during the postthymic maturation period by leading to the avoidance of inappropriate immune responses, particularly in lymphopenic neonates and adults.

DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes

PubMed Central

Guha, Mithu; Saare, Mario; Maslovskaja, Julia; Kisand, Kai; Liiv, Ingrid; Haljasorg, Uku; Tasa, Tõnis; Metspalu, Andres; Milani, Lili; Peterson, Pärt

2017-01-01

The autoimmune regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by the TOP1 inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes. PMID:28242760

When self-destructive thoughts flash through the mind: Failure to meet standards affects the accessibility of suicide-related thoughts.

PubMed

Chatard, Armand; Selimbegović, Leila

2011-04-01

When individuals realize that they fail to attain important standards or expectations, they may be motivated to escape the self, which could lead thoughts of suicide to become more accessible. Six studies examined this hypothesis, mainly derived from escape theory (Baumeister, 1990). The results indicated that whenever individuals realize that they fail to attain an important standard, they experience increased accessibility of suicide-related thoughts (Studies 1-6). In line with the idea that such effects reflect motivations to escape from negative self-awareness, they were especially pronounced when associated with high levels of self-consciousness and escapist motivations (Study 1) and with a large discrepancy between self and standards (Studies 2-4). Moreover, failure to attain standards increased suicide-thought accessibility along with the desire for an altered state of consciousness (Study 5). Finally, increases in suicide-thought accessibility after failure were associated with simultaneous increases in accessibility of general concepts related to escape (Study 6). Implications of these findings for escape and terror management theories are discussed.

Use of the Exponential and Exponentiated Demand Equations to Assess the Behavioral Economics of Negative Reinforcement

PubMed Central

Fragale, Jennifer E. C.; Beck, Kevin D.; Pang, Kevin C. H.

2017-01-01

Abnormal motivation and hedonic assessment of aversive stimuli are symptoms of anxiety and depression. Symptoms influenced by motivation and anhedonia predict treatment success or resistance. Therefore, a translational approach to the study of negatively motivated behaviors is needed. We describe a novel use of behavioral economics demand curve analysis to investigate negative reinforcement in animals that separates hedonic assessment of footshock termination (i.e., relief) from motivation to escape footshock. In outbred Sprague Dawley (SD) rats, relief increased as shock intensity increased. Likewise, motivation to escape footshock increased as shock intensity increased. To demonstrate the applicability to anxiety disorders, hedonic and motivational components of negative reinforcement were investigated in anxiety vulnerable Wistar Kyoto (WKY) rats. WKY rats demonstrated increased motivation for shock cessation with no difference in relief as compared to control SD rats, consistent with a negative bias for motivation in anxiety vulnerability. Moreover, motivation was positively correlated with relief in SD, but not in WKY. This study is the first to assess the hedonic and motivational components of negative reinforcement using behavioral economic analysis. This procedure can be used to investigate positive and negative reinforcement in humans and animals to gain a better understanding of the importance of motivated behavior in stress-related disorders. PMID:28270744

Advanced and recurring thymic carcinoma is target of new clinical trial | Center for Cancer Research

Cancer.gov

Adults diagnosed with thymic carcinoma who overexpress the protein mesothelin may be eligible to participate in a new clinical trial at the NIH Clinical Center. The study will look at the safety and effectiveness of an investigational drug, anetumab ravtansine, developed by Bayer HealthCare Pharmaceuticals. The drug works by binding to mesothelin, therefore overexpression of the protein could be useful for targeting cancer cells. Read more...

Pembrolizumab and Vorinostat in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, or Hodgkin Lymphoma

ClinicalTrials.gov

2018-04-23

Grade 3a Follicular Lymphoma; Grade 3b Follicular Lymphoma; Recurrent Classical Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Classical Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma

Association of nbl gene expression and glucocorticoid-induced apoptosis in mouse thymus in vivo.

PubMed

Naora, H; Nishida, T; Shindo, Y; Adachi, M; Naora, H

1995-05-01

A gene of unknown biological function, nbl, was originally isolated by virtue of its abundance in a Namalwa Burkitt Lymphoma cDNA library. nbl expression was initially found to be higher in tissues which exhibited internucleosomal DNA cleavage characteristic of apoptosis, than in tissues which did not exhibit a 'DNA ladder'. nbl expression was therefore examined in mouse thymus in vivo, in which apoptosis is induced by the glucocorticoid, dexamethasone. nbl expression was markedly enhanced by dexamethasone treatment and then sharply decreased prior to the occurrence of maximal 'DNA ladder' formation. In contrast, expression of myc, which is believed to be involved in apoptosis in other cell systems, declined as thymic apoptosis increased. Thymic apoptosis was blocked by the transcriptional inhibitor actinomycin D, if administered when nbl expression was enhanced, but not before or after the peak of nbl expression. These results suggest that nbl expression is associated with thymic apoptosis.

A zinc-dependent epitope on the molecule of thymulin, a thymic hormone.

PubMed Central

Dardenne, M; Savino, W; Berrih, S; Bach, J F

1985-01-01

Thymulin is a nonapeptide hormone produced by thymic epithelial cells. Its biological activity is strictly dependent on the presence of the metal zinc in the molecule. Antithymulin monoclonal antibodies have been produced against either the synthetic (AS1) or the natural intraepithelial (AE1) molecule. These monoclonal antibodies were screened for their abilities to inhibit the zinc-dependent biological activity of the hormone and were shown to bind to thymic epithelial cells. By using biological and immunofluorescence assays, the two antibodies were shown to recognize exclusively the zinc-coupled thymulin molecule. Other antithymulin antibodies screened by RIA or ELISA (using a zinc-deprived substrate) recognized a zinc-independent epitope on the thymulin molecule. These data indicate the existence of a zinc-specific conformation on the thymulin molecule. They are in agreement with NMR studies showing that the zinc-containing hormone has a unique structure. Images PMID:2413455

[Successful treatment with rituximab in a patient with primary thymic MALT lymphoma complicated with acquired von Willebrand syndrome and Sjögren syndrome].

PubMed

Iwabuchi, Tamiko; Kimura, Yukihiko; Suzuki, Takashi; Hayashi, Haeru; Fujimoto, Hiroaki; Hashimoto, Yuko; Ogawa, Takashi; Kusama, Hiroshi; Fukutake, Katsuyuki; Ohyashiki, Kazuma

2011-04-01

A 53-year-old female developed epigastric discomfort and back pain in 2007. Diagnostic imaging studies demonstrated a soft tissue tumor with heterogeneous enhancement in the anterior mediastinum and multiple nodules in the right lung. She underwent expanded thymectomy with subtotal resection of the right lung. The pathological diagnosis was primary thymic mucosa-associated lymphoid tissue (MALT) lymphoma. The patient complained of ocular discomfort, oral dryness and continuous nasal bleeding in 2007. Detailed examination led to a diagnosis of Sjögren syndrome and acquired von Willebrand syndrome. Rituximab treatment for residual disease achieved not only a reduction of the lung MALT lymphoma but also clinical and hematological remission of both syndromes. This is, to our knowledge, the first reported case of primary thymic MALT lymphoma accompanied by Sjögren and acquired von Willebrand syndromes.

Personality affects aspects of health-related quality of life in Parkinson's disease via psychological coping strategies.

PubMed

Whitworth, Stephanie R; Loftus, Andrea M; Skinner, Timothy C; Gasson, Natalie; Barker, Roger A; Bucks, Romola S; Thomas, Meghan G

2013-01-01

Personality traits influence health-related quality of life (HRQoL) in Parkinson's disease (PD). Further, an individual's personality traits can influence the strategies they use to cope with a particular stressful situation. However, in PD, the interplay between personality traits, choice of coping strategy, and their subsequent effect on HRQoL remains unclear. The objective of this study was to examine whether personality (neuroticism and extraversion) indirectly affects HRQoL through the use of specific psychological coping strategies. One hundred and forty-six patients with PD completed questionnaires on personality (Big Five Aspects Scale; BFAS), coping (Ways of Coping Questionnaire; WCQ), and mood-specific (Depression, Anxiety and Stress Scale; DASS-21) and disease-specific HRQoL (Parkinson's Disease Questionnaire; PDQ-39). After controlling for gender, age at diagnosis, and age at testing, the emotion-focused coping strategy of escape-avoidance was significantly correlated with neuroticism and certain aspects of HRQoL (cognitive impairment and social support). This suggests that neurotic personality traits may negatively impact on some aspects of HRQoL due to an increased use of escape-avoidance coping strategies. By contrast, planned problem-solving and escape-avoidance coping strategies were both significantly linked to extraversion and interpersonal and mood-related domains of HRQoL. This suggests that extraversion may positively impact on some aspects of HRQoL due to patients adopting greater planned, problem-solving coping strategies, and using fewer escape-avoidance coping mechanisms. Psychological interventions aimed at targeting maladaptive coping strategies, such as the use of escape-avoidance coping, may be effective in minimising the negative impact of neuroticism on HRQoL in PD.

Avoidant coping partially mediates the relationship between patient problem behaviors and depressive symptoms in spousal Alzheimer caregivers.

PubMed

Mausbach, Brent T; Aschbacher, Kirstin; Patterson, Thomas L; Ancoli-Israel, Sonia; von Känel, Roland; Mills, Paul J; Dimsdale, Joel E; Grant, Igor

2006-04-01

Caring for a loved one with Alzheimer disease is a highly stressful experience that is associated with significant depressive symptoms. Previous studies indicate a positive association between problem behaviors in patients with Alzheimer disease (e.g., repeating questions, restlessness, and agitation) and depressive symptoms in their caregivers. Moreover, the extant literature indicates a robust negative relationship between escape-avoidance coping (i.e., avoiding people, wishing the situation would go away) and psychiatric well-being. The purpose of this study was to test a mediational model of the associations between patient problem behaviors, escape-avoidance coping, and depressive symptoms in Alzheimer caregivers. Ninety-five spousal caregivers (mean age: 72 years) completed measures assessing their loved ones' frequency of problem behaviors, escape-avoidance coping, and depressive symptoms. A mediational model was tested to determine if escape-avoidant coping partially mediated the relationship between patient problem behaviors and caregiver depressive symptoms. Patient problem behaviors were positively associated with escape-avoidance coping (beta = 0.38, p < 0.01) and depressive symptoms (beta = 0.26, p < 0.05). Escape-avoidance coping was positively associated with depressive symptoms (beta = 0.33, p < 0.01). In a final regression analysis, the impact of problem behaviors on depressive symptoms was less after controlling for escape-avoidance coping. Sobel's test confirmed that escape-avoidance coping significantly mediated the relationship between problem behaviors and depressive symptoms (z = 2.07, p < 0.05). Escape-avoidance coping partially mediates the association between patient problem behaviors and depressive symptoms among elderly caregivers of spouses with dementia. This finding provides a specific target for psychosocial interventions for caregivers.

Learned helplessness: effects of response requirement and interval between treatment and testing.

PubMed

Hunziker, M H L; Dos Santos, C V

2007-11-01

Three experiments investigated learned helplessness in rats manipulating response requirements, shock duration, and intervals between treatment and testing. In Experiment 1, rats previously exposed to uncontrollable or no shocks were tested under one of four different contingencies of negative reinforcement: FR 1 or FR 2 escape contingency for running, and FR1 escape contingency for jumping (differing for the maximum shock duration of 10s or 30s). The results showed that the uncontrollable shocks produced a clear operant learning deficit (learned helplessness effect) only when the animals were tested under the jumping FR 1 escape contingency with 10-s max shock duration. Experiment 2 isolated of the effects of uncontrollability from shock exposure per se and showed that the escape deficit observed using the FR 1 escape jumping response (10-s shock duration) was produced by the uncontrollability of shock. Experiment 3 showed that using the FR 1 jumping escape contingency in the test, the learned helplessness effect was observed one, 14 or 28 days after treatment. These results suggest that running may not be an appropriate test for learned helplessness, and that many diverging results found in the literature might be accounted for by the confounding effects of respondent and operant contingencies present when running is required of rats.

Exxon Valdez oil spill: State/federal natural resource damage assessment final report. Effects of pink salmon (oncorhynchus gorbuscha) escapement level on egg retention, preemergent fry, and adult returns to the kodiak and chignik management areas caused by the Exxon Valdez oil spill. Fish/shellfish study numbers 7b and 8b. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1993-12-01

As a result of the 1989 Exxon Valdez oil spill, commercial salmon fishing in and around the Kodiak and Chignik areas was severely restricted throughout the 1989 season. Consequently, pink salmon escapements for these areas greatly exceeded targeted escapement objectives. Investigations were conducted within the Kodiak and Chignik Management Areas during 1989 and 1990 to determine if negative impacts on future odd-year brood line pink salmon production occurred as a result of overescapement in 1989.

Negative Reinforcement and Premonitory Urges in Youth With Tourette Syndrome: An Experimental Evaluation.

PubMed

Capriotti, Matthew R; Brandt, Bryan C; Turkel, Jennifer E; Lee, Han-Joo; Woods, Douglas W

2014-03-01

Tourette syndrome (TS) is marked by the chronic presence of motor and vocal tics that are usually accompanied by aversive sensory experiences called "premonitory urges." Phenomenological accounts suggest that these urges occur before tics and diminish following their occurrence. This has led some to suggest that tics are negatively reinforced by removal of premonitory urges. This hypothesis has proven difficult to test experimentally, however, due in part to challenges in measuring premonitory urge strength. We tested predictions of the negative reinforcement conceptualization of premonitory urges using novel experimental tactics within the context of the "tic detector" paradigm. We compared tic rates and ratings of premonitory urge strength exhibited by youth with TS or chronic tic disorder under free-to-tic baseline (BL), reinforced tic suppression (RTS), and reinforced tic suppression with escape (RTS + E) conditions. Results were consistent with previous research and hypotheses of the present study. Participants rated the strength of their premonitory urges as higher during RTS conditions than during BL conditions. Within RTS + E conditions, tic rates were higher during escape portions when the contingency supporting tic suppression was inactive than during components where the contingency was active, and ratings of urge strength were higher at the onset of break periods than at the offset. All participants engaged in some level of escape from reinforced suppression during the course of the experiment. Results of this study support the notion that tics may be negatively reinforced by removal of aversive premonitory urges. Future directions for basic and clinical research are discussed. © The Author(s) 2014.

22. Photocopy of photograph (original negative in files of Irving ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

22. Photocopy of photograph (original negative in files of Irving I. Herzberg, 2942 West 5th Street, Apt. 4P, Brooklyn, New York 11224) Irving I. Herzberg, Photographer January 1966 THEATRE MARQUEE WITH CLOSING PROGRAM, FIRE ESCAPE AT LEFT - Fox Theatre, 20 Flatbush Avenue & 1 Nevins Street, Brooklyn, Kings County, NY

Pain-Relief Learning in Flies, Rats, and Man: Basic Research and Applied Perspectives

ERIC Educational Resources Information Center

Gerber, Bertram; Yarali, Ayse; Diegelmann, Sören; Wotjak, Carsten T.; Pauli, Paul; Fendt, Marcus

2014-01-01

Memories relating to a painful, negative event are adaptive and can be stored for a lifetime to support preemptive avoidance, escape, or attack behavior. However, under unfavorable circumstances such memories can become overwhelmingly powerful. They may trigger excessively negative psychological states and uncontrollable avoidance of locations,…

Mediastinal mass following chemotherapy in patients with Ewing sarcoma and osteosarcoma.

PubMed

Panadero, M A; Cruz, J J; Gomez, A; Fonseca, E; Garcia, M J; Garcia, J; Martin, G; Sanchez, P; Dueñas, G A

1996-05-01

Thymic hyperplasia following combination chemotherapy for malignant disease is very uncommon in adolescents and adults. Our experience includes a thymic enlargement noted on the sequential computed tomography (CT) in three patients who were disease-free after chemotherapy for Ewing sarcoma (2) and osteosarcoma (1). The development of an anterior mediastinal mass after successful chemotherapy does not always imply relapse of malignant disease. To prevent inappropriate treatment, the possibility of benign aetiology must be considered.

HTLV-1-infected thymic epithelial cells convey the virus to CD4+ T lymphocytes.

PubMed

Carvalho Barros, Luciana Rodrigues; Linhares-Lacerda, Leandra; Moreira-Ramos, Klaysa; Ribeiro-Alves, Marcelo; Machado Motta, Maria Cristina; Bou-Habib, Dumith Chequer; Savino, Wilson

2017-12-01

The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4 + T cells are the main target of HTLV-1, but other cell types are known to be infected, including immature lymphocytes. Developing T cells undergo differentiation in the thymus, through migration and interaction with the thymic microenvironment, in particular with thymic epithelial cells (TEC) the major component of this three dimensional meshwork of non-lymphoid cells. Herein, we show that TEC express the receptors for HTLV-1 and can be infected by this virus through cell-cell contact and by cell-free virus suspensions. The expression of anti-apoptosis, chemokine and adhesion molecules genes are altered in HTLV-1-infected TEC, although gene expression of antigen presentation molecules remained unchanged. Furthermore, HTLV-1-infected TEC transmitted the virus to a CD4 + T cell line and to CD4 + T cells from healthy donors, during in vitro cellular co-cultures. Altogether, our data point to the possibility that the human thymic epithelial cells play a role in the establishment and progression of HTLV-1 infection, functioning as a reservoir and transmitting the virus to maturing CD4 + T lymphocytes, which in turn will cause disease in the periphery. Copyright © 2017. Published by Elsevier GmbH.

Thymic involution and corticosterone level in Sandhoff disease model mice: new aspects the pathogenesis of GM2 gangliosidosis.

PubMed

Matsuoka, Kazuhiko; Tsuji, Daisuke; Taki, Takao; Itoh, Kohji

2011-10-01

Sandhoff disease (SD) is a lysosomal disease caused by a mutation of the HEXB gene associated with excessive accumulation of GM2 ganglioside (GM2) in lysosomes and neurological manifestations. Production of autoantibodies against the accumulated gangliosides has been reported to be involved in the progressive pathogenesis of GM2 gangliosidosis, although the underlying mechanism has not been fully elucidated. The thymus is the key organ in the acquired immune system including the development of autoantibodies. We showed here that thymic involution and an increase in cell death in the organ occur in SD model mice at a late stage of the pathogenesis. Dramatic increases in the populations of Annexin-V(+) cells and terminal deoxynucletidyl transferase dUTP nick end labeling (TUNEL) (+) cells were observed throughout the thymuses of 15-week old SD mice. Enhanced caspase-3/7 activation, but not that of caspase-1/4, -6 ,-8, or -9, was also demonstrated. Furthermore, the serum level of corticosterone, a potent inducer of apoptosis of thymocytes, was elevated during the same period of apoptosis. Our studies suggested that an increase in endocrine corticosterone may be one of the causes that accelerate the apoptosis of thymocytes leading to thymic involution in GM2 gangliosidosis, and thus can be used as a disease marker for evaluation of the thymic condition and disease progression.

Expression of 11beta-hydroxysteroid-dehydrogenase type 2 in human thymus.

PubMed

Almanzar, Giovanni; Mayerl, Christina; Seitz, Jan-Christoph; Höfner, Kerstin; Brunner, Andrea; Wild, Vanessa; Jahn, Daniel; Geier, Andreas; Fassnacht, Martin; Prelog, Martina

2016-06-01

11beta-hydroxysteroid-dehydrogenase type 2 (11β-HSD2) is a high affinity dehydrogenase which rapidly inactivates physiologically-active glucocorticoids to protect key tissues. 11β-HSD2 expression has been described in peripheral cells of the innate and the adaptive immune system as well as in murine thymus. In absence of knowledge of 11β-HSD2 expression in human thymus, the study aimed to localize 11β-HSD2 in human thymic tissue. Thymic tissue was taken of six healthy, non-immunologically impaired male infants below 12months of age with congenital heart defects who had to undergo correction surgery. 11β-HSD2 protein expression was analyzed by immunohistochemistry and Western blot. Kidney tissue, peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVEC) were taken as positive controls. Significant expression of 11β-HSD2 protein was found at single cell level in thymus parenchyma, at perivascular sites of capillaries and small vessels penetrating the thymus lobuli and within Hassall's bodies. The present study demonstrates that 11β-HSD2 is expressed in human thymus with predominant perivascular expression and also within Hassall's bodies. To our knowledge, this is the first report confirming 11β-HSD2 expression at the protein level in human thymic tissue underlining a potential role of this enzyme in regulating glucocorticoid function at the thymic level. Copyright © 2016 Elsevier Inc. All rights reserved.

Use of Toll-Like Receptor Agonists to Induce Ectopic Lymphoid Structures in Myasthenia Gravis Mouse Models

PubMed Central

Robinet, Marieke; Villeret, Bérengère; Maillard, Solène; Cron, Mélanie A.; Berrih-Aknin, Sonia; Le Panse, Rozen

2017-01-01

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. MG symptoms are characterized by muscle weaknesses. The thymus of MG patients is very often abnormal and possesses all the characteristics of tertiary lymphoid organs such as neoangiogenesis processes, overexpression of inflammatory cytokines and chemokines, and infiltration of B lymphocytes leading to ectopic germinal center (GC) development. We previously demonstrated that injections of mice with polyinosinic–polycytidylic acid [Poly(I:C)], a synthetic double-stranded RNA mimicking viral infection, induce thymic changes and trigger MG symptoms. Upon Poly(I:C) injections, we observed increased thymic expressions of α-AChR, interferon-β and chemokines such as CXCL13 and CCL21 leading to B-cell recruitment. However, these changes were only transient. In order to develop an experimental MG model associated with thymic GCs, we used Poly(I:C) in the classical experimental autoimmune MG model induced by immunizations with purified AChR emulsified in complete Freund’s adjuvant. We observed that Poly(I:C) strongly favored the development of MG as almost all mice displayed MG symptoms. Nevertheless, we did not observe any ectopic GC development. We next challenged mice with Poly(I:C) together with other toll-like receptor (TLR) agonists known to be involved in GC development and that are overexpressed in MG thymuses. Imiquimod and CpG oligodeoxynucleotides that activate TLR7 and TLR9, respectively, did not induce thymic changes. In contrast, lipopolysaccharide that activates TLR4 potentiated Poly(I:C) effects and induced a significant expression of CXCL13 mRNA in the thymus associated with a higher recruitment of B cells that induced over time thymic B-lymphoid structures. Altogether, these data suggest that tertiary lymphoid genesis in MG thymus could result from a combined activation of TLR signaling pathways. PMID:28970832

Cellular mechanism of estrogen-induced thymic involution in wall lizard: caspase-dependent action.

PubMed

Hareramadas, Batchu; Rai, Umesh

2006-05-01

The present study, for the first time in an ectothermic vertebrate, demonstrates the cellular mechanism of estrogen-induced thymic involution. Ovariectomy in lizards during the preparatory phase of the reproductive cycle resulted in distinct differentiation of cortico-medullary regions and increase in cellularity, especially in the cortical region. The ovariectomy-induced changes were reversed following administration of 17-estradiol (E2), suggesting a primary role of E2 in causing thymic atrophy. To understand the cellular mechanism of E2-induced thymic atrophy, in vitro effect of E2 was investigated on thymocyte proliferation and apoptosis. E2 decreased the uptake of tritiated thymidine (3H-TdR) by thymocytes in a dose-dependent manner, suggesting that estrogen directly inhibits the thymocyte proliferation. Unlike proliferation, E2 did not have any direct effect on thymocyte apoptosis, as evident by DNA gel electrophoretic, flow cytometric or fluorescence microscopic studies. However, in the presence of thymic epithelial cell-rich stromal components (TEC), E2 treatment at low or high concentrations resulted in depolarization of plasma membrane, DNA fragmentation and decrease in DNA content. This suggests that E2 indirectly, through TEC-secreted factors, controls thymocyte apoptosis. Similar result was observed following fluorescence microscopy. The indirect effect of E2 was further ascertained with the findings that E2-pretreated TEC-conditioned medium accelerated the thymocyte apoptosis. Nevertheless, exposure of thymocytes to E2 was seen to be inevitable for the apoptotic action of TEC-secreted paracrine factors. In the presence of TEC, a positive reaction for caspase-3, -7 and -9 and enzyme substrate, poly(ADP-ribose) polymerase (PARP) in response to E2 suggests the caspase-dependent thymocyte apoptosis in the wall lizard Hemidactylus flaviviridis. Further, E2 was shown to act through genomic pathway, since the receptor antagonist tamoxifen and transcription/translation inhibitors blocked its apoptotic action. Interestingly, the apoptotic effect of E2 was effectively decreased by progesterone.

Neuroendocrine thymic carcinoma metastatic to the parathyroid gland that was reimplanted into the forearm in patient with multiple endocrine neoplasia type 1 syndrome: a challenging management dilemma.

PubMed

Shifrin, Alexander L; LiVolsi, Virginia A; Zheng, Min; Lann, Danielle E; Fomin, Svetlana; Naylor, Evan C; Mencel, Peter J; Fay, Angela M; Erler, Brian S; Matulewicz, Theodore J

2013-01-01

To describe a unique case of a metastatic thymic carcinoma to the hyperplastic parathyroid gland and to present a challenging management dilemma. Our patient is 60-year-old, intellectually disabled man with history of the multiple endocrine neoplasia type 1 (MEN1) syndrome, a surgery in 1985 for hypercalcemia with removal of one parathyroid gland, surgery in 2007 with findings of extensively necrotic well differentiated neuroendocrine carcinoma (carcinoid tumor) of the thymus. In 2012, he presented with persistent hypercalcemia (calcium level 11.7 mg/dL [range, 8.6-10.2]), and a parathyroid hormone (PTH) level of 225 pg/mL (range, 15-65 pg/mL). He underwent a repeat neck exploration with removal of 2 small inferior and a large left superior 4.5 × 2.5 × 1.5 cm parathyroid glands, all of which showed hyperplasia on intraoperative frozen section. A small portion of the superior gland was reimplanted into the patient's forearm. Final pathology showed the presence of a focus of neuroendocrine tumor within the left superior parathyroid gland with immunostain identical to the thymic carcinoma. His postoperative PTH level was 14 pg/mL and calcium 8.5 mg/dL. A positron emission tomography-computed tomography (PET-CT) and octreotide scans revealed an extensive metastatic disease within the lung, mediastinum, and bones. We decided to leave a portion of the reimplanted parathyroid gland with possible metastatic thymic carcinoid in his forearm because of the presence a widespread metastatic disease and his intellectual disability that would result in noncompliance with calcium replacement in case of permanent hypocalcemia. Metastatic thymic carcinoma to the parathyroid gland has never been reported in the literature. We have described the first case and presented a challenging management dilemma.

De novo activation of HBV with escape mutations from hepatitis B surface antibody after living donor liver transplantation.

PubMed

Ueda, Yoshihide; Marusawa, Hiroyuki; Egawa, Hiroto; Okamoto, Shinya; Ogura, Yasuhiro; Oike, Fumitaka; Nishijima, Norihiro; Takada, Yasutsugu; Uemoto, Shinji; Chiba, Tsutomu

2011-01-01

De novo activation of HBV occurs after liver transplantation from hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (anti-HBc)-positive donors, even under hepatitis B immunoglobulin (HBIG) prophylaxis. One reason for the activation of HBV is the emergence of HBV with escape mutations from hepatitis B surface antibody (anti-HBs). The aim of this study is to clarify the clinical features for de novo activation of HBV with anti-HBs escape mutations after liver transplantation. Clinical features of 75 patients who received HBIG prophylaxis >6 months after liver transplantation with liver grafts from anti-HBc-positive donors were retrospectively analysed. Among the 75 recipients, 19 (25%) developed de novo activation of HBV. Of the 19 recipients, the emergence of HBV with anti-HBs escape mutations was confirmed in 7 patients. The rate of de novo activation of HBV with anti-HBs escape mutations was 12% at 5 years. Sequence analysis revealed mutations in the common 'a' determinant region of the surface gene, including G145R, G145A and Q129P, in HBsAg. Administration of entecavir immediately after the occurrence of de novo HBV activation resolved hepatitis and induced clearance of serum HBsAg and HBV DNA in all four patients receiving entecavir. Escape mutations from anti-HBs caused de novo activation of HBV under HBIG prophylaxis after liver transplantation. Early administration of entecavir was effective on de novo activation of HBV with anti-HBs escape mutations.

Light escape cones in local reference frames of Kerr-de Sitter black hole spacetimes and related black hole shadows

NASA Astrophysics Data System (ADS)

Stuchlík, Zdeněk; Charbulák, Daniel; Schee, Jan

2018-03-01

We construct the light escape cones of isotropic spot sources of radiation residing in special classes of reference frames in the Kerr-de Sitter (KdS) black hole spacetimes, namely in the fundamental class of `non-geodesic' locally non-rotating reference frames (LNRFs), and two classes of `geodesic' frames, the radial geodesic frames (RGFs), both falling and escaping, and the frames related to the circular geodesic orbits (CGFs). We compare the cones constructed in a given position for the LNRFs, RGFs, and CGFs. We have shown that the photons locally counter-rotating relative to LNRFs with positive impact parameter and negative covariant energy are confined to the ergosphere region. Finally, we demonstrate that the light escaping cones govern the shadows of black holes located in front of a radiating screen, as seen by the observers in the considered frames. For shadows related to distant static observers the LNRFs are relevant.

Study of RpI22 in MDS and AML

DTIC Science & Technology

2016-12-01

developed significantly larger and markedly more vascularized thymic tumors than those observed in Rpl22þ/þ control mice. But, unlike Rpl22þ/þ or Rpl22þ...hypoxia (31). Alternatively, we did not observe obvious necrosis in the center of the large thymic tumors from Rpl22-deficent mice, suggesting Rpl22...Orthop Res 2004;22:1175–81. 32. Loeffler S, Fayard B, Weis J, Weissenberger J. Interleukin-6 induces tran- scriptional activation of vascular endothelial

A combined third and fourth branchial arch anomaly: clinical and embryological implications.

PubMed

Mehrzad, H; Georgalas, C; Huins, C; Tolley, N S

2007-08-01

Embryological abnormalities of the branchial apparatus present an interesting diagnostic and surgical challenge. Thymic cysts are a rare form of branchial apparatus anomaly, resulting from abnormal development of the third pharyngeal pouch. We present two cases of a thymic cyst coexisting with a non recurrent inferior laryngeal nerve (NRILN), two anomalies that to our knowledge have not been associated previously. A possible embryological explication for this double abnormality is discussed, while the clinical implications of this association are presented.

Radioimmunoassays for the serum thymic factor (FTS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erickson, B.W.; Fok, K.F.; Incefy, G.S.

1987-01-06

This patent describes a radioimmunoassay of serum thymic factor (FTS) in a test sample, comprising: (a) contacting a first aliquot of the sample with anti-FTS antibody, with a known amount of FTS hormone standard and a known amount of radiolabeled FTS analogue; and (b) contacting a second aliquot of the sample with anti-FTS antibody and a known amount of radiolabeled FTS analogue; and (c) measuring the radioactivity of the antigen-antibody complex in each aliquot; and (d) calculating the amount of FTS in the test sample.

Motor planning modulates sensory-motor control of collision avoidance behavior in the bullfrog, Rana catesbeiana

PubMed Central

Nakagawa, Hideki; Nishida, Yuuya

2012-01-01

Summary In this study, we examined the collision avoidance behavior of the frog, Rana catesbeiana to an approaching object in the upper visual field. The angular velocity of the frog's escape turn showed a significant positive correlation with the turn angle (r2 = 0.5741, P<0.05). A similar mechanism of velocity control has been known in head movements of the owl and in human saccades. By analogy, this suggests that the frog planned its escape velocity in advance of executing the turn, to make the duration of the escape behavior relatively constant. For escape turns less than 60°, the positive correlation was very strong (r2 = 0.7097, P<0.05). Thus, the frog controlled the angular velocity of small escape turns very accurately and completed the behavior within a constant time. On the other hand, for escape turns greater than 60°, the same correlation was not significant (r2 = 0.065, P>0.05). Thus, the frog was not able to control the velocity of the large escape turns accurately and did not complete the behavior within a constant time. In the latter case, there was a small but significant positive correlation between the threshold angular size and the angular velocity (r2 = 0.1459, P<0.05). This suggests that the threshold is controlled to compensate for the insufficient escape velocity achieved during large turn angles, and could explain a significant negative correlation between the turn angle and the threshold angular size (r2 = 0.1145, P<0.05). Thus, it is likely that the threshold angular size is also controlled by the turn angle and is modulated by motor planning. PMID:23213389

Treatment and prognosis of primary thymic carcinoma.

PubMed

Yano, T; Hara, N; Ichinose, Y; Asoh, H; Yokoyama, H; Ohta, M

1993-04-01

From 1972 to 1990, we treated eight cases of thymic carcinoma (6 squamous cell and 2 small cell carcinomas). According to the classification by Masaoka et al., they consisted of one stage I, four stage III, one stage IVa, and two stage IVb. A complete resection of the primary tumour could be done in only three patients; the others had diagnostic biopsy and then radiation treatment. Four of five patients had a prolonged regression of the primary tumors after irradiation at 40-61.2 Gy. Six patients suffered from extrathoracic metastases. All patients received systemic chemotherapy with different regimens to counter either metastatic or locally recurrent lesions. Only two patients (with a regimen including cyclophosphamide, doxorubicin, and vincristine) obtained a partial response. The median survival of the eight patients was 70 months after surgical operation. The identification of an effective drug combination may thus improve the long-term prognosis of thymic carcinoma since radiotherapy is able to control primary lesions, even in the case of unresectable advanced disease.

Thymic DCs derived IL-27 regulates the final maturation of CD4+ SP thymocytes

PubMed Central

Tang, Hui; Zhang, Jie; Sun, Xiuyuan; Qian, Xiaoping; Zhang, Yu; Jin, Rong

2016-01-01

IL-27, as a pleiotropic cytokine, promotes the differentiation of naïve T cells to Th1, while suppressing Th2 and Th17 differentiation in the periphery. However, the role of IL-27 in the thymocyte development remains unknown. Here we showed that IL-27 was highly expressed in thymic plasmacytoid dendritic cells (pDCs) while its receptor expression was mainly detected in CD4+ single-positive (SP) thymocytes. Deletion of the p28 subunit in DCs resulted in a reduction of the most mature Qa-2+ subsets of CD4+ SP T cells. This defect was rescued by intrathymic administration of exogenous IL-27. In vitro differentiation assay further demonstrated that IL-27 alone was able to drive the maturation of the newly generated 6C10+CD69+CD4+ SP cells into Qa-2+ cells. Collectively, this study has revealed an important role of thymic DCs-derived IL-27 in the regulation of the phenotypic maturation of CD4+ SP thymocytes. PMID:27469302

Cutting Edge: Defective Aerobic Glycolysis Defines the Distinct Effector Function in Antigen-Activated CD8+ Recent Thymic Emigrants.

PubMed

Cunningham, Cody A; Bergsbaken, Tessa; Fink, Pamela J

2017-06-15

Recent thymic emigrants (RTEs) are the youngest peripheral T cells that have completed thymic selection and egress to the lymphoid periphery. RTEs are functionally distinct from their more mature but still naive T cell counterparts, because they exhibit dampened proliferation and reduced cytokine production upon activation. In this article, we show that, compared with more mature but still naive T cells, RTEs are impaired in their ability to perform aerobic glycolysis following activation. Impaired metabolism underlies the reduced IFN-γ production observed in activated RTEs. This failure to undergo Ag-induced aerobic glycolysis is caused by reduced mTORC1 activity and diminished Myc induction in RTEs. Critically, exogenous IL-2 restores Myc expression in RTEs, driving aerobic glycolysis and IFN-γ production to the level of mature T cells. These results reveal a previously unknown metabolic component to postthymic T cell maturation. Copyright © 2017 by The American Association of Immunologists, Inc.

Enhanced clonal burst size corrects an otherwise defective memory response by CD8+ recent thymic emigrants

PubMed Central

Deets, Katherine A.; Berkley, Amy M.; Bergsbaken, Tessa; Fink, Pamela J.

2016-01-01

The youngest peripheral T cells (recent thymic emigrants or RTEs) are functionally distinct from naïve T cells that have completed post-thymic maturation. We now assess the RTE memory response, and find that RTEs produced less granzyme B than their mature counterparts during infection, but proliferated more and therefore generated equivalent target killing in vivo. After infection, RTE numbers contracted less dramatically than those of mature T cells, but RTEs were delayed in their transition to central memory, displaying impaired expression of CD62L, IL-2, Eomesodermin, and CXCR4, which resulted in impaired bone marrow localization. RTE-derived and mature memory cells expanded equivalently during rechallenge, indicating the robust proliferative capacity of RTEs was maintained independently of central memory phenotype. Thus, the diminished effector function and delayed central memory differentiation of RTE-derived memory cells are counterbalanced by their increased proliferative capacity, driving the efficacy of the RTE response to that of mature T cells. PMID:26873989

Association of nbl gene expression and glucocorticoid-induced apoptosis in mouse thymus in vivo.

PubMed Central

Naora, H; Nishida, T; Shindo, Y; Adachi, M; Naora, H

1995-01-01

A gene of unknown biological function, nbl, was originally isolated by virtue of its abundance in a Namalwa Burkitt Lymphoma cDNA library. nbl expression was initially found to be higher in tissues which exhibited internucleosomal DNA cleavage characteristic of apoptosis, than in tissues which did not exhibit a 'DNA ladder'. nbl expression was therefore examined in mouse thymus in vivo, in which apoptosis is induced by the glucocorticoid, dexamethasone. nbl expression was markedly enhanced by dexamethasone treatment and then sharply decreased prior to the occurrence of maximal 'DNA ladder' formation. In contrast, expression of myc, which is believed to be involved in apoptosis in other cell systems, declined as thymic apoptosis increased. Thymic apoptosis was blocked by the transcriptional inhibitor actinomycin D, if administered when nbl expression was enhanced, but not before or after the peak of nbl expression. These results suggest that nbl expression is associated with thymic apoptosis. Images Figure 1 Figure 3 Figure 4 Figure 6 PMID:7635523

Induction of Simian AIDS in Infant Rhesus Macaques Infected with CCR5- or CXCR4-Utilizing Simian-Human Immunodeficiency Viruses Is Associated with Distinct Lesions of the Thymus

PubMed Central

Reyes, R. A.; Canfield, Don R.; Esser, Ursula; Adamson, Lourdes A.; Brown, Charles R.; Cheng-Mayer, Cecilia; Gardner, Murray B.; Harouse, Janet M.; Luciw, Paul A.

2004-01-01

Newborn rhesus macaques were infected with two chimeric simian-human immunodeficiency virus (SHIV) strains which contain unique human immunodeficiency virus type 1 (HIV-1) env genes and exhibit distinct phenotypes. Infection with either the CCR5-specific SHIVSF162P3 or the CXCR4-utilizing SHIVSF33A resulted in clinical manifestations consistent with simian AIDS. Most prominent in this study was the detection of severe thymic involution in all SHIVSF33A-infected infants, which is very similar to HIV-1-induced thymic dysfunction in children who exhibit a rapid pattern of disease progression. In contrast, SHIVSF162P3 induced only a minor disruption in thymic morphology. Consistent with the distribution of the coreceptors CXCR4 and CCR5 within the thymus, the expression of SHIVSF162P3 was restricted to the thymic medulla, whereas SHIVSF33A was preferentially detected in the cortex. This dichotomy of tissue tropism is similar to the differential tropism of HIV-1 isolates observed in the reconstituted human thymus in SCID-hu mice. Accordingly, our results show that the SHIV-monkey model can be used for the molecular dissection of cell and tissue tropisms controlled by the HIV-1 env gene and for the analysis of mechanisms of viral immunopathogenesis in AIDS. Furthermore, these findings could help explain the rapid progression of disease observed in some HIV-1-infected children. PMID:14747577

Characterization of thymus-associated lymphoid depletion in bovine calves acutely or persistently infected with bovine viral diarrhea virus 1, bovine viral diarrhea virus 2 or HoBi-like pestivirus.

PubMed

Falkenberg, Shollie M; Bauermann, Fernando V; Ridpath, Julia F

2017-11-01

Naïve pregnant cattle exposed to pestiviruses between 40-125 days of gestation can give birth to persistently infected (PI) calves. Clinical presentation and survivability, in PI cattle, is highly variable even with the same pestivirus strain whereas the clinical presentation in acute infections is more uniform with severity of symptoms being primarily a function of virulence of the infecting virus. The aim of this study was to compare thymic depletion, as measured by comparing the area of the thymic cortex to the medulla (corticomedullary ratio), in acute and persistent infections of the same pestivirus isolate. The same general trends were observed with each pestivirus isolate. Thymic depletion was observed in both acutely and persistently infected calves. The average thymic depletion observed in acutely infected calves was greater than that in age matched PI calves. PI calves, regardless of infecting virus, revealed a greater variability in amount of depletion compared to acutely infected calves. A trend was observed between survivability and depletion of the thymus, with PI calves surviving less than 5 weeks having lower corticomedullary ratios and greater depletion. This is the first study to compare PI and acutely infected calves with the same isolates as well as to evaluate PI calves based on survivability. Further, this study identified a quantifiable phenotype associated with potential survivability.

An Age-Associated Decline in Thymic Output Differs in Dog Breeds According to Their Longevity.

PubMed

Holder, Angela; Mella, Stephanie; Palmer, Donald B; Aspinall, Richard; Catchpole, Brian

2016-01-01

The age associated decline in immune function is preceded in mammals by a reduction in thymic output. Furthermore, there is increasing evidence of a link between immune competence and lifespan. One approach to determining thymic output is to quantify signal joint T cell receptor excision circles (sj-TRECs), a method which has been developed and used in several mammalian species. Life expectancy and the rate of aging vary in dogs depending upon their breed. In this study, we quantified sj-TRECs in blood samples from dogs of selected breeds to determine whether there was a relationship between longevity and thymic output. In Labrador retrievers, a breed with a median expected lifespan of 11 years, there was an age-associated decline in sj-TREC values, with the greatest decline occurring before 5 years of age, but with sj-TREC still detectable in some geriatric animals, over 13 years of age. In large short-lived breeds (Burnese mountain dogs, Great Danes and Dogue de Bordeaux), the decline in sj-TREC values began earlier in life, compared with small long-lived breeds (Jack Russell terriers and Yorkshire terriers), and the presence of animals with undetectable sj-TRECs occurred at a younger age in the short-lived breeds. The study findings suggest that age-associated changes in canine sj-TRECs are related to breed differences in longevity, and this research highlights the use of dogs as a potential model of immunosenescence.

Development of donor-derived thymic lymphomas after allogeneic bone marrow transplantation in AKR/J mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yasumizu, R.; Hiai, H.; Sugiura, K.

1988-09-15

The transplantation of bone marrow cells from BALB/c (but not C57BL/6 and C3H/HeN) mice was observed to lead to the development of thymic lymphomas (leukemias) in AKR/J mice. Two leukemic cell lines, CAK1.3 and CAK4.4, were established from the primary culture of two thymic lymphoma, and surface phenotypes of these cell lines found to be H-2d and Thy-1.2+, indicating that these lymphoma cells are derived from BALB/c donor bone marrow cells. Further analyses of surface markers revealed that CAK1.3 is L3T4+ Lyt2+ IL2R-, whereas CAK4.4 is L3T4- Lyt2- IL2R+. Both CAK1.3 and CAK4.4 were transplantable into BALB/c but not AKR/Jmore » mice, further indicating that these cells are of BALB/c bone marrow donor origin. The cells were found to produce XC+-ecotropic viruses, but xenotropic and mink cell focus-forming viruses were undetectable. Inasmuch as thymic lymphomas are derived from bone marrow cells of leukemia-resistant BALB/c strain of mice under the allogeneic environment of leukemia-prone AKR/J mice, this animal model may serve as a useful tool not only for the analysis of leukemic relapse after bone marrow transplantation but also for elucidation of the mechanism of leukemogenesis.« less

Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood.

PubMed

Duggal, Niharika Arora; Pollock, Ross D; Lazarus, Norman R; Harridge, Stephen; Lord, Janet M

2018-04-01

It is widely accepted that aging is accompanied by remodelling of the immune system including thymic atrophy and increased frequency of senescent T cells, leading to immune compromise. However, physical activity, which influences immunity but declines dramatically with age, is not considered in this literature. We assessed immune profiles in 125 adults (55-79 years) who had maintained a high level of physical activity (cycling) for much of their adult lives, 75 age-matched older adults and 55 young adults not involved in regular exercise. The frequency of naïve T cells and recent thymic emigrants (RTE) were both higher in cyclists compared with inactive elders, and RTE frequency in cyclists was no different to young adults. Compared with their less active counterparts, the cyclists had significantly higher serum levels of the thymoprotective cytokine IL-7 and lower IL-6, which promotes thymic atrophy. Cyclists also showed additional evidence of reduced immunesenescence, namely lower Th17 polarization and higher B regulatory cell frequency than inactive elders. Physical activity did not protect against all aspects of immunesenescence: CD28 -ve CD57 +ve senescent CD8 T-cell frequency did not differ between cyclists and inactive elders. We conclude that many features of immunesenescence may be driven by reduced physical activity with age. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Hematological alterations and thymic function in newborns of HIV-infected mothers receiving antiretroviral drugs.

PubMed

Wongnoi, Rotjanee; Penvieng, Nawaporn; Singboottra, Panthong; Kingkeow, Doungnapa; Oberdorfer, Peninnah; Sirivatanapa, Pannee; Pornprasert, Sakorn

2013-06-08

To investigate the effects of antiretroviral (ARV) drugs on hematological parameters and thymic function in HIV-uninfected newborns of HIV-infected mothers. Cross sectional study. Chiang-Mai University Hospital, Chiang-Mai, Thailand. 49 HIV-uninfected and 26 HIV-infected pregnancies. Cord blood samples of newborns from HIV-uninfected and HIV-infected mothers were collected. Hematological parameters were measured using automatic blood cell count. T-cell receptor excision circles (TRECs) levels in cord blood mononuclear cells (CBMCs), CD4+ and CD8+ T-cells were quantified using real-time PCR.. Hemotological parameters and thymic function. Newborn of HIV-infected mother tended to have lower mean levels of hemoglobin than those of HIV-uninfected mother (137 ±22 vs 146 ±17 g/L, P = 0.05). Furthermore, mean of red blood cell (RBC) counts and hematocrit and median of TRECs in CD4+ T-cells in the newborns of the former were significantly lower than those of the latter [3.6 ±0.7 vs 4.8 ±0.6 x 1012 cells/L, P <0.001; 0.40 ±0.07 vs 0.46 ±0.05 L/L, P < 0.001 and 0.53 (IQR: 0.03-5.76) vs 13.20 (IQR: 2.77-27.51) x 10-3 pg/uL, P = 0.02, respectively]. ARV drugs altered hematological parameters and thymic function (TRECs CD4+ T-cells) in HIV-uninfected newborns of HIV-infected mothers.

Mesothelioma and thymic tumors: Treatment challenges in (outside) a network setting.

PubMed

Imbimbo, Martina; Maury, Jean-Michel; Garassino, Marina; Girard, Nicolas

2018-02-02

The management of patients with mesothelioma and thymic malignancy requires continuous multidisciplinary expertise at any step of the disease. A dramatic improvement in our knowledge has occurred in the last few years, through the development of databases, translational research programs, and clinical trials. Access to innovative strategies represents a major challenge, as there is a lack of funding for clinical research in rare cancers and their rarity precludes the design of robust clinical trials that could lead to specific approval of drugs. In this context, patient-centered initiatives, such as the establishment of dedicated networks, are warranted. International societies, such as IMIG (International Mesothelioma Interest Group) and ITMIG (International Thymic Malignancy Interest Group) provide infrastructure for global collaboration, and there are many advantages to having strong regional groups working on the same issues. There may be regional differences in risk factors, susceptibility, management and outcomes. The ability to address questions both regionally as well as globally is ideal to develop a full understanding of mesothelioma and thymic malignancies. In Europe, through the integration of national networks with EURACAN, the collaboration with academic societies and international groups, the development of networks in thoracic oncology provides multiplex integration of clinical care and research, ultimately ensuring equal access to high quality care to all patients, with the opportunity of conducting high level clinical and translational research projects. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Association between histological alterations in the thymus and sudden infant death syndrome.

PubMed

Varga, Ivan; Bódi, Ildikó; Mešťanová, Veronika; Kováč, Martin; Klein, Martin

2018-04-01

Sudden infant death syndrome (SIDS) involves the death of an infant during the first year of life and it is among the leading causes of infant mortality worldwide. One hypothesis regarding the pathogenesis of SIDS is that it results from a combination of three independent factors: endogenous vulnerability, a critical time window during postnatal development, and exogenous stressors. This hypothesis is known as the "triple-risk model". In this study, we used an immunohistological approach to compare the cellular microenvironments of thymuses from 19 infants whose sudden death was classified as SIDS and a control group, which consisted of thymuses from age-matched children undergoing surgery for various congenital heart defects. We hypothesized that morphological signs of stress-related thymic involution would be present. Based on our observations, we found evidence that the proliferation and maturation of T-lymphocytes in the thymuses of infants with SIDS were suppressed. We observed enhanced macrophage activity, suggesting an increase in the apoptosis of lymphocytes and decrease in number of thymic dendritic cells and myoid cells. Significant apoptosis of thymic lymphocytes without cell regeneration typically leads to atrophy of the thymus. All cellular events we observed resemble the initial stage of stress-related thymic involution. These results support the "triple-risk model," suggesting that certain exogenous stressors might be involved in the pathogenesis of SIDS. This was probably not recognized during the autopsies of infants who died suddenly. Copyright © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells

PubMed Central

Gerson, Stanton L.

2017-01-01

Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs), creating a preleukemic stem cell (PLSC). Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC). Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM), but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment. PMID:28767666

Characterization of CD34+ thymic stromal cells located in the subcapsular cortex of the human thymus.

PubMed

Martínez-Cáceres, E; Jaleco, A C; Res, P; Noteboom, E; Weijer, K; Spits, H

1998-07-01

In this paper we report that suspensions of human fetal thymocytes contain cells that express high levels of CD34 and Thy-1. These cells were characterized with regard to location within the thymus, phenotype, and function. Confocal laser scan analysis of frozen sections of fetal thymus with anti-CD34 and Thy-1 antibodies revealed that the double-labeled cells were located in the pericortical area. In addition, it was found that the CD34+Thy-1+ cells lacked CD45 and CD50, indicating that these cells are not of hematopoietic origin; this was confirmed by the finding that these cells could be cultured as adherent cells in a medium with cholera toxin and dexamethasone, but failed to grow in mixtures of hematopoietic growth factors. Further analysis indicated that most cultured CD34+Thy-1+ cells expressed cytokeratin (CK) 14 but lacked CK 13, suggesting that these cells are immature epithelial cells. Cultured CD34+Thy-1+ cells were able to induce differentiation of CD1-CD34+CD3-CD4-CD8- thymic precursors into CD4+CD8+ cells in a reaggregate culture in the absence of exogenous cytokines. The CD4+CD8+ cells that developed in these cultures did not express CD3, indicating that CD34+Thy-1+ thymic stromal cells are not capable of completing full T cell differentiation of thymic hematopoietic progenitor cells.

Enhanced pathogenicity of diabetogenic T cells escaping a non-MHC gene-controlled near death experience.

PubMed

Choisy-Rossi, Caroline-Morgane; Holl, Thomas M; Pierce, Melissa A; Chapman, Harold D; Serreze, David V

2004-09-15

For unknown reasons, the common MHC class I variants encoded by the H2g7 haplotype (Kd, Db) aberrantly elicit autoreactive CD8 T cell responses essential to type 1 diabetes development when expressed in NOD mice, but not other strains. In this study, we show that interactive non-MHC genes allow a NOD-derived diabetogenic CD8 T cell clonotype (AI4) to be negatively selected at far greater efficiency in C57BL/6 mice congenically expressing H2g7 (B6.H2g7). However, the few AI4 T cells escaping negative selection in B6.H2g7 mice are exported from the thymus more efficiently, and are more functionally aggressive than those of NOD origin. This provides mechanistic insight to previous findings that resistant mouse strains carry some genes conferring greater diabetes susceptibility than the corresponding NOD allele. In the B6.H2g7 stock, non-MHC gene-controlled elevations in TCR expression are associated with both enhanced negative selection of diabetogenic CD8 T cells and increased aggressiveness of those escaping this process. An implication of this finding is that the same phenotype, in this case relatively high TCR expression levels, could have double-edged sword effects, contributing to type 1 diabetes resistance at one level of T cell development, but at another actually promoting pathogenesis. Copyright 2004 The American Association of Immunologists, Inc.

Tests of the Aversive Summation Hypothesis in Rats: Effects of Restraint Stress on Consummatory Successive Negative Contrast and Extinction in the Barnes Maze

ERIC Educational Resources Information Center

Ortega, Leonardo A.; Prado-Rivera, Mayerli A.; Cardenas-Poveda, D. Carolina; McLinden, Kristina A.; Glueck, Amanda C.; Gutierrez, German; Lamprea, Marisol R.; Papini, Mauricio R.

2013-01-01

The present research explored the effects of restraint stress on two situations involving incentive downshift: consummatory successive negative contrast (cSNC) and extinction of escape behavior in the Barnes maze. First, Experiment 1 confirmed that the restraint stress procedure used in these experiments increased levels of circulating…

Spacecraft charging and ion wake formation in the near-Sun environment

NASA Astrophysics Data System (ADS)

Ergun, R. E.; Malaspina, D. M.; Bale, S. D.; McFadden, J. P.; Larson, D. E.; Mozer, F. S.; Meyer-Vernet, N.; Maksimovic, M.; Kellogg, P. J.; Wygant, J. R.

2010-07-01

A three-dimensional, self-consistent code is employed to solve for the static potential structure surrounding a spacecraft in a high photoelectron environment. The numerical solutions show that, under certain conditions, a spacecraft can take on a negative potential in spite of strong photoelectron currents. The negative potential is due to an electrostatic barrier near the surface of the spacecraft that can reflect a large fraction of the photoelectron flux back to the spacecraft. This electrostatic barrier forms if (1) the photoelectron density at the surface of the spacecraft greatly exceeds the ambient plasma density, (2) the spacecraft size is significantly larger than local Debye length of the photoelectrons, and (3) the thermal electron energy is much larger than the characteristic energy of the escaping photoelectrons. All of these conditions are present near the Sun. The numerical solutions also show that the spacecraft's negative potential can be amplified by an ion wake. The negative potential of the ion wake prevents secondary electrons from escaping the part of spacecraft in contact with the wake. These findings may be important for future spacecraft missions that go nearer to the Sun, such as Solar Orbiter and Solar Probe Plus.

Synchronous B3 thymoma and lung bronchoalveolar carcinoma.

PubMed

Patella, Miriam; Anile, Marco; Vitolo, Domenico; Venuta, Federico

2011-01-01

The association between thymic tumors and other intrathoracic or extrathoracic neoplasms is relatively rare; the synchronous occurrence of thymoma and bronchoalveolar carcinoma of the lung has never been described so far. A huge B3 cystic thymoma was found at thoracotomy to be associated with stage IV bronchoalveolar carcinoma (intraparenchymal and pleural metastases). The thymic tumor was completely resected; lung cancer was biopsied only for diagnosis and staging purposes. After an uneventful postoperative course the patient underwent chemotherapy; she is still alive and well one year after surgery.

Absence of cellular hypersensitivity to muscle and thymic antigens in myasthenia gravis.

PubMed Central

Behan, W M; Behan, P O; Simpson, J A

1975-01-01

Humoral antibodies to skeletal muscle and its components and to thymus have been demonstrated in the sera of patients with myasthenia gravis. A role for cellular hypersensitivity to similar antigens in the pathogenesis of the disease has been suggested by some reports of the presence of cellular immunity. A detailed immunological study using muscle and thymic antigens, including those prepared from the patients' own tissues, failed to confirm these findings. It is suggested that previous reports of cellular hypersensitivity represent the demonstration of an epiphenomenon. PMID:1206412

Impact of ocean acidification on the early development and escape behavior of marine medaka (Oryzias melastigma).

PubMed

Wang, Xiaojie; Song, Lulu; Chen, Yi; Ran, Haoyu; Song, Jiakun

2017-10-01

Ocean acidification is predicted to affect a wide diversity of marine organisms. However, no studies have reported the effects of ocean acidification on Indian Ocean fish. We have used the Indian Ocean medaka (Oryzias melastigma) as a model species for a marine fish that lives in coastal waters. We investigated the impact of ocean acidification on the embryonic development and the stereotyped escape behavior (mediated by the Mauthner cell) in newly hatched larvae. Newly fertilized eggs of medaka were reared in seawater at three different partial pressures of carbon dioxide (pCO 2 ): control at 450 μatm, moderate at 1160 μatm, and high at 1783 μatm. Hatch rates, embryonic duration, and larval malformation rates were compared and were not significantly different between the treatments and the control. In the high pCO 2 group, however, the yolks of larvae were significantly smaller than in the control group, and the newly hatched larvae were significantly longer than the larvae in the control. In the moderate pCO 2 group, the eye distance decreased significantly. No significantly negative growth effects were observed in the larvae when exposed to pCO 2 levels that are predicted as a result of ocean acidification in the next 100-200 years. Larvae reared under control conditions readily produced C-start escape behavior to mechanosensory stimuli; however, in the moderate and high pCO 2 experimental groups, the probabilities of C-start were significantly lower than those of the control group. Therefore, the sensory integration needed for the C-start escape behavior appears to be vulnerable to ocean acidification. Altered behavior in marine larval fish, particularly behaviors involved in escape from predation, could have potentially negative implications to fish populations, and, further, to the marine ecosystems at the levels of CO 2 projected for the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

High-CO 2 Requirement as a Mechanism for the Containment of Genetically Modified Cyanobacteria

DOE PAGES

Clark, Ryan L.; Gordon, Gina C.; Bennett, Nathaniel R.; ...

2018-01-10

As researchers engineer cyanobacteria for biotechnological applications, we must consider potential environmental release of these organisms. Previous theoretical work has considered cyanobacterial containment through elimination of the CO 2-concentrating mechanism (CCM) to impose a high-CO 2 requirement (HCR), which could be provided in the cultivation environment but not in the surroundings. In this work, we experimentally implemented an HCR containment mechanism in Synechococcus sp. strain PCC7002 (PCC7002) through deletion of carboxysome shell proteins and showed that this mechanism contained cyanobacteria in a 5% CO 2 environment. We considered escape through horizontal gene transfer (HGT) and reduced the risk of HGTmore » escape by deleting competence genes. We showed that the HCR containment mechanism did not negatively impact the performance of a strain of PCC7002 engineered for L-lactate production. In conclusion, we showed through coculture experiments of HCR strains with ccm-containing strains that this HCR mechanism reduced the frequency of escape below the NIH recommended limit for recombinant organisms of one escape event in 10 8 CFU.« less

High-CO 2 Requirement as a Mechanism for the Containment of Genetically Modified Cyanobacteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clark, Ryan L.; Gordon, Gina C.; Bennett, Nathaniel R.

As researchers engineer cyanobacteria for biotechnological applications, we must consider potential environmental release of these organisms. Previous theoretical work has considered cyanobacterial containment through elimination of the CO 2-concentrating mechanism (CCM) to impose a high-CO 2 requirement (HCR), which could be provided in the cultivation environment but not in the surroundings. In this work, we experimentally implemented an HCR containment mechanism in Synechococcus sp. strain PCC7002 (PCC7002) through deletion of carboxysome shell proteins and showed that this mechanism contained cyanobacteria in a 5% CO 2 environment. We considered escape through horizontal gene transfer (HGT) and reduced the risk of HGTmore » escape by deleting competence genes. We showed that the HCR containment mechanism did not negatively impact the performance of a strain of PCC7002 engineered for L-lactate production. In conclusion, we showed through coculture experiments of HCR strains with ccm-containing strains that this HCR mechanism reduced the frequency of escape below the NIH recommended limit for recombinant organisms of one escape event in 10 8 CFU.« less

Effect of Boron on Thymic Cytokine Expression, Hormone Secretion, Antioxidant Functions, Cell Proliferation, and Apoptosis Potential via the Extracellular Signal-Regulated Kinases 1 and 2 Signaling Pathway.

PubMed

Jin, Erhui; Ren, Man; Liu, Wenwen; Liang, Shuang; Hu, Qianqian; Gu, Youfang; Li, Shenghe

2017-12-27

Boron is an essential trace element in animals. Appropriate boron supplementation can promote thymus development; however, a high dose of boron can lead to adverse effects and cause toxicity. The influencing mechanism of boron on the animal body remains unclear. In this study, we examined the effect of boron on cytokine expression, thymosin and thymopoietin secretion, antioxidant function, cell proliferation and apoptosis, and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway in the thymus of rats. We found that supplementation with 10 and 20 mg/L boron to the drinking water significantly elevated levels of interleukin 2 (IL-2), interferon γ (IFN-γ), interleukin 4 (IL-4), and thymosin α1 in the thymus of rats (p < 0.05), increased the number of positive proliferating cell nuclear antigen (PCNA + ) cells and concentrations of glutathione peroxidase (GSH-Px) and phosphorylated extracellular signal-regulated kinase (p-ERK) (p < 0.05), and promoted mRNA expression of PCNA and ERK1/2 in thymocytes (p < 0.05). However, the number of caspase-3 + cells and the expression level of caspase-3 mRNA were reduced (p < 0.05). Supplementation with 40, 80, and 160 mg/L boron had no apparent effect on many of the above indicators. In contrast, supplementation with 480 and 640 mg/L boron had the opposite effect on the above indicators in rats and elevated levels of pro-inflammatory cytokines, such as interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α) (p < 0.05). Our study showed that supplementation of various doses of boron to the drinking water had a U-shaped dose-effect relationship with thymic cytokine expression, hormone secretion, antioxidant function, cell proliferation, and apoptosis. Specifically, supplementation with 10 and 20 mg/L boron promoted thymocyte proliferation and enhanced thymic functions. However, supplementation with 480 and 640 mg/L boron inhibited thymic functions and increased the number of apoptotic thymocytes, suggesting that the effects of boron on thymic functions may be caused via the ERK1/2 signaling pathway.

The Relation Between Death Attitude and Distress: Tolerance, Aggression, and Anger.

PubMed

Esnaashari, Fatemeh; Kargar, Flor Rezaei

2018-06-01

The aim of this research was to determine the relation between death attitude and distress tolerance and aggression and anger. For this, 135 subjects among 7,535 professional and specialist members of the Iran National Library were selected using convenience sampling method. They replied to Death Attitudes Profile-Revised, distress tolerance questionnaire, and aggression questionnaire. The results showed that the attitudes of approach acceptance, neutral acceptance, and escape acceptance had positive relation to distress tolerance and negative relation to aggression and anger while the attitudes of fear of death and death avoidance had negative relation to distress tolerance and positive relation to aggression and anger. Furthermore, all death attitudes predicted distress tolerance. But only the attitudes of approach acceptance, escape acceptance, fear of death, and death avoidance predicted aggression, and only approach acceptance, neutral acceptance, fear of death, and death avoidance predicted anger.

The effects of variable-time versus contingent reinforcement delivery on problem behavior maintained by escape.

PubMed

Lomas Mevers, Joanna E; Fisher, Wayne W; Kelley, Michael E; Fredrick, Laura D

2014-01-01

Results of previous research indicate that the delivery of positive reinforcement (e.g., food) for an appropriate, alternative target response (e.g., compliance) or delivery of food on a time-based schedule can decrease problem behavior reinforced by escape, even when problem behavior continues to produce negative reinforcement (e.g., Lalli et al., ; Lomas, Fisher, & Kelley, ). In this study, we compared the levels of both compliance and problem behavior when food and praise were delivered either contingent on compliance or on a time-based schedule. Results for 3 of the 4 participants showed that contingent delivery of preferred edible items and praise was more effective in both reducing problem behavior and increasing compliance compared to variable-time delivery of these same items. These findings are discussed in the context of motivating operations and competition between positive and negative reinforcement. © Society for the Experimental Analysis of Behavior.

Cholinergic epithelial cell with chemosensory traits in murine thymic medulla.

PubMed

Panneck, Alexandra Regina; Rafiq, Amir; Schütz, Burkhard; Soultanova, Aichurek; Deckmann, Klaus; Chubanov, Vladimir; Gudermann, Thomas; Weihe, Eberhard; Krasteva-Christ, Gabriela; Grau, Veronika; del Rey, Adriana; Kummer, Wolfgang

2014-12-01

Specialized epithelial cells with a tuft of apical microvilli ("brush cells") sense luminal content and initiate protective reflexes in response to potentially harmful substances. They utilize the canonical taste transduction cascade to detect "bitter" substances such as bacterial quorum-sensing molecules. In the respiratory tract, most of these cells are cholinergic and are approached by cholinoceptive sensory nerve fibers. Utilizing two different reporter mouse strains for the expression of choline acetyltransferase (ChAT), we observed intense labeling of a subset of thymic medullary cells. ChAT expression was confirmed by in situ hybridization. These cells showed expression of villin, a brush cell marker protein, and ultrastructurally exhibited lateral microvilli. They did not express neuroendocrine (chromogranin A, PGP9.5) or thymocyte (CD3) markers but rather thymic epithelial (CK8, CK18) markers and were immunoreactive for components of the taste transduction cascade such as Gα-gustducin, transient receptor potential melastatin-like subtype 5 channel (TRPM5), and phospholipase Cβ2. Reverse transcription and polymerase chain reaction confirmed the expression of Gα-gustducin, TRPM5, and phospholipase Cβ2. Thymic "cholinergic chemosensory cells" were often in direct contact with medullary epithelial cells expressing the nicotinic acetylcholine receptor subunit α3. These cells have recently been identified as terminally differentiated epithelial cells (Hassall's corpuscle-like structures in mice). Contacts with nerve fibers (identified by PGP9.5 and CGRP antibodies), however, were not observed. Our data identify, in the thymus, a previously unrecognized presumptive chemosensitive cell that probably utilizes acetylcholine for paracrine signaling. This cell might participate in intrathymic infection-sensing mechanisms.

FK506 attenuates thymic output in patients with myasthenia gravis

PubMed Central

Kuroda, Yukiko; Ueno, Shu-ichi; Matsui, Naoko; Kaji, Ryuji

2013-01-01

Introduction Myasthenia gravis (MG) is an antibody-mediated, T-cell-dependent autoimmune disease. The symptoms are caused by high-affinity IgG against the muscle acetylcholine receptor (AChR) at the neuromuscular junction. The production of these antibodies in B-cells depends on AChR-specific CD4+ T-cells and the thymus gland seems to play a significant role in the pathogenesis of MG. Altered thymic T-cell export seems to be associated with a pathological mechanism in myasthenia gravis. Tacrolimus (FK506) has recently been used to treat MG. Material and methods We examined the effects of tacrolimus on thymic T-cell export in patients with MG. Sixteen patients with nonthymomatous and/or thymectomized MG were treated with oral administrations of tacrolimus. To assess the effect of tacrolimus on the thymic output, we assayed the levels of T-cell receptor excision circle (TREC), a molecular marker of thymus emigrants. Results T-cell receptor excision circle was not significantly different from those in age-matched controls before tacrolimus therapy, but they were partially decreased 4 months after tacrolimus therapy. T-cell receptor excision circle levels were significantly decreased in the thymomatous group (p < 0.05), but not in the nonthymomatous group. Tacrolimus treatment significantly attenuated TREC levels in cultured CD4–CD8+ cells (p < 0.05), but total cell counts were not significantly changed. Conclusions These results indicate that TREC levels may become a marker of the curative effect of tacrolimus therapy for thymomatous MG, and that tacrolimus suppresses not only activating T-lymphocytes, but also naïve T-cells. PMID:24482655

Clinical application of SPECT-CT with 99mTc-Tektrotyd in bronchial and thymic neuroendocrine tumors (NETs).

PubMed

Sergieva, Sonya; Robev, Bozhil; Dimcheva, Milena; Fakirova, Albena; Hristoskova, Radka

2016-01-01

Neuroendocrine tumors (NETs) of the thorax including bronchial and thymic tumors belong to foregut NETs. Limited loco-regional thoracic NETs can be resected with surgery, but in extensive metastatic disease the treatment is mainly palliative. A high incidence and density of somatostatin receptors (SSTR2, SSTR3, and SSTR5) are found in thoracic NETs. The purpose of this study was to evaluate the role of SPECT-CT somatostatin receptor scintigraphy (SRS) with 99mTc-Tektrotyd for imaging, staging and follow up of patients with bronchial and thymic neuroendocrine tumors. Forty-one patients with thoracic tumors with neuroendocrine differentiation were studied. Sixty-eight examinations including SPECT-CT studies of the neck and chest and/or abdomen and pelvis were carried out 2-4 hrs. post i.v. administration of aver-age 740 MBq activity dose of 99mTc-EDDA/HYNIC-TOC (Tektrotyd, Polatom). In all 41 investigated patients we obtained 81.25% (13/16), 88% (22/25) and 85.36% (35/41) of sensitivity, specificity and accuracy of this diagnostic approach, respectively. Somatostatin-receptor scintigraphy correctly identified all primary NETs located in the lungs and thymus. SPECT-CT studies with 99mTc-EDDA/HYNIC-TOC resulted in exact pre-surgical and pre-treatment N/M staging of bronchial and thymic NETs, except 2 cases with multiple hepatic metastases and 1 with massive suprarenal metastasis. It can be concluded that SPECT-CT with 99mTc-EDDA/HYNIC-TOC is a valuable tool for staging and follow-up of patients with thoracic NETs.

Are the Negative Effects of Divorce on Well-Being Dependent on Marital Quality?

ERIC Educational Resources Information Center

Kalmijn, Matthijs; Monden, Christiaan W. S.

2006-01-01

We test the so-called escape hypothesis, which argues that for people from a poor marriage, a divorce has a less negative or even a positive effect on well-being. In an analysis of two waves of the National Survey of Families and Households (N = 4,526), we find only limited evidence. When people divorce from a dissatisfactory or unfair marriage,…

MHC drives TCR repertoire shaping, but not maturation, in recent thymic emigrants.

PubMed

Houston, Evan G; Fink, Pamela J

2009-12-01

After developing in the thymus, recent thymic emigrants (RTEs) enter the lymphoid periphery and undergo a maturation process as they transition into the mature naive (MN) T cell compartment. This maturation presumably shapes RTEs into a pool of T cells best fit to function robustly in the periphery without causing autoimmunity; however, the mechanism and consequences of this maturation process remain unknown. Using a transgenic mouse system that specifically labels RTEs, we tested the influence of MHC molecules, key drivers of intrathymic T cell selection and naive peripheral T cell homeostasis, in shaping the RTE pool in the lymphoid periphery. We found that the TCRs expressed by RTEs are skewed to longer CDR3 regions compared with those of MN T cells, suggesting that MHC does streamline the TCR repertoire of T cells as they transition from the RTE to the MN T cell stage. This conclusion is borne out in studies in which the representation of individual TCRs was followed as a function of time since thymic egress. Surprisingly, we found that MHC is dispensable for the phenotypic and functional maturation of RTEs.

5-Lipoxygenase gene expression in the thymus.

PubMed

Hostein, I; Dorion-Bonnet, F; Bloch, B; Vaillier, D; Juzan, M; Gualde, N

1992-09-01

Eicosanoids are arachidonic acid metabolites issued both the cyclooxygenase and the lipoxygenase pathways. Many of these products were reported to modulate the immune response. Since most of eicosanoids have a short half life they are considered as local immunomodulators. Interactions between eicosanoids and thymocytes appear to be complex within the thymus. It was reported that cyclooxegenase derivatives of arachidonic acid are produced in this primary lymphoid organ mostly by cells of the thymic microenvironment. On the other hand it is not yet clearly established (1) what is the location of the lipoxygenase-positive cells within the gland and (2) what is the ratio of cells producing lipoxygenase metabolites of arachidonic acid when compared to the whole thymocyte population. Using two oligonucleotides complementary to the rat 5-lipoxygenase mRNA we demonstrated (by both hybridization on Northern blots and in situ hybridization) the expression of the 5-lipoxygenase gene in the thymus. 5-lipoxygenase positive cells appear to be associated in "clusters" and are mostly located in the thymic cortex. It is likely that they belong to the thymic microenvironment.

An evaluation of two differential reinforcement procedures with escape extinction to treat food refusal.

PubMed

Patel, Meeta R; Piazza, Cathleen C; Martinez, Cheryl J; Volkert, Valerie M; Christine, M Santana

2002-01-01

Consumption of solids and liquids occurs as a chain of behaviors that may include accepting, swallowing, and retaining the food or drink. In the current investigation, we evaluated the relative effectiveness of differential reinforcement of the first behavior in the chain (acceptance) versus differential reinforcement for the terminal behavior in the chain (mouth clean). Three children who had been diagnosed with a feeding disorder participated. Acceptance remained at zero when differential reinforcement contingencies were implemented for acceptance or mouth clean. Acceptance and mouth clean increased for all 3 participants once escape extinction was added to the differential reinforcement procedures, independent of whether reinforcement was provided for acceptance or for mouth clean. Maintenance was observed in 2 children when escape extinction was removed from the treatment package. The mechanism by which consumption increased is discussed in relation to positive and negative reinforcement contingencies.

huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-05-25

Adult B Acute Lymphoblastic Leukemia; BCL2 Gene Rearrangement; BCL6 Gene Rearrangement; CD19 Positive; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; MYC Gene Rearrangement; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Adult Acute Lymphoblastic Leukemia; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

Primary adenocarcinoma of the thymus: an immunohistochemical and molecular study with review of the literature.

PubMed

Maghbool, Maryam; Ramzi, Mani; Nagel, Inga; Bejarano, Pablo; Siebert, Reiner; Saeedzadeh, Abolfazl; Daneshbod, Yahya

2013-05-31

Primary adenocarcinoma of thymus is extremely rare. This is a case of primary adenocarcinoma with intestinal differentiation and focal mucin production in the thymus. Thymic cyst was associated with this tumor. Intestinal differentiation was confirmed by immunohistochemical stain with positivity for CDX-2, CK20, villin, MOC31 and focal positivity of CK7. Array comperative genomic hybridization (CGH) analysis showed a complex pattern of chromosomal imbalances including homozygous deletion at the HLA locus in chromosomal region 6p21.32. This rare tumor shows a similar genetic aberration with other studied thymic epithelial tumors.

Cutting edge: Contact with secondary lymphoid organs drives postthymic T cell maturation.

PubMed

Houston, Evan G; Nechanitzky, Robert; Fink, Pamela J

2008-10-15

T cell development, originally thought to be completed in the thymus, has recently been shown to continue for several weeks in the lymphoid periphery. The forces that drive this peripheral maturation are unclear. The use of mice transgenic for GFP driven by the RAG2 promoter has enabled the ready identification and analysis of recent thymic emigrants. Here, we show that recent thymic emigrant maturation is a progressive process and is promoted by T cell exit from the thymus. Further, we show that this maturation occurs within secondary lymphoid organs and does not require extensive lymphocyte recirculation.

CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Patients With Recurrent or Refractory CD19 Positive Diffuse Large B-Cell Lymphoma or B Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2018-01-25

B Acute Lymphoblastic Leukemia; CD19 Positive; Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma of the Elderly; Minimal Residual Disease; Philadelphia Chromosome Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

Mediastinal pathology and the contributions of Dr. Juan Rosai.

PubMed

Wick, Mark R

2016-09-01

Dr. Juan Rosai is one of the most prolific contributors to the literature on mediastinal pathology, and he has added steadily to that body of work over a 50-year period. Rosai has written several landmark articles in this topical area, including articles on thymic epithelial lesions, mediastinal neuroendocrine tumors, mediastinal lymphoma and other hematopoietic lesions, thymolipoma, thymoliposarcoma, mediastinal solitary fibrous tumor, intrathymic langerhans-cell histiocytosis, mediastinal germ cell neoplasms, and multilocular thymic cyst. This review recounts his role as one of the principal figures in the surgical pathology of mediastinal diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Thymic pathological examination of non-thymomatous myasthenia gravis patients: A pilot study for prediction of outcome

PubMed Central

Peimani, Zeinab; Banihashemi, Mohammad Amin; Namazi, Niloofar; Monabati, Ahmad; Mojallal, Mehra; Borhani-Haghighi, Afshin

2014-01-01

Background Myasthenia gravis (MG) is an autoimmune disorder characterized by weakness and fatigability of skeletal muscles. The aim of this study was to determine if pathological characteristics in non-thymomatous patients of MG would correlate with prognosis in a three year follow up. Methods Patients who had had their thymectomy at least three years prior to the study were selected from three hospitals and were followed for 3 years. Prognosis was assessed via a devised prognostic scoring system. A pathological exam of the specimen from the thymus was done using the following immunohistochemical markers: Bcl2, CD 3, CD 4, CD 5, CD 7, CD 10, CD 20cy, CD 23, CD 43, and Ki67. Results Fifteen patients fulfilled the inclusion criteria and had a complete follow-up. This included 3 males and 12 females with a mean age of 36.6 years at the start of the study. The dominant cell population was T lymphocytes. All T cells expressed CD 3, CD 43, CD 5, and Bcl-2. In 2 patients, CD 10 marker was positive in T cells. B cells were negative for activation marker CD 23, except for germinal center dendritic cells. Due to the limited number of patients in the study, the power of the study would not allow for an analysis to assess correlation between histopathological data and prognosis. Conclusion This pilot study was an attempt to discover any prognostic indices from the histopathological examination of the resected thymic tissue in the patients with myasthenia gravis. PMID:24800046

Further examination of factors that influence preference for positive versus negative reinforcement.

PubMed

Kodak, Tiffany; Lerman, Dorothea C; Volkert, Valerie M; Trosclair, Nicole

2007-01-01

Factors that influence choice between qualitatively different reinforcers (e.g., a food item or a break from work) are important to consider when arranging treatments for problem behavior. Previous findings indicate that children who engage in problem behavior maintained by escape from demands may choose a food item over the functional reinforcer during treatment (DeLeon, Neidert, Anders, & Rodriguez-Catter, 2001; Lalli et al., 1999). However, a number of variables may influence choice between concurrently available forms of reinforcement. An analogue for treatment situations in which positive reinforcement for compliance is in direct competition with negative reinforcement for problem behavior was used in the current study to evaluate several variables that may influence choice. Participants were 5 children who had been diagnosed with developmental disabilities and who engaged in problem behavior maintained by escape from demands. In the first phase, the effects of task preference and schedule of reinforcement on choice between a 30-s break and a high-preference food item were evaluated. The food item was preferred over the break, regardless of the preference level of the task or the reinforcement schedule, for all but 1 participant. In the second phase, the quality of the break was manipulated by combining escape with toys, attention, or both. Only 1 participant showed preference for the enriched break. In the third phase, choice of a medium- or low-preference food item versus the enriched break was evaluated. Three of 4 participants showed preference for the break over the less preferred food item. Results extend previous research by identifying some of the conditions under which individuals who engage in escape-maintained behavior will prefer a food reinforcer over the functional one.

Further Examination of Factors that Influence Preference for Positive Versus Negative Reinforcement

PubMed Central

Kodak, Tiffany; Lerman, Dorothea C; Volkert, Valerie M; Trosclair, Nicole

2007-01-01

Factors that influence choice between qualitatively different reinforcers (e.g., a food item or a break from work) are important to consider when arranging treatments for problem behavior. Previous findings indicate that children who engage in problem behavior maintained by escape from demands may choose a food item over the functional reinforcer during treatment (DeLeon, Neidert, Anders, & Rodriguez-Catter, 2001; Lalli et al., 1999). However, a number of variables may influence choice between concurrently available forms of reinforcement. An analogue for treatment situations in which positive reinforcement for compliance is in direct competition with negative reinforcement for problem behavior was used in the current study to evaluate several variables that may influence choice. Participants were 5 children who had been diagnosed with developmental disabilities and who engaged in problem behavior maintained by escape from demands. In the first phase, the effects of task preference and schedule of reinforcement on choice between a 30-s break and a high-preference food item were evaluated. The food item was preferred over the break, regardless of the preference level of the task or the reinforcement schedule, for all but 1 participant. In the second phase, the quality of the break was manipulated by combining escape with toys, attention, or both. Only 1 participant showed preference for the enriched break. In the third phase, choice of a medium- or low-preference food item versus the enriched break was evaluated. Three of 4 participants showed preference for the break over the less preferred food item. Results extend previous research by identifying some of the conditions under which individuals who engage in escape-maintained behavior will prefer a food reinforcer over the functional one. PMID:17471792

Emerging strategies to boost thymic function

PubMed Central

Holländer, Georg A.; Krenger, Werner; Blazar, Bruce R.

2011-01-01

The thymus constitutes the primary lymphoid organ for the generation of T cells. Its function is particularly susceptible to various negative influences ranging from age-related involution to atrophy as a consequence of malnutrition, infection or harmful iatrogenic influences such as chemotherapy and radiation. The loss of regular thymus function significantly increases the risk for infections and cancer because of a restricted capacity for immune surveillance. In recent years, thymus-stimulatory, -regenerative and -protective strategies have been developed to enhance and repair thymus function in the elderly and in individuals undergoing hematopoietic stem cell transplantation. These strategies include the use of sex steroid ablation, the administration of growth and differentiation factors, the inhibition of p53, and the transfer of T cell progenitors to alleviate the effects of thymus dysfunction and consequent T cell deficiency. PMID:20447867

Escape driven by alpha-stable white noises.

PubMed

Dybiec, B; Gudowska-Nowak, E; Hänggi, P

2007-02-01

We explore the archetype problem of an escape dynamics occurring in a symmetric double well potential when the Brownian particle is driven by white Lévy noise in a dynamical regime where inertial effects can safely be neglected. The behavior of escaping trajectories from one well to another is investigated by pointing to the special character that underpins the noise-induced discontinuity which is caused by the generalized Brownian paths that jump beyond the barrier location without actually hitting it. This fact implies that the boundary conditions for the mean first passage time (MFPT) are no longer determined by the well-known local boundary conditions that characterize the case with normal diffusion. By numerically implementing properly the set up boundary conditions, we investigate the survival probability and the average escape time as a function of the corresponding Lévy white noise parameters. Depending on the value of the skewness beta of the Lévy noise, the escape can either become enhanced or suppressed: a negative asymmetry parameter beta typically yields a decrease for the escape rate while the rate itself depicts a non-monotonic behavior as a function of the stability index alpha that characterizes the jump length distribution of Lévy noise, exhibiting a marked discontinuity at alpha=1. We find that the typical factor of 2 that characterizes for normal diffusion the ratio between the MFPT for well-bottom-to-well-bottom and well-bottom-to-barrier-top no longer holds true. For sufficiently high barriers the survival probabilities assume an exponential behavior versus time. Distinct non-exponential deviations occur, however, for low barrier heights.

How nonuniform contact profiles of T cell receptors modulate thymic selection outcomes

NASA Astrophysics Data System (ADS)

Chen, Hanrong; Chakraborty, Arup K.; Kardar, Mehran

2018-03-01

T cell receptors (TCRs) bind foreign or self-peptides attached to major histocompatibility complex (MHC) molecules, and the strength of this interaction determines T cell activation. Optimizing the ability of T cells to recognize a diversity of foreign peptides yet be tolerant of self-peptides is crucial for the adaptive immune system to properly function. This is achieved by selection of T cells in the thymus, where immature T cells expressing unique, stochastically generated TCRs interact with a large number of self-peptide-MHC; if a TCR does not bind strongly enough to any self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T cell dies. Past theoretical work cast thymic selection as an extreme value problem and characterized the statistical enrichment or depletion of amino acids in the postselection TCR repertoire, showing how T cells are selected to be able to specifically recognize peptides derived from diverse pathogens yet have limited self-reactivity. Here, we investigate how the diversity of the postselection TCR repertoire is modified when TCRs make nonuniform contacts with peptide-MHC. Specifically, we were motivated by recent experiments showing that amino acids at certain positions of a TCR sequence have large effects on thymic selection outcomes, and crystal structure data that reveal a nonuniform contact profile between a TCR and its peptide-MHC ligand. Using a representative TCR contact profile as an illustration, we show via simulations that the statistical enrichment or depletion of amino acids now varies by position according to the contact profile, and, importantly, it depends on the implementation of nonuniform contacts during thymic selection. We explain these nontrivial results analytically. Our study has implications for understanding the selection forces that shape the functionality of the postselection TCR repertoire.

Critical role for the chemokine receptor CXCR6 in homeostasis and activation of CD1d-restricted NKT cells.

PubMed

Germanov, Elitza; Veinotte, Linnea; Cullen, Robyn; Chamberlain, Erin; Butcher, Eugene C; Johnston, Brent

2008-07-01

NK T (NKT) cells play important roles in the regulation of diverse immune responses. However, little is known about the mechanisms that regulate homeostasis and activation of these cells. Thymic NKT cells up-regulated the chemokine receptor CXCR6 following positive selection and migrated toward CXCL16 in vitro. However, CXCR6 was not essential for thymic development or maturation. In contrast, liver and lung NKT cells were depleted in CXCR6+/- and CXCR6-/- mice. The reduction in liver and lung NKT cells coincided with an increase in bone marrow NKT cells, suggesting a redistribution of NKT cells in CXCR6-/- animals. In wild-type mice, CXCL16 neutralization reduced accumulation of mature NK1.1+, but not immature NK1.1- NKT cell recent thymic emigrants in the liver. Given that thymic NKT cells are preferentially exported as NK1.1- cells, this suggests an additional role for CXCR6/CXCL16 in maturation or survival of immature liver NKT cells. CXCL16 blockade did not deplete resident NK1.1+ NKT cells, indicating that CXCR6/CXCL16 are not required to retain mature NKT cells in the liver. Cytokine production by liver and spleen NKT cells was impaired in CXCR6-/- mice following in vivo stimulation with alpha-galactosylceramide, implicating a novel role for CXCR6 in NKT cell activation. Reduced IFN-gamma production was not due to an intrinsic defect as production was normal following PMA and ionomycin stimulation. Preformed transcripts for IL-4, but not IFN-gamma, were reduced in CXCR6-/- liver NKT cells. These data identify critical roles for CXCR6/CXCL16 in NKT cell activation and the regulation of NKT cell homeostasis.

Emv30null NOD-scid mice. An improved host for adoptive transfer of autoimmune diabetes and growth of human lymphohematopoietic cells.

PubMed

Serreze, D V; Leiter, E H; Hanson, M S; Christianson, S W; Shultz, L D; Hesselton, R M; Greiner, D L

1995-12-01

When used as hosts in passive transfer experiments, a stock of NOD/Lt mice congenic for the severe combined immunodeficiency (scid) mutation have provided great insight to the contributions of various T-cell populations in the pathogenesis of autoimmune insulin-dependent diabetes mellitus (IDDM). Moreover, NOD-scid mice support higher levels of human lymphohematopoietic cell growth than the C.B-17-scid strain in which the mutation originated. However, the ability to perform long-term lymphohematopoietic repopulation studies in the NOD-scid stock has been limited by the fact that most of these mice develop lethal thymic lymphomas beginning at 20 weeks of age. These thymic lymphomas are characterized by activation and subsequent genomic reintegrations of Emv30, an endogenous murine ecotropic retrovirus unique to the NOD genome. To test the role of this endogenous retrovirus in thymomagenesis, we produced a stock of Emv30null NOD-scid mice by congenic replacement of the proximal end of chromosome 11 with genetic material derived from the closely related NOR/Lt strain. Thymic lymphomas still initiate in Emv30null NOD-scid females, but their rate of progression is significantly retarded since the frequency of tumors weighing between 170 and 910 mg at 25 weeks of age was reduced to 20.8% vs. 76.2% in Emv30% segregants. The thymic lymphomas that did develop in Emv30null NOD-scid mice were not characterized by a compensatory increase in mink cell focus-forming proviral integrations, which initiate thymomagenesis in other susceptible mouse strains. Significantly, the ability of standard NOD T-cells to transfer IDDM to the Emv30null NOD-scid stock was not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

Rationale and early outcomes for the management of thymoma with proton therapy.

PubMed

Zhu, He J; Hoppe, Bradford S; Flampouri, Stella; Louis, Debbie; Pirris, John; Nichols, R Charles; Henderson, Randal H; Mercado, Catherine E

2018-04-01

Radiotherapy for thymic malignancies is technically challenging due to their close proximity to the heart, lungs, esophagus, and breasts, raising concerns about significant acute and late toxicities from conventional photon radiotherapy. Proton therapy (PT) may reduce the radiation dose to these vital organs, leading to less toxicity. We reviewed the dosimetry and outcomes among patients treated with PT for thymic malignancies at our institution. From January 2008 to March 2017, six patients with de novo Masaoka stages II-III thymic malignancies were treated with PT on an IRB-approved outcomes tracking protocol. Patients were evaluated weekly during treatment, then every 3 months for 2 years, then every 6 months for 3 more years, and then annually for CTCAE vs. four toxicities and disease recurrence. Comparison intensity-modulated radiotherapy (IMRT) plans were developed for each patient. Mean doses to the heart, esophagus, bilateral breasts, lungs, and V20 of bilateral lungs were evaluated for the two treatment plans. At last follow-up (median follow-up, 2.6 years), there were two patients with recurrences, including metastatic disease in the patient treated definitively with chemotherapy and PT without surgery and a local-regional recurrence in the lung outside the proton field in one of the post-operative cases. No patients with de novo disease experienced grade ≥3 toxicities after PT. The mean dose to the heart, lung, and esophagus was reduced on average by 36.5%, 33.5%, and 60%, respectively, using PT compared with IMRT (P<0.05 for each dose parameter). PT achieved superior dose sparing to the heart, lung, and esophagus compared to IMRT for thymic malignancies. Patients treated with PT had few radiation-induced toxicities and similar survival compared to historic proton data.

Interleukin-1 stimulates zinc uptake by human thymic epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coto, J.A.; Hadden, J.W.

1991-03-15

Thymic epithelial cells (TEC) are known to secrete peptides which influence the differentiation and maturation of T-lymphocytes. These peptides include the thymic hormones thymulin, thymosin-{alpha}1, and thymopoietin. The biological activity of thymulin is dependent on the presence of zinc in an equimolar ratio. The authors have shown that both interleukin-1{alpha}(IL-1{alpha}) and interleukin-1{beta}(IL-1{beta}), which stimulate proliferation of TEC, stimulate the uptake of Zn-65 in-vitro independent of this proliferation. Mitomycin-C was used to inhibit the proliferation of TEC. Two other stimulators of proliferation of TEC, bovine pituitary extract (BPE) and epidermal growth factor (EGF), did not stimulate zinc uptake by the TECmore » independent of proliferation. They have also shown, utilizing in-situ hybridization, that IL-1 and zinc induce metallothionein(MT) mRNA expression in human thymic epithelial cells. The exact role of metallothionein is not clear, but it is thought to be involved in regulation of trace metal metabolism, especially in maintenance of zinc homeostasis. Their current hypothesis is that IL-1 stimulates uptake of zinc into the TEC, followed by its complexing with metallothionein. Zinc is then thought to be transferred from metallothionein to thymulin. Immunostaining, utilizing an antithymulin antibody and a fluoresceinated goat anti-rabbit second antibody, confirms the presence of thymulin in TEC and its dependence on zinc. Upon stimulation, thymulin is then secreted. Known stimulants for thymulin include progesterone, dexamethasone, estradiol, testosterone, and prolactin. None of these secretagogues increase zinc uptake, suggesting the priming of the zinc-thymulin complex is unrelated to the regulation of its secretion.« less

Primary adenocarcinoma of the thymus: an immunohistochemical and molecular study with review of the literature

PubMed Central

2013-01-01

Background Primary adenocarcinoma of thymus is extremely rare. Case presentation This is a case of primary adenocarcinoma with intestinal differentiation and focal mucin production in the thymus. Thymic cyst was associated with this tumor. Intestinal differentiation was confirmed by immunohistochemical stain with positivity for CDX-2, CK20, villin, MOC31 and focal positivity of CK7. Array comperative genomic hybridization (CGH) analysis showed a complex pattern of chromosomal imbalances including homozygous deletion at the HLA locus in chromosomal region 6p21.32. Conclusion This rare tumor shows a similar genetic aberration with other studied thymic epithelial tumors. PMID:23725376

Diffuse Alveolar Hemorrhage Induced by Irinotecan for a Patient with Metastatic Thymic Carcinoma: A Case Report and Literature Review.

PubMed

Kim, Sung-Ho; Minami, Seigo; Ogata, Yoshitaka; Yamamoto, Suguru; Komuta, Kiyoshi

2017-01-01

We herein report a 73-year-old Japanese woman with metastatic thymic carcinoma who developed diffuse alveolar hemorrhage (DAH) during irinotecan chemotherapy. She presented with a mild fever and exertional dyspnea after the second cycle of weekly irinotecan monotherapy. Chest images showed diffuse ground-glass opacities. The diagnosis of DAH was based on the findings of the bronchoalveolar lavage fluid, which was bloody and contained hemosiderin-laden macrophages. The discontinuation of irinotecan and introduction of oral prednisolone improved her symptoms and chest abnormal shadows. This is the first case of DAH caused by irinotecan.

Prevention of recrudescent malaria in nude mice by thymic grafting or by treatment with hyperimmune serum.

PubMed Central

Roberts, D W; Rank, R G; Weidanz, W P; Finerty, J F

1977-01-01

Nude mice died when infected with the normally avirulent malarial parasite Plasmodium berghei yoelii. Furthermore, malaria recrudesced in Nu/Nu mice after the termination of acute disease by treatment with clindamycin. Recrudescence was not observed in Nu/Nu mice that had been grafted with thymic tissue or treated with hyperimmune serum. Mice mad B cell deficient by treatment with anti-mu-chain serum also died when infected with P. berghei yoelii. The data suggest that a crucial role of the thymus in preventing recrudescent malaria in this model system is to provide a helper function in the production of protective antibody. PMID:330396

A case of thymic Langerhans cell histiocytosis with diabetes insipidus as the first presentation.

PubMed

Chen, Xiaoyan; Huang, Xiaochun; Qiu, Yuan; Chen, Hanzhang; Fu, Yingyu; Li, Xinchun

2013-03-01

Langerhans cell histiocytosis (LCH) is an idiopathic group of reactive proliferative diseases linked to aberrant immunity, pathologically characterized by clonal proliferation of Langerhans cells. LCH rarely involves the thymus. We report a case of thymic LCH with diabetes insipidus as the first presentation, without evidence of myasthenia gravis and without evidenced involvement of the skin, liver, spleen, bones, lungs and superficial lymph nodes. This present case may have important clinical implications. In screening for LCH lesions, attention should be attached to rarely involved sites in addition to commonly involved organs. Follow-up and imageological examination are very important to a final diagnosis.

Tumor-induced thymic atrophy: alteration in interferons and Jak/Stats signaling pathways.

PubMed

Carrio, Roberto; Torroella-Kouri, Marta; Iragavarapu-Charyulu, Vijaya; Lopez, Diana M

2011-02-01

The thymus is the major site of T cell differentiation and a key organ of the immune system. Thym atrophy has been observed in several model systems including aging, and tumor development. Previous results from our laboratory have reported that the thymic atrophy seen in mammary tumor bearers is associated with a severe depletion of CD4+CD8+ double positive immature cells and changes in the levels of cytokines expressed in the thymus microenvironment. Cytokines regulate numerous aspects of hematopoiesis via activation of the Jak/Stat pathways. In the present study we have used our mammary tumor model to investigate whether changes in the levels of cytokines in the thymus could affect the normal expression of the aforementioned pathways. RNA and protein analysis revealed an overexpression of the different members of interferons, a downregulation of most of the Jak/Stat pathways, and an increased expression of several suppressors of cytokine signaling (SOSC) in the thymuses of tumor bearers. Together, our data suggest that the impaired Jak/Stat signaling pathways observed in the whole thymus of tumor-bearing mice could be contributing to the abnormal T cell development and apoptosis observed during the tumor-induced thymic atrophy.

Transplantation of autoimmune regulator-encoding bone marrow cells delays the onset of experimental autoimmune encephalomyelitis.

PubMed

Ko, Hyun-Ja; Kinkel, Sarah A; Hubert, François-Xavier; Nasa, Zeyad; Chan, James; Siatskas, Christopher; Hirubalan, Premila; Toh, Ban-Hock; Scott, Hamish S; Alderuccio, Frank

2010-12-01

The autoimmune regulator (AIRE) promotes "promiscuous" expression of tissue-restricted antigens (TRA) in thymic medullary epithelial cells to facilitate thymic deletion of autoreactive T-cells. Here, we show that AIRE-deficient mice showed an earlier development of myelin oligonucleotide glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). To determine the outcome of ectopic Aire expression, we used a retroviral transduction system to over-express Aire in vitro, in cell lines and in bone marrow (BM). In the cell lines that included those of thymic medullary and dendritic cell origin, ectopically expressed Aire variably promoted expression of TRA including Mog and Ins2 (proII) autoantigens associated, respectively, with the autoimmune diseases multiple sclerosis and type 1 diabetes. BM chimeras generated from BM transduced with a retrovirus encoding Aire displayed elevated levels of Mog and Ins2 expression in thymus and spleen. Following induction of EAE with MOG(35-55), transplanted mice displayed significant delay in the onset of EAE compared with control mice. To our knowledge, this is the first example showing that in vivo ectopic expression of AIRE can modulate TRA expression and alter autoimmune disease development. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator

PubMed Central

Takizawa, Nobukazu; Miyauchi, Maki; Yanai, Hiromi; Tateishi, Ryosuke; Shinzawa, Miho; Yoshinaga, Riko; Kurihara, Masaaki; Yasuda, Hisataka; Sakamoto, Reiko; Yoshida, Nobuaki

2016-01-01

Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire+ mTECs) is unclear. Here, we describe novel embryonic precursors of Aire+ mTECs. We found the candidate precursors of Aire+ mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire+ mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire+ mTECs and efficiently suppressed the onset of autoimmunity induced by Aire+ mTEC deficiency. Mechanistically, pMECs differentiated into Aire+ mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire+ mTECs. PMID:27401343

Recent thymic emigrants and mature naïve T cells exhibit differential DNA methylation at key cytokine loci

PubMed Central

Berkley, Amy M.; Hendricks, Deborah W.; Simmons, Kalynn B.; Fink, Pamela J.

2013-01-01

Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery, and exhibit phenotypic and functional characteristics distinct from those of their more mature counterparts in the naïve peripheral T cell pool. We show here that the Il2 and Il4 promoter regions of naïve CD4+ RTEs are characterized by site-specific hypermethylation compared to those of both mature naïve (MN) T cells and the thymocyte precursors of RTEs. Thus, RTEs do not merely occupy a midpoint between the thymus and the mature T cell pool, but represent a distinct transitional T cell population. Furthermore, RTEs and MN T cells exhibit distinct CpG DNA methylation patterns both before and after activation. Compared to MN T cells, RTEs express higher levels of several enzymes that modify DNA methylation, and inhibiting methylation during culture allows RTEs to reach MN T cell levels of cytokine production. Collectively, these data suggest that the functional differences that distinguish RTEs from MN T cells are influenced by epigenetic mechanisms and provide clues to a mechanistic basis for post-thymic maturation. PMID:23686491

Derivation of Thymic Lymphoma T-cell Lines from Atm-/- and p53-/- Mice

PubMed Central

Jinadasa, Rasika; Balmus, Gabriel; Gerwitz, Lee; Roden, Jamie; Weiss, Robert; Duhamel, Gerald

2011-01-01

Established cell lines are a critical research tool that can reduce the use of laboratory animals in research. Certain strains of genetically modified mice, such as Atm-/- and p53-/- consistently develop thymic lymphoma early in life 1,2, and thus, can serve as a reliable source for derivation of murine T-cell lines. Here we present a detailed protocol for the development of established murine thymic lymphoma T-cell lines without the need to add interleukins as described in previous protocols 1,3. Tumors were harvested from mice aged three to six months, at the earliest indication of visible tumors based on the observation of hunched posture, labored breathing, poor grooming and wasting in a susceptible strain 1,4. We have successfully established several T-cell lines using this protocol and inbred strains ofAtm-/- [FVB/N-Atmtm1Led/J] 2 and p53-/- [129/S6-Trp53tm1Tyj/J] 5 mice. We further demonstrate that more than 90% of the established T-cell population expresses CD3, CD4 and CD8. Consistent with stably established cell lines, the T-cells generated by using the present protocol have been passaged for over a year. PMID:21490582

Drop or fly? Negative genetic correlation between death-feigning intensity and flying ability as alternative anti-predator strategies

PubMed Central

Ohno, Tatsunori; Miyatake, Takahisa

2006-01-01

A prey animal may have the alternative of flying away or feigning death when it encounters predators. These alternatives have a genetic base as anti-predator strategies in the adzuki bean beetle, Callosobruchus chinensis. A negative genetic correlation between death-feigning intensity and flying ability was found in C. chinensis, i.e. lower flying ability is genetically connected to escaping by dropping from a perch and then feigning death, whereas higher flying ability does not correspond to death-feigning behaviour. Two bidirectional artificial selections for death-feigning duration and flying ability were conducted independently in C. chinensis. The strains selected for shorter (longer) duration of death-feigning had higher (lower) flying ability, while the strains selected for lower (higher) flying ability showed longer (shorter) duration of death-feigning. When the two traits were compared in 21 populations of C. chinensis derived from different geographical regions, a significant negative correlation was found between death-feigning intensity and flying ability. Based on these results, the choice between alternative escaping behaviours in animals is discussed from two points of view: phenotypic plasticity, an individual with two tactics; and pleiotropic genetic correlation, different individuals with opposite strategies. PMID:17476776

Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles

USDA-ARS?s Scientific Manuscript database

A central challenge to the development of protein-based therapeutics is the inefficiency of delivery of protein cargo across the mammalian cell membrane, including escape from endosomes. Here we report that combining bioreducible lipid nanoparticles with negatively supercharged Cre recombinase or an...

Parental Flooding During Conflict: A Psychometric Evaluation of a New Scale

PubMed Central

Del Vecchio, Tamara; Lorber, Michael F.; Slep, Amy M. Smith; Malik, Jill; Heyman, Richard E.; Foran, Heather M.

2016-01-01

Parents who are overwhelmed by the intensity and aversive nature of child negative affect — those who are experiencing flooding — may be less likely to react effectively and instead may focus on escaping the aversive situation, disciplining either overly permissively or punitively to escape quickly from child negative affect. However, there are no validated self-report measures of the degree to which parents experience flooding, impeding the exploration of these relations. Thus, we created and evaluated the Parent Flooding scale (PFS), assessing the extent to which parents believe their children's negative affect during parent-child conflicts is unexpected, overwhelming and distressing. We studied its factorial validity, reliability, and concurrent validity in a community sample of 453 couples with 3- to 7-year-old children (51.9% girls) recruited via random digit dialing. Confirmatory factor analyses indicated a one-factor solution with excellent internal consistency. Test-retest stability over an average of 5.6 months was high. Concurrent validity was suggested by the associations of flooding with parents’ aggression toward their children, overreactive and lax discipline, parenting satisfaction, and parents’ anger, as well as with child externalizing behavior and negative affect. Incrementally concurrent validity analyses indicated that flooding was a unique predictor of mothers’ and fathers’ overreactive discipline and fathers’ parent-child aggression and lax discipline, over and above the contributions of parents’ anger and children's negative affect. The present results support the psychometric validity of the PFS. PMID:26909682

HIV-related thought avoidance, sexual risk, and alcohol use among men who have sex with men.

PubMed

Pérez, Ashley E; Wray, Tyler B; Celio, Mark A; Monti, Peter M

2018-07-01

HIV-related "cognitive escape" refers to a tendency to avoid thoughts associated with HIV, which may be particularly common among men who have sex with men (MSM) who are often inundated with HIV information, potentially to the point of fatigue. HIV-related cognitive escape is associated with increased sexual risk behaviors, such as condomless sex, and heavier alcohol use patterns. Other studies show that some MSM may use alcohol specifically to facilitate sex. These sexual motives for drinking (SMDs) could be one mechanism whereby cognitive escape leads to health risk behaviors. In this study, we tested models exploring whether cognitive escape was associated with markers of sex risk (condom use, number of sex partners) and alcohol use/problems, and examined whether SMDs mediated these associations. Heavy drinking, HIV-negative men (N = 196) aged ≥ 21 years who self-reported past year condomless anal sex with men completed assessments as part of a larger study. Results suggest that cognitive escape was associated with higher number of anal sex partners (incidence rate ratio [IRR] = 1.50, SE = 0.04, p < .001), decreased condom use (B = -0.30, SE = 0.14, p = .028), and increased alcohol-related problems (IRR = 1.28, SE = 0.07, p = .001) but not with drinking quantity. Sexual motives for drinking appeared to partially mediate the observed relationship between cognitive escape and alcohol-related problems, but other relationships did not show evidence of mediation. Findings suggest that those who tend to avoid HIV-related thoughts may be at increased risk for HIV and alcohol-related problems. Drinking to facilitate sex may partially account for the higher risk for alcohol-related problems conferred by cognitive escape. Alcohol interventions for MSM may be more effective if they address alcohol's role in coping with HIV threat and in facilitating sex under these circumstances.

A new insight into diffusional escape from a biased cylindrical trap

NASA Astrophysics Data System (ADS)

Berezhkovskii, Alexander M.; Dagdug, Leonardo; Bezrukov, Sergey M.

2017-09-01

Recent experiments with single biological nanopores, as well as single-molecule fluorescence spectroscopy and pulling studies of protein and nucleic acid folding raised a number of questions that stimulated theoretical and computational investigations of barrier crossing dynamics. The present paper addresses a closely related problem focusing on trajectories of Brownian particles that escape from a cylindrical trap in the presence of a force F parallel to the cylinder axis. To gain new insights into the escape dynamics, we analyze the "fine structure" of these trajectories. Specifically, we divide trajectories into two segments: a looping segment, when a particle unsuccessfully tries to escape returning to the trap bottom again and again, and a direct-transit segment, when it finally escapes moving without touching the bottom. Analytical expressions are derived for the Laplace transforms of the probability densities of the durations of the two segments. These expressions are used to find the mean looping and direct-transit times as functions of the biasing force F. It turns out that the force-dependences of the two mean times are qualitatively different. The mean looping time monotonically increases as F decreases, approaching exponential F-dependence at large negative forces pushing the particle towards the trap bottom. In contrast to this intuitively appealing behavior, the mean direct-transit time shows rather counterintuitive behavior: it decreases as the force magnitude, |F|, increases independently of whether the force pushes the particles to the trap bottom or to the exit from the trap, having a maximum at F = 0.

Depression is associated with sexual risk among men who have sex with men, but is mediated by cognitive escape and self-efficacy.

PubMed

Alvy, Lisa M; McKirnan, David J; Mansergh, Gordon; Koblin, Beryl; Colfax, Grant N; Flores, Stephen A; Hudson, Sharon

2011-08-01

Men who have sex with men (MSM) show high rates of HIV infection, and higher rates of depression than non-MSM. We examined the association between depression and sexual risk among "high risk" MSM. Evidence has been mixed regarding the link between depression and risky sex, although researchers have rarely considered the role of psychosocial vulnerabilities such as self-efficacy for sexual safety or "escape" coping styles. In a national sample (N = 1,540) of HIV-positive and HIV-negative MSM who reported unprotected sex and drug use with sex partners, we found evidence that depression is related to HIV transmission risk. Self-efficacy for sexual safety and cognitive escape mediated the link between depression and risk behavior, suggesting that psychosocial vulnerability plays an important role in the association of depression with sexual risk. These findings may help us construct more accurate theories regarding depression and sexual behavior, and may inform the design of sexual safety interventions.

Use of a latency-based demand assessment to identify potential demands for functional analyses.

PubMed

Call, Nathan A; Miller, Sarah J; Mintz, Joslyn Cynkus; Mevers, Joanna Lomas; Scheithauer, Mindy C; Eshelman, Julie E; Beavers, Gracie A

2016-12-01

Unlike potential tangible positive reinforcers, which are typically identified for inclusion in functional analyses empirically using preference assessments, demands are most often selected arbitrarily or based on caregiver report. The present study evaluated the use of a demand assessment with 12 participants who exhibited escape-maintained problem behavior. Participants were exposed to 10 demands, with aversiveness measured by average latency to the first instance of problem behavior. In subsequent functional analyses, results of a demand condition that included the demand with the shortest latency to problem behavior resulted in identification of an escape function for 11 of the participants. In contrast, a demand condition that included the demand with the longest latency resulted in identification of an escape function for only 5 participants. The implication of these findings is that for the remaining 7 participants, selection of the demand for the functional analysis without using the results of the demand assessment could have produced a false-negative finding. © 2016 Society for the Experimental Analysis of Behavior.

Siskiyou summit negative grade arrester bed for runaway trucks : final report.

DOT National Transportation Integrated Search

1986-01-01

Most escape ramps are designed to use gravity as the primary deceleration mechanism. These ramps provide an exit from the roadway to an adjacent hillside, ascending at grades of up to 40%. Loose gravel is often used on these ramps which, while aiding...

[Negative hallucination, self-onsciousness and ageing].

PubMed

Hazif-Thomas, C; Stephan, F; Walter, M; Thomas, P

2015-04-01

Negative hallucinations are characterized by a defect in perception of an object or a person, or a denial of the existence of their perception. Negative hallucinations create blank spaces, due to both an impossible representation and an incapability of investment in reality. They have a close relationship with Cotard's syndrome, delusional theme of organ denial observed in melancholic syndromes in the elderly. Phenomenological approach. The phenomenology of negative hallucinations provides quite an amount of information on the origin of the psychotic symptoms when one is rather old. The connections between hallucinations, mood disorders and negative symptoms are often difficult to live with for the nearest and dearest. Negative hallucinations require a strict approach to identify their expression that is crucial because a wide heterogeneity exists within the pathological pictures, as in Cotard's syndrome. Although the negative hallucination has an anti traumatic function in elderly people fighting against mental pain, it still represents a deficiency in symbolization. The prevalence of this symptom is without doubt underestimated, although its presence often underlines thymic suffering that is more striking. These hallucinatory symptoms have an important impact on the patients' daily life, and they appear to be prisoners of a suffering, which cannot be revealed. We propose in this article to review the clinical symptoms of negative hallucinations in the elderly and the way to manage them. The medicinal approaches are not always effective. A greater place must be given to what is in connection with the body, aiming at a strong impact and thus to offer non-pharmacological approaches, such as somatic ones, which can be either invasive (electroconvulsive therapy) or not (transcranial magnetic stimulation). Copyright © 2014. Published by Elsevier Masson SAS.

Thymus-dependent T cell tolerance of neuroendocrine functions: principles, reflections, and implications for tolerogenic/negative self-vaccination.

PubMed

Geenen, Vincent

2006-11-01

Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk of horror autotoxicus, the thymus appeared some 500 million years ago as a novel lymphoid structure able to prevent autoimmunity and to orchestrate self-tolerance as a cornerstone in the physiology of the immune system. Also, the thymus plays a prominent role in T cell education to neuroendocrine principles. Some self-antigens (oxytocin, neurotensin, insulin-like growth factor 2 [IGF-2]) have been selected to be predominantly expressed in thymic epithelium and to be presented to thymus T cells for educating them to tolerate other antigens related to them. In the insulin family, IGF2 is dominantly transcribed in cortical (c) and medullary (m) thymic epithelial cells (TECs), whereas the insulin gene (INS) is expressed at low level by only a few subsets of mTECs. Intrathymic transcription of both IGF2 and INS is under the control of the autoimmune regulator (Aire) gene. The highest concentrations of IGF-2 in the thymus explain why this peptide is much more tolerated than insulin, and why tolerance to IGF-2 is so difficult to break by active immunization. The high level of tolerance to IGF-2 is correlated to the development of a tolerogenic/regulatory profile when the sequence B11-25 of IGF-2 (homologous to the autoantigen insulin B9-23) is presented to DQ8+ type 1 diabetic patients. Since subcutaneous and oral insulin does not exert any tolerogenic properties, IGF-2 and other thymus self-antigens related to type 1 diabetes (T1D) should be preferred to insulin for the design of novel specific antigen-based preventive approaches against T1D.

Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance.

PubMed

Muthukumarana, Poorni A D S; Lyons, Gary E; Miura, Yuji; Thompson, Lorraine H; Watson, Tracy; Green, Colin J; Shurey, Sandra; Hess, Allan D; Rosengard, Bruce R; Metcalfe, Su M

2006-12-20

In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen. However, we did find an effect of axotrophin on Foxp3: in the axotrophin null mouse, thymic Foxp3 transcripts were reduced compared to axotrophin wildtype littermates. To test whether these findings in the mouse were of potential significance in man we measured transcript levels of axotrophin and LIF in peripheral blood cell samples collected for a recently published clinical study concerning haematopoietic stem cell recipients. In controls, human peripheral blood CD4+CD25+cells contained significantly more FOXP3 and axotrophin than CD4+CD25-cells. In bone marrow autograft recipients, where peripheral blood cell samples directly represent both the grafted tissue and the immune response, both FOXP3 and axotrophin negatively correlated with graft versus host disease (GVHD). These data suggest that (i) thymic Foxp3+T cell development is influenced by axotrophin; and (ii) clinical auto-GVHD inversely correlates with axotrophin transcript expression as has been previously reported for FOXP3.

MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice

PubMed Central

Wu, Limin; Li, Nainong; Zhang, Mingfeng; Xue, Sheng-Li; Cassady, Kaniel; Lin, Qing; Riggs, Arthur D.; Zeng, Defu

2015-01-01

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system with demyelination, axon damage, and paralysis. Induction of mixed chimerism with allogeneic donors has been shown to not cause graft-versus-host disease (GVHD) in animal models and humans. We have reported that induction of MHC-mismatched mixed chimerism can cure autoimmunity in autoimmune NOD mice, but this approach has not yet been tested in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). Here, we report that MHC-mismatched mixed chimerism with C57BL/6 (H-2b) donor in SJL/J (H-2s) EAE recipients eliminates clinical symptoms and prevents relapse. This cure is demonstrated by not only disappearance of clinical signs but also reversal of autoimmunity; elimination of infiltrating T, B, and macrophage cells in the spinal cord; and regeneration of myelin sheath. The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4+ T cells and significant increase in the percentage of Foxp3+ Treg among host-type CD4+ T cells in the spleen and lymph nodes. The latter is associated with a marked reduction of the percentage of host-type CD4+CD8+ thymocytes and an increase of Treg percentage among the CD4+CD8+ and CD4+CD8− thymocytes. Thymectomy leads to loss of prevention of EAE relapse by induction of mixed chimerism, although there is a dramatic expansion of host-type Treg cells in the lymph nodes. These results indicate that induction of MHC-mismatched mixed chimerism can restore thymic negative selection of autoreactive CD4+ T cells, augment production of Foxp3+ Treg, and cure EAE. PMID:26647186

Radiation of partially ionized atomic hydrogen

NASA Technical Reports Server (NTRS)

Soon, W. H.; Kunc, J. A.

1990-01-01

A nonlinear collisional-radiative model for determination of production of electrons, positive and negative ions, excited atoms, and spectral and continuum line intensities in stationary partially ionized atomic hydrogen is presented. Transport of radiation is included by coupling the rate equations for production of the electrons, ions, and excited atoms with the radiation escape factors, which are not constant but depend on plasma conditions. It is found that the contribution of the negative ion emission to the total continuum emission can be important. Comparison of the calculated total continuum emission coefficient, including the negative ion emission, is in good agreement with experimental results.

Emotional Responses to Self-Injury Imagery among Adults with Borderline Personality Disorder

ERIC Educational Resources Information Center

Welch, Stacy Shaw; Linehan, Marsha M.; Sylvers, Patrick; Chittams, Jesse; Rizvi, Shireen L.

2008-01-01

Nonsuicidal self-injury (NSSI) and suicide attempts (SAs) are especially prevalent in borderline personality disorder. One proposed mechanism for the maintenance of NSSI and SAs is escape conditioning, whereby immediate reductions in aversive emotional states negatively reinforce the behaviors. Psychophysiological and subjective indicators of…

The glycoconjugate sugar residues of the sessile and motile cells in the thymus of normal and cyclosporin-A-treated rats: lectin histochemistry.

PubMed

Gheri, G; Gheri Bryk, S; Riccardi, R; Sgambati, E; Cirri Borghi, M B

2002-01-01

It is well known that cell surface glycoconjugates play a determinant role in cellular recognition, cell-to-cell adhesion and serve as receptor molecules. T-lymphocytes are in strict contact with the thymic epithelial cells, which control their process of maturation and proliferation. On the other hand the normal maturation of the epithelial cells is believed to be induced by T-lymphocytes. For these reasons we have studied the glycoconjugates saccharidic moieties of the sessile and motile cells in the thymus of normal male albino Wistar rats and their changes following cyclosporin-A treatment, using a battery of seven HRP-lectins. Cytochemical controls were performed for specificity of lectin-sugar reaction. Some sections were pre-treated with neuraminidase prior to staining with HRP-lectins. Our results have demonstrated, in the control rats, a large amount and a variety of terminal and subterminal oligosaccharides within and/or on the epithelial thymic cells and in macrophages. After cyclosporin-A treatment, among the thymic epithelial cells, the subcapsular, paraseptal and perivascular cells showed the loss of some sugar residues, which characterized the same cells in the intact thymus. Some hypotheses are reported on the role played by the glycoconjugate sugar residues in control and cyclosporin-A treated rats.

Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation

PubMed Central

Gallegos, Alena M.; Bevan, Michael J.

2004-01-01

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs. PMID:15492126

How many TCR clonotypes does a body maintain?

PubMed Central

Lythe, Grant; Callard, Robin E.; Hoare, Rollo L.; Molina-París, Carmen

2016-01-01

We consider the lifetime of a T cell clonotype, the set of T cells with the same T cell receptor, from its thymic origin to its extinction in a multiclonal repertoire. Using published estimates of total cell numbers and thymic production rates, we calculate the mean number of cells per TCR clonotype, and the total number of clonotypes, in mice and humans. When there is little peripheral division, as in a mouse, the number of cells per clonotype is small and governed by the number of cells with identical TCR that exit the thymus. In humans, peripheral division is important and a clonotype may survive for decades, during which it expands to comprise many cells. We therefore devise and analyse a computational model of homeostasis of a multiclonal population. Each T cell in the model competes for self pMHC stimuli, cells of any one clonotype only recognising a small fraction of the many subsets of stimuli. A constant mean total number of cells is maintained by a balance between cell division and death, and a stable number of clonotypes by a balance between thymic production of new clonotypes and extinction of existing ones. The number of distinct clonotypes in a human body may be smaller than the total number of naive T cells by only one order of magnitude. PMID:26546971

MSA Mimic? Rare Occurrence of Anti-Hu Autonomic Failure and Thymoma in a Patient with Parkinsonism: Case Report and Literature Review

PubMed Central

Ricigliano, Vito A. G.; Fossati, Barbara; Saraceno, Lorenzo; Cavalli, Michele; Bazzigaluppi, Elena; Meola, Giovanni

2018-01-01

Thymoma is a tumor originating from thymic gland, frequently manifesting with paraneoplastic neurological disorders. Its association with paraneoplastic dysautonomia is relatively uncommon. Here, we describe the challenging case of a 71 year-old female who developed subacute autonomic failure with digestive pseudo-obstruction, dysphagia, urinary tract dysfunction and orthostatic hypotension complicating an underlying extrapyramidal syndrome that had started 3 months before hospital admission. Autonomic symptoms had 2-month course and acutely worsened just before and during hospitalization. Combination of severe dysautonomia and parkinsonism mimicked rapidly progressing multiple system atrophy. However, diagnostic exams showed thymic tumor with positive anti-Hu antibodies on both serum and cerebrospinal fluid. Complete response of dysautonomia to immunoglobulins followed by thymectomy confirmed the diagnosis of anti-Hu-related paraneoplastic neurological syndrome. With regards to extrapyramidal symptoms, despite previous descriptions of paraneoplastic parkinsonism caused by other antineuronal antibodies, in our case no relation between anti-Hu and parkinsonism could be identified. A literature review of published reports describing anti-Hu positivity in thymic neoplasms highlighted that a definite autonomic disease due to anti-Hu antibodies is extremely rare in patients with thymoma but without myasthenia gravis, with only one case published so far. PMID:29416500

Quantitative impact of thymic selection on Foxp3+ and Foxp3- subsets of self-peptide/MHC class II-specific CD4+ T cells.

PubMed

Moon, James J; Dash, Pradyot; Oguin, Thomas H; McClaren, Jennifer L; Chu, H Hamlet; Thomas, Paul G; Jenkins, Marc K

2011-08-30

It is currently thought that T cells with specificity for self-peptide/MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4(+) T cells, what is unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3(+) regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4(+) T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3(-) cells, but also contained a subset of Foxp3(+) regulatory cells. Both Foxp3(-) and Foxp3(+) pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3(+) subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII-specific CD4(+) T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells.

Following the Fate of One Insulin-Reactive CD4 T cell

PubMed Central

Fousteri, Georgia; Jasinski, Jean; Dave, Amy; Nakayama, Maki; Pagni, Philippe; Lambolez, Florence; Juntti, Therese; Sarikonda, Ghanashyam; Cheng, Yang; Croft, Michael; Cheroutre, Hilde; Eisenbarth, George; von Herrath, Matthias

2012-01-01

In diabetic patients and susceptible mice, insulin is a targeted autoantigen. Insulin B chain 9-23 (B:9-23) autoreactive CD4 T cells are key for initiating autoimmune diabetes in NOD mice; however, little is known regarding their origin and function. To this end, B:9-23–specific, BDC12-4.1 T-cell receptor (TCR) transgenic (Tg) mice were studied, of which, despite expressing a single TCR on the recombination activating gene–deficient background, only a fraction develops diabetes in an asynchronous manner. BDC12-4.1 CD4 T cells convert into effector (Teff) and Foxp3+-expressing adaptive regulatory T cells (aTregs) soon after leaving the thymus as a result of antigen recognition and homeostatic proliferation. The generation of aTreg causes the heterogeneous diabetes onset, since crossing onto the scurfy (Foxp3) mutation, BDC12-4.1 TCR Tg mice develop accelerated and fully penetrant diabetes. Similarly, adoptive transfer and bone marrow transplantation experiments showed differential diabetes kinetics based on Foxp3+ aTreg’s presence in the BDC12-4.1 donors. A single-specificity, insulin-reactive TCR escapes thymic deletion and simultaneously converts into aTreg and Teff, establishing an equilibrium that determines diabetes penetrance. These results are of particular importance for understanding disease pathogenesis. They suggest that once central tolerance is bypassed, autoreactive cells arriving in the periphery do not by default follow solely a pathogenic fate upon activation. PMID:22403296

Motivational Profiles of Gambling Behavior: Self-determination Theory, Gambling Motives, and Gambling Behavior.

PubMed

Rodriguez, Lindsey M; Neighbors, Clayton; Rinker, Dipali V; Tackett, Jennifer L

2015-12-01

Gambling among young adults occurs at a higher rate than in the general population and is associated with a host of negative consequences. Self-determination theory (SDT) posits that individuals develop general motivational orientations which predict a range of behavioral outcomes. An autonomy orientation portrays a choiceful perspective facilitating personal growth, whereas a controlled orientation represents a chronic proclivity toward external pressures and a general lack of choice. Further, an impersonal orientation is characterized by alack of intention and feeling despondent and ineffective. Controlled orientation has previously been associated with more frequent and problematic gambling. This research was designed to examine gambling motives as mediators of associations between motivational orientations and gambling behaviors. Undergraduates (N = 252) who met 2+ criteria on the South Oaks Gambling Screen participated in a laboratory survey assessing their motivational orientations, gambling motives, and gambling behavior (quantity, frequency, and problems). Mediation analyses suggested that autonomy was negatively associated with gambling problems through lower levels of chasing and escape motives. Further, controlled orientation was associated with more problems through higher levels of chasing and interest motives. Finally, impersonal orientation was negatively associated with amount won through escape motives. Overall, results support exploring gambling behavior and motives using a SDT framework.

Effect of cloacal plugging on microbial recovery from partially processed broilers.

PubMed

Musgrove, M T; Cason, J A; Fletcher, D L; Stern, N J; Cox, N A; Bailey, J S

1997-03-01

Experiments were performed to test the contribution of bacteria contained in the intestinal tract of broilers at the beginning of processing to counts on the exterior of modified New York-dressed carcasses. Thirty-two birds were processed for each of seven replications. Within each replication, batches of four birds were electrocuted, scalded, and picked, with batches alternating between treatment and control groups. Treated birds were cloacally plugged with rayon fiber tampons prior to electrocution to prevent escape of intestinal contents during scalding and picking. Control birds were processed in the same manner, except that cloacal plugs were inserted immediately after defeathering to reduce escape of intestinal contents during sampling. Gram-negative enteric bacteria and Campylobacter spp. were enumerated on carcasses by whole carcass rinse procedure and in cecal contents. Counts were converted to log10 and subjected to analysis of variance. Cecal levels of Gram-negative enterics were significantly higher for plugged birds, but there was not a significant difference between levels of cecal Campylobacter spp. between treatment groups. Plugging before electrocution resulted in significantly lower levels (2.5 vs 3.0 log10 cfu/mL) of Campylobacter spp. and Gram-negative enteric bacteria (3.0 vs 3.4 log10 cfu/mL) in carcass rinses of treatment birds than in those of controls. All carcasses were positive for Gram-negative enterics. Cloacal plugging resulted in significantly lower incidence of Campylobacter spp. carcass contamination as determined by chi-square. Intestinal carriage of both campylobacters and Gram-negative enteric bacteria appears to influence the microbial quality of the carcass during processing.

Transcriptional control of behavior: Engrailed knockout changes cockroach escape trajectories

PubMed Central

Booth, David; Marie, Bruno; Domenici, Paolo; Blagburn, Jonathan M; Bacon, Jonathan P

2009-01-01

The cerci of the cockroach are covered with identified sensory hairs, which detect air movements. The sensory neurons which innervate these hairs synapse with giant interneurons (GIs) in the terminal ganglion which in turn synapse with interneurons and leg motorneurons in thoracic ganglia. This neural circuit mediates the animal's escape behavior. The transcription factor Engrailed (En) is expressed only in the medially born sensory neurons, which suggested it could work as a positional determinant of sensory neuron identity. Previously, we used dsRNA interference to abolish En expression, and found that the axonal arborization and synaptic outputs of an identified En-positive sensory neuron changed so that it came to resemble a nearby En-negative cell, which was itself unaffected. We thus demonstrated directly that En controls synaptic choice, as well as axon projections. Is escape behavior affected as a result of this mis-wiring? We recently showed that adult cockroaches keep each escape unpredictable by running along one of a set of preferred escape trajectories (ETs) at fixed angles from the direction of the threatening stimulus. The probability of selecting a particular ET is influenced by wind direction. In this present study we show that early instar juvenile cockroaches also use those same ETs. En knockout significantly perturbs the animals' perception of posterior wind, altering the choice of ETs to one more appropriate for anterior wind. This is the first time that it has been shown that knockout of a transcription factor controlling synaptic connectivity can alter the perception of a directional stimulus. PMID:19494140

Chronic predation risk reduces escape speed by increasing oxidative damage: a deadly cost of an adaptive antipredator response.

PubMed

Janssens, Lizanne; Stoks, Robby

2014-01-01

Prey organisms evolved a multitude of plastic responses to avoid being eaten by predators. Besides the evolution of plastic morphological responses to escape predation, prey also evolved a set of physiological stress responses to avoid dying because of chronic predator stress per se due to disruption of cellular homeostasis. As physiological stress theory predicts increased energy consumption and the inhibition of essential nonemergency body functions, we tested whether chronic predation risk may increase oxidative damage thereby generating negative effects on escape performance. Specifically, we evaluated whether predation risk reduces escape swimming speed in damselfly larvae and whether this operates through stress-associated increases in oxidative damage. Counterintuitively and in contrast with many empirical studies, chronic predation risk decreased escape performance. This is however entirely consistent with the expectation of it being a long-term cost of responding to predation risk (e.g. by increasing respiration or upregulating the stress protein levels). The decreased swimming speed could be explained by an increased oxidative damage to proteins, thereby providing one of the poorly studied ecological links between oxidative damage and whole-animal performance. This likely widespread, understudied cost of chronic predation risk may provide an important pathway of non-consumptive predator effects on prey population dynamics. Moreover, it could play an evolutionary role by acting as a selective force causing prey organisms to adjust the magnitude of the physiological stress response and should be considered when evaluating life history trade-offs thought to be mediated by oxidative damage.

Chronic Predation Risk Reduces Escape Speed by Increasing Oxidative Damage: A Deadly Cost of an Adaptive Antipredator Response

PubMed Central

Janssens, Lizanne; Stoks, Robby

2014-01-01

Prey organisms evolved a multitude of plastic responses to avoid being eaten by predators. Besides the evolution of plastic morphological responses to escape predation, prey also evolved a set of physiological stress responses to avoid dying because of chronic predator stress per se due to disruption of cellular homeostasis. As physiological stress theory predicts increased energy consumption and the inhibition of essential nonemergency body functions, we tested whether chronic predation risk may increase oxidative damage thereby generating negative effects on escape performance. Specifically, we evaluated whether predation risk reduces escape swimming speed in damselfly larvae and whether this operates through stress-associated increases in oxidative damage. Counterintuitively and in contrast with many empirical studies, chronic predation risk decreased escape performance. This is however entirely consistent with the expectation of it being a long-term cost of responding to predation risk (e.g. by increasing respiration or upregulating the stress protein levels). The decreased swimming speed could be explained by an increased oxidative damage to proteins, thereby providing one of the poorly studied ecological links between oxidative damage and whole-animal performance. This likely widespread, understudied cost of chronic predation risk may provide an important pathway of non-consumptive predator effects on prey population dynamics. Moreover, it could play an evolutionary role by acting as a selective force causing prey organisms to adjust the magnitude of the physiological stress response and should be considered when evaluating life history trade-offs thought to be mediated by oxidative damage. PMID:24968142

Effects of Signaled Positive Reinforcement on Problem Behavior Maintained by Negative Reinforcement

ERIC Educational Resources Information Center

Schieltz, Kelly M.; Wacker, David P.; Romani, Patrick W.

2017-01-01

We evaluated the effects of providing positive reinforcement for task completion, signaled via the presence of a tangible item, on escape-maintained problem behavior displayed by three typically developing children during one-time 90-min outpatient evaluations. Brief functional analyses of problem behavior, conducted within a multielement design,…

Descriptive Analysis of Teachers' Responses to Problem Behavior Following Training

ERIC Educational Resources Information Center

Addison, Laura; Lerman, Dorothea C.

2009-01-01

The procedures described by Sloman et al. (2005) were extended to an analysis of teachers' responses to problem behavior after they had been taught to withhold potential sources of positive and negative reinforcement following instances of problem behavior. Results were consistent with those reported previously, suggesting that escape from child…

Renal transplantation from hepatitis B surface antigen (HBsAg)-positive donors to HBsAg-negative recipients: a case of post-transplant fulminant hepatitis associated with an extensively mutated hepatitis B virus strain and review of the current literature.

PubMed

Magiorkinis, E; Paraskevis, D; Pavlopoulou, I D; Kantzanou, M; Haida, C; Hatzakis, A; Boletis, I N

2013-08-01

The purpose of this study was to present a fatal case of fulminant hepatitis B (FHB) that developed in a renal transplant recipient, immunized against hepatitis B, 1 year post transplantation. Polymerase chain reaction amplification and full genome sequencing were performed to investigate whether specific mutations were associated with hepatitis B virus (HBV) transmission and FHB. Molecular analysis revealed multiple mutations in various open reading frames of HBV, the most important being the G145R escape mutation and a frameshift mutation-insertion (1838insA) within the pre-C/C reading frame. Our results highlight the possibility of developing FHB, despite previous immunization against HBV or administration of hyperimmune gammaglobulin, because of the selection of escape virus mutants. The current literature and guidelines regarding renal transplantation from hepatitis B surface antigen (HBsAg)-positive to HBsAg-negative patients were also reviewed. © 2013 John Wiley & Sons A/S.

AN EVALUATION OF THE INTERACTION BETWEEN QUALITY OF ATTENTION AND NEGATIVE REINFORCEMENT WITH CHILDREN WHO DISPLAY ESCAPE-MAINTAINED PROBLEM BEHAVIOR

PubMed Central

Gardner, Andrew W; Wacker, David P; Boelter, Eric W

2009-01-01

The choice-making behavior of 2 typically developing children who engaged in problem behavior maintained by negative reinforcement was evaluated within a concurrent-operants assessment that varied the quality of attention across free-play and demand conditions. The results demonstrated that it was possible to bias responding towards academic demands for both participants by providing high-quality attention, despite the continuous availability of negative reinforcement. The current study extended brief clinical methods with typically developing children and demonstrated how different qualities of attention provided across concurrent schedules could bias responding. PMID:19949522

Quantifying six decades of fishery selection for size and age at maturity in sockeye salmon

PubMed Central

Kendall, Neala W; Hard, Jeffrey J; Quinn, Thomas P

2009-01-01

Life history traits of wild animals can be strongly influenced, both phenotypically and evolutionarily, by hunting and fishing. However, few studies have quantified fishery selection over long time periods. We used 57 years of catch and escapement data to document the magnitude of and trends in gillnet selection on age and size at maturity of a commercially and biologically important sockeye salmon stock. Overall, the fishery has caught larger fish than have escaped to spawn, but selection has varied over time, becoming weaker and less consistent recently. Selection patterns were strongly affected by fish age and sex, in addition to extrinsic factors including fish abundance, mesh size regulations, and fish length variability. These results revealed a more complex and changing pattern of selective harvest than the ‘larger is more vulnerable’ model, emphasizing the need for quantified, multi-year studies before conclusions can be drawn about potential evolutionary and ecological effects of fishery selection. Furthermore, the results indicate that biologically robust escapement goals and prevention of harvest of the largest individuals may help prevent negative effects of size-selective harvest. PMID:25567896

Effect on IgE production of transplanted cultured thymic fragments.

PubMed Central

Nishikawa, M; Hong, R

1987-01-01

The effect of cultured thymic fragment (CTF) transplantation on the IgE response of nude mice was studied. Nude mice (BALB/c nu/nu) were immunized with a mixture of tetanus toxoid and aluminium gel intraperitoneally. Non-CTF transplanted nude mice could not regulate IgE production nor synthesize specific IgE antibody, and all died at 16 weeks of age. Nude mice that were transplanted with CTF from allogeneic low responder strains (C57BL/6, SJL), allogeneic high responder strain (ASW) and syngeneic high responder strain (BALB/c) could regulate IgE production, and these lived a normal life span. Additionally, the tetanus toxoid-specific IgE antibody response, which was estimated by PCA, paralleled that seen in the strain of the thymus donor, i.e. BALB/c and ASW thymus reconstitution produced the highest response, whereas SJL and C57BL/6 recipients' levels were significantly less (P less than 0.05). We postulate that the lesser responses were due to the determination of the phenotype response by the thymic microenvironment. The low responses were shown to be due to regulator T-cell imbalance. These data show that BALB/c T-cell precursors developing in non-BALB/c thymuses interact with BALB/c B cells to produce levels of IgE antibody that are more characteristic of the non-BALB/c differentiating microenvironment than of their own genetic background. PMID:3493208

A comparative study of PD-L1 immunohistochemical assays with four reliable antibodies in thymic carcinoma.

PubMed

Sakane, Tadashi; Murase, Takayuki; Okuda, Katsuhiro; Takino, Hisashi; Masaki, Ayako; Oda, Risa; Watanabe, Takuya; Kawano, Osamu; Haneda, Hiroshi; Moriyama, Satoru; Saito, Yushi; Yamada, Takeshi; Nakanishi, Ryoichi; Inagaki, Hiroshi

2018-01-23

Currently, four immunohistochemical assays are registered with the US Food and Drug Administration to detect the expression of PD-L1. We investigated the PD-L1 expression in thymic carcinomas using these four diagnostic assays. The cases of 53 patients were reviewed and their specimens were subjected to four PD-L1 assays with different antibodies (SP142, SP263, 22C3, and 28-8). The PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was evaluated. In TCs, the four assays showed similar scores in each case. Histopathologically, high TC scores were observed in squamous cell carcinomas (SqCCs). Meanwhile, there were no significant relationships among the IC scores in the four assays. In SqCCs, the high expression of PD-L1 (defined as ≥50% TC score) in TCs tended to be associated with early stage cancer. The patients with high expression levels of PD-L1 tended to show longer overall survival in the 22C3 assays (p=0.0200). In thymic carcinomas, the staining pattern showed high concordance among the four assays when TCs - rather than ICs - were stained. High PD-L1 positivity in TCs, especially in SqCCs, indicated that PD-1/PD-L1 targeted therapy may be a promising therapeutic approach.

IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage.

PubMed

Barik, Subhasis; Miller, Mindy M; Cattin-Roy, Alexis N; Ukah, Tobechukwu K; Chen, Weirong; Zaghouani, Habib

2017-10-15

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/EBPα, 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, HR - 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. Copyright © 2017 by The American Association of Immunologists, Inc.

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients.

PubMed

Fallen, P R; McGreavey, L; Madrigal, J A; Potter, M; Ethell, M; Prentice, H G; Guimarães, A; Travers, P J

2003-11-01

The factors affecting T cell reconstitution post haematopoietic cell transplantation (HCT) are not well characterised. We carried out a longitudinal analysis of T cell reconstitution in 32 HCT recipients during the first 12 months post transplant. We analysed reconstitution of naïve, memory and effector T cells, their diversity and monitored thymic output using TCR rearrangement excision circles (TRECs). Thymic-independent pathways were responsible for the rapid reconstitution of memory and effector T cells less than 6 months post HCT. Thymic-dependent pathways were activated between 6 and 12 months in the majority of patients with naïve T cell numbers increasing in parallel with TREC levels. Increasing patient age, chronic GVHD and T cell depletion (with or without pretransplant Campath-1H) predicted low TREC levels and slow naïve T cell recovery. Furthermore, increasing patient age also predicted high memory and effector T cell numbers. The effects of post HCT immunosuppression, total body irradiation, donor leucocyte infusions, T cell dose and post HCT infections on T cell recovery were also analysed. However, no effects of these single variables across a variety of different age, GVHD and T cell depletion groups were apparent. This study suggests that future analysis of the factors affecting T cell reconstitution and studies aimed at reactivating the thymus through therapeutic intervention should be analysed in age-, GVHD- and TCD-matched patient groups.

Thymus medulla under construction: Time and space oddities.

PubMed

Alves, Nuno L; Ribeiro, Ana R

2016-04-01

The development of effective T-cell-based immunotherapies to treat infection, cancer, and autoimmunity should incorporate the ground rules that control differentiation of T cells in the thymus. Within the thymus, thymic epithelial cells (TECs) provide microenvironments supportive of the generation and selection of T cells that are responsive to pathogen-derived antigens, and yet tolerant to self-determinants. Defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental and clinical importance to comprehend how immunity and tolerance are balanced. Critical to tolerance induction are medullary thymic epithelial cells (mTECs), which purge autoreactive T cells, or redirect them to a regulatory T-cell lineage. In this issue of the European Journal of Immunology, studies by Baik et al. and Mayer et al. [Eur. J. Immunol. 2016. 46: XXXX-XXXX and 46: XXXX-XXXX]) document novel spatial-temporal singularities in the lineage specification and maintenance of mTECs. While Baik et al. define a developmental checkpoint during mTEC specification in the embryo, Mayer et al. reveal that the generation and maintenance of the adult mTEC compartment is temporally controlled in vivo. The two reports described new developmentally related, but temporally distinct principles that underlie the homeostasis of the thymic medulla across life. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis

PubMed Central

Shi, Jianjun; Fallahi, Mohammad; Luo, Jun-Li

2011-01-01

Notch1 signaling is absolutely essential for steady-state thymic lymphopoiesis, but the role of other Notch receptors, and their potential overlap with the function of Notch1, remains unclear. Here we show that like Notch1, Notch3 is differentially expressed by progenitor thymocytes, peaking at the DN3 progenitor stage. Using mice carrying a gene-trapped allele, we show that thymic cellularity is slightly reduced in the absence of Notch3, although progression through the defined sequence of TCR-αβ development is normal, as are NKT and TCRγδ cell production. The absence of a profound effect from Notch3 deletion is not explained by residual function of the gene-trapped allele because insertion mapping suggests that the targeted allele would not encode functional signaling domains. We also show that although Notch1 and Notch3 are coexpressed on some early intrathymic progenitors, the relatively mild phenotype seen after Notch3 deletion does not result from the compensatory function of Notch1, nor does Notch3 function explain the likewise mild phenotype seen after conditional (intrathymic) deletion of Notch1. Our studies indicate that Notch1 and Notch3 carry out nonoverlapping functions during thymocyte differentiation, and that while Notch1 is absolutely required early in the lymphopoietic process, neither receptor is essential at later stages. PMID:21768299

Thymic Stromal Lymphopoietin: To Cut a Long Story Short.

PubMed

Tsilingiri, Katerina; Fornasa, Giulia; Rescigno, Maria

2017-03-01

Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform.

Analysis of free-time contingencies as positive versus negative reinforcement.

PubMed

Zarcone, J R; Fisher, W W; Piazza, C C

1996-01-01

Providing a short break contingent on completed work may increase responding through positive reinforcement (e.g., access to preferred activities) or negative reinforcement (e.g., escape form work). In this investigation, three analyses conducted with a boy with profound mental retardation showed that (a) a 20-s break increased responding more than a positive reinforcer (cola) did, and (b) the reinforcing effect of a 20-s break were affected by the availability of positive reinforcers during the break were affected by the availability of positive reinforcers during the break.

A Case Report: A Third/Fourth Branchial Pouch Anomaly Presented by Solid Thyroid and Lateral Cervical Neck Masses.

PubMed

Nasreldin, Magda H A; Ibrahim, Eman A; Saad El-Din, Somaia A

2016-01-01

Branchial pouch-derived anomalies may arise from remnants of the first, second, or third/fourth branchial arches. Branchial pouch-related structures are found within the thyroid gland in the form of solid cell rests, epithelial lined cyst with or without an associated lymphoid component, thymic and/or parathyroid tissue, and less commonly in the form of heterotopic cartilage. We present a rare case of left solid thyroid swelling nearby two cervical nodules in a seven-year-old female with a clinical diagnosis suggestive of malignant thyroid tumor with metastasis to the cervical lymph nodes. Histopathological examination revealed that it was compatible with third/fourth branchial pouch-derived anomaly composed of mature cartilage and thymic and parathyroid tissues for clinical and radiological correlations.

A Case Report: A Third/Fourth Branchial Pouch Anomaly Presented by Solid Thyroid and Lateral Cervical Neck Masses

PubMed Central

Nasreldin, Magda H. A.; Ibrahim, Eman A.; Saad El-Din, Somaia A.

2016-01-01

Branchial pouch-derived anomalies may arise from remnants of the first, second, or third/fourth branchial arches. Branchial pouch-related structures are found within the thyroid gland in the form of solid cell rests, epithelial lined cyst with or without an associated lymphoid component, thymic and/or parathyroid tissue, and less commonly in the form of heterotopic cartilage. We present a rare case of left solid thyroid swelling nearby two cervical nodules in a seven-year-old female with a clinical diagnosis suggestive of malignant thyroid tumor with metastasis to the cervical lymph nodes. Histopathological examination revealed that it was compatible with third/fourth branchial pouch-derived anomaly composed of mature cartilage and thymic and parathyroid tissues for clinical and radiological correlations. PMID:26819565

The transcriptional landscape of αβ T cell differentiation

PubMed Central

Mingueneau, Michael; Kreslavsky, Taras; Gray, Daniel; Heng, Tracy; Cruse, Richard; Ericson, Jeffrey; Bendall, Sean; Spitzer, Matt; Nolan, Garry; Kobayashi, Koichi; von Boehmer, Harald; Mathis, Diane; Benoist, Christophe

2013-01-01

αβT cell differentiation from thymic precursors is a complex process, explored here with the breadth of ImmGen expression datasets, analyzing how differentiation of thymic precursors gives rise to transcriptomes. After surprisingly gradual changes though early T commitment, transit through the CD4+CD8+ stage involves a shutdown or rare breadth, and correlating tightly with MYC. MHC-driven selection promotes a large-scale transcriptional reactivation. We identify distinct signatures that mark cells destined for positive selection versus apoptotic deletion. Differential expression of surprisingly few genes accompany CD4 or CD8 commitment, a similarity that carries through to peripheral T cells and their activation, revealed by mass cytometry phosphoproteomics. The novel transcripts identified as candidate mediators of key transitions help define the “known unknown” of thymocyte differentiation. PMID:23644507

bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship.

PubMed

Strasser, A; Harris, A W; Cory, S

1991-11-29

Early death is the fate of most developing T lymphocytes. Because bcl-2 can promote cell survival, we tested its impact in mice expressing an E mu-bcl-2 transgene within the T lymphoid compartment. The T cells showed remarkably sustained viability and some spontaneous differentiation in vitro. They also resisted killing by lymphotoxic agents. Although total T cell numbers and the rate of thymic involution were unaltered, the response to immunization was enhanced, consistent with reduced death of activated T cells. No T cells reactive with self-superantigens appeared in the lymph nodes, but an excess was found in the thymus. These observations, together with previous findings on B cells, suggest that modulated bcl-2 expression is a determinant of life and death in normal lymphocytes.

Use of Escape and Reward in the Management of Young Children during Dental Treatment.

ERIC Educational Resources Information Center

Allen, Keith D.; Stokes, Trevor F.

1987-01-01

A contingency management procedure using both positive and negative reinforcement was used to strengthen cooperative behavior in five children (ages 3-6) during a series of restorative dental treatment sessions lasting from 15-60 minutes. Baseline levels of disruptive behavior as high as 90 percent were reduced to less than 15 percent. (JW)

Past Forward: Nostalgia as a Motivational Force.

PubMed

Sedikides, Constantine; Wildschut, Tim

2016-05-01

Nostalgia has endured a negative reputation, being branded an unhealthy preoccupation with one's past. This reputation is unwarranted. Nostalgia has remarkable implications for one's future. It strengthens approach orientation, raises optimism, evokes inspiration, boosts creativity, and kindles prosociality. Far from reflecting escapism from the present, nostalgia potentiates an attainable future. Copyright © 2016 Elsevier Ltd. All rights reserved.

Further Examination of Factors that Influence Preference for Positive versus Negative Reinforcement

ERIC Educational Resources Information Center

Kodak, Tiffany; Lerman, Dorothea C.; Volkert, Valerie M.; Trosclair, Nicole

2007-01-01

Factors that influence choice between qualitatively different reinforcers (e.g., a food item or a break from work) are important to consider when arranging treatments for problem behavior. Previous findings indicate that children who engage in problem behavior maintained by escape from demands may choose a food item over the functional reinforcer…

Escape behaviour of birds in urban parks and cemeteries across Europe: Evidence of behavioural adaptation to human activity.

PubMed

Morelli, Federico; Mikula, Peter; Benedetti, Yanina; Bussière, Raphaël; Jerzak, Leszek; Tryjanowski, Piotr

2018-08-01

Urban environments are very heterogeneous, and birds living in the proximity of humans have to adapt to local conditions, e.g. by changing their behavioural response to potential predators. In this study, we tested whether the escape distance of birds (measured as flight initiation distance; FID) differed between parks and cemeteries, areas characterized by different microhabitat conditions and human conduct, that are determinants of animal behaviour at large spatial scales. While escape behaviour of park populations of birds was often examined, cemetery populations have not been studied to the same extent and a large-scale comparison is still missing. Overall, we collected 2139 FID estimates for 44 bird species recorded in 79 parks and 90 cemeteries in four European countries: Czech Republic, France, Italy and Poland. Mixed model procedure was applied to study escape behaviour in relation to type of area (park or cemetery), environmental characteristics (area size, coverage by trees, shrubs, grass, chapels, tombstones, flowerbeds, number of street lamps) and human activity (human density, pedestrians speed and ratio of men/women). Birds allowed people closer in cemeteries than in parks in all countries. This pattern was persistent even when focusing on intraspecific differences in FID between populations of the most common bird species. Escape distance of birds was negatively correlated with the size of parks/cemeteries, while positively associated with tombstone coverage and human density in both types of habitat. Our findings highlight the ability of birds to adapt their behaviour to different types of urban areas, based on local environmental conditions, including the character of human-bird interactions. Our results also suggest that this behavioural pattern may be widespread across urban landscapes. Copyright © 2018 Elsevier B.V. All rights reserved.

Teens With Heavy Prenatal Cocaine Exposure Respond to Experimental Social Provocation with Escape Not Aggression

PubMed Central

Greenwald, M.K.; Chiodo, L.M.; Hannigan, J.H.; Sokol, R.J.; Janisse, J.; Delaney-Black, V.

2010-01-01

Preclinical data show that, compared to no exposure, prenatal cocaine exposure (PCE) has age-dependent effects on social interaction and aggression. The aim of this clinical study was to determine how heavy/persistent PCE – after controlling for other prenatal drug exposures, sex and postnatal factors – predicts behavioral sensitivity to provocation (i.e., reactive aggression) using a well-validated human laboratory model of aggression. African American teens (mean = 14.2 yrs old) with histories of heavy/persistent PCE (maternal cocaine use ≥ 2 times/week during pregnancy, or positive maternal or infant urine/meconium test at delivery; n = 86) or none/some exposure (NON: maternal cocaine use < 2 times/week during pregnancy; n = 330) completed the Point Subtraction Aggression Paradigm. In this task, teens competed in a computer game against a fictitious opponent. There were three possible responses: (a) earn points, to exchange for money later; or (b) “aggress” against the fictitious opponent by subtracting their points; or (c) escape temporarily from point subtraction perpetrated by the fictitious opponent. The PCE group responded significantly more frequently on the escape option than the NON group, but did not differ in aggressive or money-earning responses. These data indicate that PCE-teens provoked with a social stressor exhibit a behavioral preference for escape (negative reinforcement) more than for aggressive (retaliatory) or appetitive (point- or money-reinforced) responses. These findings are consistent with preclinical data showing that social provocation of adolescent or young adult offspring after PCE is associated with greater escape behavior, inferring greater submission, social withdrawal, or anxiety, as opposed to aggressive behavior. PMID:20600841

The transition from HLA-I positive to HLA-I negative primary tumors: the road to escape from T-cell responses.

PubMed

Aptsiauri, Natalia; Ruiz-Cabello, Francisco; Garrido, Federico

2018-04-01

MHC/HLA class I loss in cancer is one of the main mechanisms of tumor immune escape from T-cell recognition and destruction. Tumor infiltration by T lymphocytes (TILs) and by other immune cells was first described many years ago, but has never been directly and clearly linked to the destruction of HLA-I positive and selection of HLA-I negative tumor cells. The degree and the pattern of lymphocyte infiltration in a tumor nest may depend on antigenicity and the developmental stages of the tumors. In addition, it is becoming evident that HLA-I expression and tumor infiltration have a direct correlation with tumor tissue reorganization. We observed that at early stages (permissive Phase I) tumors are heterogeneous, with both HLA-I positive and HLA-negative cancer cells, and are infiltrated by TILs and M1 macrophages as a part of an active anti-tumor Th1 response. At later stages (encapsulated Phase II), tumor nests are mostly HLA-I negative with immune cells residing in the peri-tumoral stroma, which forms a granuloma-like encapsulated tissue structure. All these tumor characteristics, including tumor HLA-I expression pattern, have an important clinical prognostic value and should be closely and routinely investigated in different types of cancer by immunologists and by pathologists. In this review we summarize our current viewpoint about the alterations in HLA-I expression in cancer and discuss how, when and why tumor HLA-I losses occur. We also provide evidence for the negative impact of tumor HLA-I loss in current cancer immunotherapies, with the focus on reversible ('soft') and irreversible ('hard') HLA-I defects. Copyright © 2018 Elsevier Ltd. All rights reserved.

Thymic lymphocytes. III. Cooperative phenomenon in the proliferation of thymocytes under Con A stimulation.

PubMed

Papiernik, M; Jacobson, J B

1986-01-01

In the present paper, the response of thymocytes to Con A is analyzed in terms of a cooperative phenomenon between medullary thymocytes, cortical thymocytes, thymic accessory cells, and interleukin 2. Medullary thymocytes respond spontaneously to Con A and produce IL-2. The addition of exogenously produced IL-2 enhances their proliferation. Small numbers of cortical (PNA+) thymocytes do not respond to Con A, even in the presence of IL-2-containing supernatant. By increasing the number of PNA+ cells per well, sensitivity to Con A and IL-2 appears. This response may be linked either to the increase in a minor PNA+-responding population and/or to the enhanced contamination by medullary thymocytes and macrophages in non-responding PNA+ thymocyte population. In this hypothesis, either the contaminating cells respond by themselves and/or cooperate with PNA+ cells to induce their proliferation. Coculture of non-responding low numbers of PNA+ thymocytes with Con A- and IL-2-containing supernatant in the presence of PNA- cells containing thymic medullary thymocytes and macrophages always produces a higher response than that of each individual population. These results show that a cooperative phenomenon occurs in the cocultures of PNA+ and PNA- thymic cells. We can show using PNA+ and PNA- thymocytes with different Thy 1 alleles, that indeed both PNA+ and populations participate PNA-thymocytes with different Thy 1 alleles, that indeed both PNA+ and PNA- populations participate in the generation of proliferating cells. We can demonstrate, by lysis experiments with monoclonal antibodies and complement that at the end of coculture, most of the proliferating cells are Lyt 1+, and part are Lyt 2+ or L3T4+. We discuss the fact that the phenotype of the cells after activation does not allow us to deduce the phenotype of their precursors. Lysis of Ia+ cells prior to coculture, reduces the level of the proliferative response but does not modify the percentage of cooperation produced by the coculture. Cooperation with medullary mature thymocytes or the presence of active Ia- accessory cells possibly able to convert to Ia expression during coculture experiments may account for these results.

Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization - A minimally invasive cancer stem cell-targeting strategy.

PubMed

Bostad, Monica; Olsen, Cathrine Elisabeth; Peng, Qian; Berg, Kristian; Høgset, Anders; Selbo, Pål Kristian

2015-05-28

The cancer stem cell (CSC) marker CD133 is an attractive target to improve antitumor therapy. We have used photochemical internalization (PCI) for the endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin (PCIAC133-saporin). PCI employs an endocytic vesicle-localizing photosensitizer, which generates reactive oxygen species upon light-activation causing a rupture of the vesicle membranes and endosomal escape of entrapped drugs. Here we show that AC133-saporin co-localizes with the PCI-photosensitizer TPCS2a, which upon light exposure induces cytosolic release of AC133-saporin. PCI of picomolar levels of AC133-saporin in colorectal adenocarcinoma WiDr cells blocked cell proliferation and induced 100% inhibition of cell viability and colony forming ability at the highest light doses, whereas no cytotoxicity was obtained in the absence of light. Efficient PCI-based CD133-targeting was in addition demonstrated in the stem-cell-like, triple negative breast cancer cell line MDA-MB-231 and in the aggressive malignant melanoma cell line FEMX-1, whereas no enhanced targeting was obtained in the CD133-negative breast cancer cell line MCF-7. PCIAC133-saporin induced mainly necrosis and a minimal apoptotic response based on assessing cleavage of caspase-3 and PARP, and the TUNEL assay. PCIAC133-saporin resulted in S phase arrest and reduced LC3-II conversion compared to control treatments. Notably, co-treatment with Bafilomycin A1 and PCIAC133-saporin blocked LC3-II conversion, indicating a termination of the autophagic flux in WiDr cells. For the first time, we demonstrate laser-controlled targeting of CD133 in vivo. After only one systemic injection of AC133-saporin and TPCS2a, a strong anti-tumor response was observed after PCIAC133-saporin. The present PCI-based endosomal escape technology represents a minimally invasive strategy for spatio-temporal, light-controlled targeting of CD133+ cells in localized primary tumors or metastasis. Copyright © 2015 Elsevier B.V. All rights reserved.

Stages of Thymoma and Thymic Carcinoma

MedlinePlus

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... cancer cells have places where hormones can attach ( receptors ), drugs, surgery, or radiation therapy is used to ...

Distribution and occupancy of introduced species: a baseline inventory from Phase 3 plots across the country

Treesearch

Bethany K. Schulz; W. Keith Moser

2012-01-01

Invasive plant species have significant negative impacts in many ecosystems and are found in many forests around the world. Although not all introduced species become invasive, there are numerous examples of species escaping cultivation and invading natural ecosystems years or even decades after their initial introduction. Regional distributions of invasive species are...

Invasive wisteria in the Southeastern United StateS: genetic diversity, hybridization and the role of urban centers

Treesearch

Jennifer L. Trusty; Leslie R. Goertzen; Wayne C. Zipperer; B Graeme Lockaby

2007-01-01

The increasing numbers and negative impacts of invasive species have prompted research on the relationship between human activities and the success of invasive horticultural plants. In this study, we use population genetic relationships to model the escape of a common garden vine, exotic Wisteria, into natural habitats. Urban and naturalized Wisteria populations in...

AD/HD and the Capture of Attention by Briefly Exposed Delay-Related Cues: Evidence from a Conditioning Paradigm

ERIC Educational Resources Information Center

Sonuga-Barke, Edmund J. S.; De Houwer, Jan; De Ruiter, Karen; Ajzenstzen, Michal; Holland, Sarah

2004-01-01

Background: The selective attention of children with attention deficit/hyperactivity disorder (AD/HD) to briefly exposed delay-related cues was examined in two experiments using a dot-probe conditioning paradigm. Method: Colour cues were paired with negatively (i.e., imposition of delay) and positively valenced cues (i.e., escape from or avoidance…

Age-related changes in the thymus gland: CT-pathologic correlation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, A.V.; Korobkin, M.; Olanow, W.

1983-08-01

Recent reports suggest that computed tomography (CT) is useful for thymoma detection in patients with myasthenia gravis. However, that usefulness may be conditioned by the state of the normal thymus. To examine this concept, the CT findings in 64 consecutive patients with histologic confirmation of thymic status after thymectomy or thymic biopsy during mediastinal exploration were reviewed. The normal thymus has a bilobed, arrowhead-shaped cross section at all ages, with gradual focal or diffuse fatty infiltration of the parenchyma usually occurring between 20 and 40 years of age. A thymoma is usually a spherical or oval mass, often producing amore » focal, distinct bulge in the adjacent pleural reflection. The differentiation of thymoma from normal thymus should be possible in most patients if age-related changes in the normal gland are appreciated.« less

In vitro induction of monoclonal antibody-defined T-cell markers in lymphocytes from immunodeficient children by synthetic serum thymic factor (FTS).

PubMed Central

Bene, M C; Faure, G; Bordigoni, P; Olive, D; Duheille, J

1982-01-01

Lymphocytes from five children suffering from ataxia telangectasia or various unclassified immune deficiencies were tested in vitro for their sensitivity to synthetic serum thymic factor (FTS). The percentages of cells bearing T cell markers were elevated after incubation with FTS at graded concentrations (0.25, 2.5 and 25 ng/ml), by microlymphocytotoxicity or indirect immunofluorescence, using monoclonal anti-Lyt1 antibodies. In four cases, more than 30% of the non-T non-B cells acquired the Lyt1 T cell marker. These four children had low levels of circulating FTS. In the fifth child, who had a normal serum FTS level, and in two age-matched controls, there was no significant increase in the percentage of cells bearing the T marker. PMID:7049454

Thymic function, anti-thymocytes globulins, and cancer after renal transplantation.

PubMed

Ducloux, Didier; Bamoulid, Jamal; Courivaud, Cécile; Gaugler, Béatrice; Rebibou, Jean-Michel; Ferrand, Christophe; Chalopin, Jean-Marc; Borg, Christophe; Tiberghien, Pierre; Saas, Philippe

2011-07-01

Prolonged CD4 T cell lymphopenia after polyclonal antithymocyte globulins (ATG) is associated with an increased rate of cancers. Here, we examined whether pre-transplant thymic function estimated by TREC levels is predictive of cancer occurrence following ATG treatment. The impact of TREC on cancer occurrence was analyzed in 115 consecutive incident renal transplant recipients having received ATG. Mean follow-up was 7.5±2.6years. After ATG induction, patients with the lowest pre-transplant TREC values had lower post-transplant CD4(+) and CD4(+) CD45RA(+) CD45RO(-) T cell counts, and a higher frequency of T cells with a regulatory phenotype (CD127(+)CD4(+)CD25(+)Foxp3(+)). Log-transformed pre-transplant TREC values were significantly lower in patients who developed cancer after transplantation (p<0.0001). The cumulative incidence of cancer was higher in patients having the lowest pre-transplant TREC values (T1 [low]: 47.4%, T2 [medium]: 12.5%, and T3 [high]: 2.7%; p<0.0001). In multivariate analysis, pre-transplant TREC value was the only predictive factor of cancer (HR, 0.39; 95% CI, 0.16 to 0.97, for one log (TREC/10(6) PBMC); p=0.046). Pre-transplant thymic function is associated with an increased rate of post-transplant cancer in patients having received ATG. Omitting ATG in recipients with low pre-transplant TREC values should be considered. Copyright © 2011 Elsevier B.V. All rights reserved.

Differential expression of thymic DNA repair genes in low-dose-rate irradiated AKR/J mice

PubMed Central

Bong, Jin Jong; Kang, Yu Mi; Shin, Suk Chul; Choi, Seung Jin

2013-01-01

We previously determined that AKR/J mice housed in a low-dose-rate (LDR) (137Cs, 0.7 mGy/h, 2.1 Gy) γ-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) (137Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice. PMID:23820165

Ex vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency and the development of a thymic T cell lymphoma.

PubMed

Kennedy, Douglas R; Hartnett, Brian J; Kennedy, Jeffrey S; Vernau, William; Moore, Peter F; O'Malley, Thomas; Burkly, Linda C; Henthorn, Paula S; Felsburg, Peter J

2011-07-15

We have previously shown that in vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo γ-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.8 × 10(6) transduced CD34(+) cells/kg successfully engrafted producing normal numbers of gene-corrected CD45RA(+) (naïve) T cells. However, this was followed by a steady decrease in CD45RA(+) T cells, T cell diversity, and thymic output as measured by T cell receptor excision circles (TRECs) resulting in a T cell lymphopenia. None of the dogs survived past 11 months post treatment. At necropsy, few gene-corrected thymocytes were observed correlating with the TREC levels and one of the dogs was diagnosed with a thymic T cell lymphoma that was attributed to the gene therapy. This study highlights the outcome differences between the ex vivo and in vivo approach to γ-retroviral gene therapy and is the first to document a serious adverse event following gene therapy in a canine model of a human genetic disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Ex Vivo γ-Retroviral Gene Therapy of Dogs with X-linked Severe Combined Immunodeficiency and the Development of a Thymic T Cell Lymphoma

PubMed Central

Kennedy, Douglas R.; Hartnett, Brian J.; Kennedy, Jeffrey S.; Vernau, William; Moore, Peter F.; O’Malley, Thomas; Burkly, Linda C.; Henthorn, Paula S.; Felsburg, Peter J.

2011-01-01

We have previously shown that in vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo γ-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.8 × 106 transduced CD34+ cells/kg successfully engrafted producing normal numbers of gene-corrected CD45RA+ (naïve) T cells. However, this was followed by a steady decrease in CD45RA+ T cells, T cell diversity, and thymic output as measured by T cell receptor excision circles (TRECs) resulting in a T cell lymphopenia. None of the dogs survived past 11 months post treatment. At necropsy, few gene-corrected thymocytes were observed correlating with the TREC levels and one of the dogs was diagnosed with a thymic T cell lymphoma that was attributed to the gene therapy. This study highlights the outcome differences between the ex vivo and in vivo approach to γ-retroviral gene therapy and is the first to document a serious adverse event following gene therapy in a canine model of a human genetic disease. PMID:21536334

Can we stop transgenes from taking a walk on the wild side?

PubMed

Dlugosch, Katrina M; Whitton, Jeannette

2008-03-01

Whether the potential costs associated with broad-scale use of genetically modified organisms (GMOs) outweigh possible benefits is highly contentious, including within the scientific community. Even among those generally in favour of commercialization of GM crops, there is nonetheless broad recognition that transgene escape into the wild should be minimized. But is it possible to achieve containment of engineered genetic elements in the context of large scale agricultural production? In a previous study, Warwick et al. (2003) documented transgene escape via gene flow from herbicide resistant (HR) canola (Brassica napus) into neighbouring weedy B. rapa populations (Fig. 1) in two agricultural fields in Quebec, Canada. In a follow-up study in this issue of Molecular Ecology, Warwick et al. (2008) show that the transgene has persisted and spread within the weedy population in the absence of selection for herbicide resistance. Certainly a trait like herbicide resistance is expected to spread when selected through the use of the herbicide, despite potentially negative epistatic effects on fitness. However, Warwick et al.'s findings suggest that direct selection favouring the transgene is not required for its persistence. So is there any hope of preventing transgene escape into the wild?

Influence of boat noises on escape behaviour of white-spotted eagle ray Aetobatus ocellatus at Moorea Island (French Polynesia).

PubMed

Berthe, Cecile; Lecchini, David

2016-02-01

The present study tested different sounds that could disturb eagle rays (Aetobatus ocellatus) during their foraging activities at Moorea, French Polynesia. Results showed that artificial white sound and single-frequency tones (40 Hz, 600 Hz or 1 kHz) did not have an effect on rays (at least 90% of rays continued to forage over sand), while playbacks of boat motor sound significantly disturbed rays during foraging activity (60% exhibited an escape behaviour). Overall, our study highlighted the negative effect of boat noises on the foraging activity of eagle rays. These noises produced by boat traffic could, however, have some positive effects for marine aquaculture if they could be used as a deterrent to repel the eagle rays, main predators of the pearl oysters. Copyright © 2016. Published by Elsevier SAS.

Treatment Options for Thymoma and Thymic Carcinoma

MedlinePlus

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... cancer cells have places where hormones can attach ( receptors ), drugs, surgery, or radiation therapy is used to ...

Immunological Aging

EPA Science Inventory

Immunosenescence is associated with an increased incidence and severity of infections with common pathogens, neoplastic disease and autoimmunity. In general, aging is associated with a decline in function at the cellular level, rather than cell loss, although thymic atrophy and ...

Optimism, coping and long-term recovery from coronary artery surgery in women.

PubMed

King, K B; Rowe, M A; Kimble, L P; Zerwic, J J

1998-02-01

Optimism, coping strategies, and psychological and functional outcomes were measured in 55 women undergoing coronary artery surgery. Data were collected in-hospital and at 1, 6, and 12 months after surgery. Optimism was related to positive moods and life satisfaction, and inversely related to negative moods. Few relationships were found between optimism and functional ability. Cognitive coping strategies accounted for a mediating effect between optimism and negative mood. Optimists were more likely to accept their situation, and less likely to use escapism. In turn, these coping strategies were inversely related to negative mood and mediated the relationship between optimism and this outcome. Optimism was not related to problem-focused coping strategies; this, these coping strategies cannot explain the relationship between optimism and outcomes.

It's not going to be that fun: negative experiences can add meaning to life.

PubMed

Vohs, Kathleen D; Aaker, Jennifer L; Catapano, Rhia

2018-04-22

People seek to spend time in positive experiences, enjoying and savoring. Yet there is no escaping negative experiences, from the mundane (e.g. arguing) to the massive (e.g. death of a child). Might negative experiences confer a hidden benefit to well-being? We propose that they do, in the form of enhanced meaning in life. Research suggests that negative experiences can serve to boost meaning because they stimulate comprehension (understanding how the event fits into a broader narrative of the self, relationships, and the world), a known pillar of meaning in life. Findings on counterfactual thinking, reflecting on events' implications, and encompassing experiences into broad-based accounts of one's identity support the role of comprehension in contributing to life's meaning from unwanted, unwelcome experiences. Copyright © 2018 Elsevier Ltd. All rights reserved.

School Attendance Revisited: A Study of Urban African American Students' Grade Point Averages and Coping Strategies

ERIC Educational Resources Information Center

Steward, Robbie J.; Steward, Astin Devine; Blair, Jonathan; Jo, Hanik; Hill, Martin F.

2008-01-01

Urban African American first-year high school students' absenteeism was found to be negatively related to grade point average (GPA) and avoidance as a means of coping (use of substances as a way to escape--food, alcohol, smoking, caffeine, etc.) and positively related to use of social support as a means of coping (efforts to stay emotionally…

An 11-year and 10-month-old girl with purpura and chest pain.

PubMed

Chen, Pei-Hsuan; Chiang, Bor-Luen; Lu, Meng-Yao; Yang, Yao-Hsu

2014-10-01

Mucosa-associated lymphoid tissue lymphoma (MALToma) is a type of B-cell lymphoma. Case reports of childhood thymic MALToma and its association with vasculitis are rarely found in the related literature. Herein, we present a report of an 11-year and 10-month-old girl who was initially diagnosed with cutaneous vasculitis characterized by nonthrombocytopenic palpable purpura, positive antinuclear antibody and anti-SSA (Ro) antibody. Eight months later, a thymic mediastinal mass was found. Surgical excision was performed and results of pathological analysis revealed an extranodal marginal zone CD20(+) B-cell MALToma. Benign response to the chemotherapeutic regimen of Berlin-Frankfurt-Münster group NHL-BFM 90 R2 without relapse was noted in 2 years of follow-up. For the first time, our case demonstrated some clinical evidence of the association between vasculitis and childhood MALToma. Copyright © 2012. Published by Elsevier B.V.

Effects of bioactive factors of the pineal gland on thymus function and cell composition of the bone marrow and spleen in mice of different age.

PubMed

Labunets, I F; Butenko, G M; Khavinson, V Kh

2004-05-01

The effects of factors from the pineal gland on the titer of thymic serum factor in the supernatant of 3-h thymus stroma cultures, number of stromal precursor fibroblasts and CD4+ cells in the bone marrow, and CD8+ cells in the spleens of adult and old CBA mice were studied in vitro. Epithalamin, Epithalon, and melatonin appreciably increased the titer of thymic serum factor in the supernatant of thymus stroma cultures from mice of different age and increased the percentage of CD4+ cells in the bone marrow suspension from old animals in vitro. The percentage of CD8+ lymphocytes decreased after incubation of splenic cells from old mice with melatonin. The percentage of bone marrow fibroblast precursor cells from adult and old mice did not appreciably change after incubation with the preparations.

Free-hand ultrasound guidance permits safe and efficient minimally invasive intrathymic injections in both young and aged mice

PubMed Central

Tuckett, Andrea Z.; Zakrzewski, Johannes L.; Li, Duan; van den Brink, Marcel R.M.; Thornton, Raymond H.

2014-01-01

The goal of this study was to evaluate whether using an aseptic free-hand approach for ultrasound-guided injection facilitates injection into the thymic gland in mice. We used this interventional radiology technique in young, aged, and immunodeficient mice and found that the thymus was visible in all cases. The mean injection period was 8 s in young mice and 19 s in aged or immunodeficient mice. Injection accuracy was confirmed by intrathymic location of an injected dye, or by in vivo bioluminescence imaging of injected luciferase-expressing cells. Accurate intrathymic injection was confirmed in 97% of cases. No major complications were observed. We conclude that an aseptic free-hand technique for ultrasound-guided intrathymic injection is safe, accurate, and reduces the time required for intrathymic injections. This method facilitates large-scale experiments, injection of individual thymic lobes, and is clinically relevant. PMID:25701534

Targeted deletion of c-Met in thymic epithelial cells leads to an autoimmune phenotype

PubMed Central

Su, Min; Hu, Rong; Song, Yinhong; Liu, Yalan; Lai, Laijun

2017-01-01

Hepatocyte growth factor (HGF) and its receptor c-Met signaling have been implicated in regulating various types of cells including epithelial cells. We have previously reported that c-Met is expressed by thymic epithelial cells (TECs), and that in vivo administration of hybrid cytokines containing IL-7 and the beta- or alpha-chain of HGF significantly increase the number of TECs. In order to study the role of c-Met signaling in TECs, we generated conditional knockout (cKO) mice in which c-Met was specifically deleted in TECs using a Foxn1-Cre transgene. We show here that c-Met deficiency in TECs results in age-progressive reduction in TEC number and reduced number of regulatory T cells. Consequently, c-Met TEC cKO mice displayed an autoimmune phenotype. Thus, c-Met signaling in TECs is important for the maintenance of TECs and immune self-tolerance. PMID:29363160

Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation

PubMed Central

Pedroza-Gonzalez, Alexander; Xu, Kangling; Wu, Te-Chia; Aspord, Caroline; Tindle, Sasha; Marches, Florentina; Gallegos, Michael; Burton, Elizabeth C.; Savino, Daniel; Hori, Toshiyuki; Tanaka, Yuetsu; Zurawski, Sandra; Zurawski, Gerard; Bover, Laura; Liu, Yong-Jun; Banchereau, Jacques

2011-01-01

The human breast tumor microenvironment can display features of T helper type 2 (Th2) inflammation, and Th2 inflammation can promote tumor development. However, the molecular and cellular mechanisms contributing to Th2 inflammation in breast tumors remain unclear. Here, we show that human breast cancer cells produce thymic stromal lymphopoietin (TSLP). Breast tumor supernatants, in a TSLP-dependent manner, induce expression of OX40L on dendritic cells (DCs). OX40L+ DCs are found in primary breast tumor infiltrates. OX40L+ DCs drive development of inflammatory Th2 cells producing interleukin-13 and tumor necrosis factor in vitro. Antibodies neutralizing TSLP or OX40L inhibit breast tumor growth and interleukin-13 production in a xenograft model. Thus, breast cancer cell–derived TSLP contributes to the inflammatory Th2 microenvironment conducive to breast tumor development by inducing OX40L expression on DCs. PMID:21339324

Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways

PubMed Central

Lee, Jun Ho; Patel, Kalpesh; Tae, Hyun Jin; Lustig, Ana; Kim, Jie Wan; Mattson, Mark P.; Taub, Dennis D.

2014-01-01

Thymic atrophy occurs during normal aging, and is accelerated by exposure to chronic stressors that elevate glucocorticoid levelsand impair the naïve T cell output. The orexigenic hormone ghrelin was recently shown to attenuate age-associated thymic atrophy. Here, we report that ghrelin enhances the proliferation of murine CD4+ primary T cells and a CD4+ T-cell line. Ghrelin induced activation of the ERK1/2 and Akt signaling pathways, via upstream activation of phosphatidylinositol-3-kinase and protein kinase C, to enhance T-cell proliferation. Moreover, ghrelin induced expression of the cell cycle proteins cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2) and retinoblastoma phosphorylation. Finally, ghrelin activated the above-mentioned signaling pathways and stimulated thymocyte proliferation in young and older mice in vivo. PMID:25447526

Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules.

PubMed

Vanneste, Y; Thome, A N; Vandersmissen, E; Charlet, C; Franchimont, D; Martens, H; Lhiaubet, A M; Schimpff, R M; Rostène, W; Geenen, V

1997-06-01

This study shows the expression at the cell surface of human thymic epithelial cells (TEC) of a neurotensin (NT)-like immunoreactivity. NT radio-immunoassay (RIA) revealed that cultured human TEC contain +/-5 ng immunoreactive (ir) NT/10(6) cells, of which 5% is associated with plasma cell membranes. HPLC analysis of NT-ir present in human TEC showed a major peak of NT-ir corresponding to NT1-13. NT-ir was not detected in the supernatant of human TEC cultures. Using an affinity column prepared with a anti-MHC class I monoclonal antibody, NT-ir-related peptides were retained on the column and eluted together with MHC class I-related proteins. According to the elution time on HPLC of these peptides, they correspond to intact NT1-13, as well as to smaller fragments of NT1-13.

Malignant mast cell tumor of the thymus in an Royal College of Surgeons (RCS) rat.

PubMed

Terayama, Yui; Matsuura, Tetsuro; Ozaki, Kiyokazu

2017-01-01

A 152-week-old male Royal College of Surgeons (RCS) rat kept as a non-treated animal in a long-term animal study presented with a soft mass in the anterior mediastinum, which adhered to the pleura of the lung. Histopathologically, the mass mainly consisted of round to short spindle-shaped tumor cells that had infiltrated through the hyperplastic thymic tissue. The tumor cells were arranged in loose to dense sheets. Nuclei were moderate in size and round to spindle-shaped, with small nucleoli. Almost all tumor cells exhibited abundant eosinophilic cytoplasm, including eosinophilic granules of a range of sizes. The granules of tumor cells exhibited metachromasia with toluidine blue stain and were positive for c-kit and mast cell protease II. These findings indicate that the tumor described here represents a rare case of spontaneous malignant mast cell tumor with thymic epithelial hyperplasia.

Successful implementation of cooperative handling eliminates the need for restraint in a complex nonhuman primate disease model

PubMed Central

Graham, Melanie L; Rieke, Eric F; Mutch, Lucas A; Zolondek, Elizabeth K; Faig, Aaron W; DuFour, Theresa A; Munson, James W; Kittredge, Jessica A; Schuurman, Henk-Jan

2011-01-01

Introduction Streptozotocin-induced diabetic nonhuman primates are used to study efficacy and safety of innovative immunosuppression after islet transplantation. We implemented a training program for medical management of a chronic disease state. Methods Cooperation with hand feeding and drinking; shifting; and limb presentation were trained utilizing predominately positive but also negative reinforcement in 52 animals compared with 28 macaques subjected to conventional physical and/or chemical restraint. The success of and timing of behavior acquisition was evaluated in a representative subset of 14 animals. Results Over 90% of animals were successful in behavior acquisition. Programmatically this resulted in complete elimination of chair restraint and negligible requirement for sedation. About half of trained animals had no to moderate thymic involution, indicative of a substantial reduction in stress. Conclusion Cooperative handling enhances animal well-being. This contributes to validity of scientific results and eliminates model-induced confounding that can obstruct interpretation of safety and efficacy data. PMID:22150842

Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors

PubMed Central

Lehar, Sophie M.; Dooley, James; Farr, Andrew G.; Bevan, Michael J.

2009-01-01

Signaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow-derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and γδ T-cell lineages. PMID:15486060

CD4+ memory T cells retain surface expression of CD31 independently of thymic function in patients with lymphoproliferative disorders following autologous hematopoietic stem-cell transplantation.

PubMed

Batorov, Egor V; Tikhonova, Marina A; Kryuchkova, Irina V; Sergeevicheva, Vera V; Sizikova, Svetlana A; Ushakova, Galina Y; Batorova, Dariya S; Gilevich, Andrey V; Ostanin, Alexander A; Shevela, Ekaterina Y; Chernykh, Elena R

2017-07-01

High-dose chemotherapy with autologous hematopoietic stem-cell transplantation (AHSCT) causes severe and long-lasting immunodeficiency in patients with lymphoproliferative disorders. The thymus begins to restore the T-cell repertoire approximately from the sixth month post-transplant. We assessed the dynamics of post-transplant recovery of CD4 + CD45RA + CD31 + T cells, "recent thymic emigrants" (RTEs), and a poorly described subtype of CD4 + CD45RA - CD31 + T cells in 90 patients with lymphoproliferative disorders following high-dose chemotherapy with AHSCT. Relative and absolute counts of CD4 + CD31 + naïve and memory T cells were evaluated before AHSCT, at the day of engraftment, and 6- and 12-month post-transplant. The pre-transplant count of CD4 + CD45RA + CD31 + T cells was lower than in healthy controls, and did not reach donors' values during the 12-month period. The pre-transplant number of CD4 + CD45RA - CD31 + T cells was higher than in healthy controls and was restored rapidly following AHSCT. Post-transplant mediastinal radiotherapy reduced counts of RTEs and elongated recovery period. Non-thymic tissue irradiation did not reduce this subset. The obtained data indicate that homeostatic proliferation may decrease the significance of CD31 expression on CD4 + CD45RA + T cells as a marker of RTEs, and suggest that evaluation of RTEs recovery by flow cytometry requires an accurate gating strategy to exclude CD31 + memory T cells.

The Petit Rat (pet/pet), a New Semilethal Mutant Dwarf Rat with Thymic and Testicular Anomalies

PubMed Central

Chiba, Junko; Suzuki, Katsushi; Suzuki, Hiroetsu

2008-01-01

The petit rat (pet/pet) is a recently discovered semilethal mutant dwarf. The neonatal pet/pet rats had a low body weight and small thymus and testis. During the first 3 d after birth, 50% of the male and 80% of the female pet/pet pups were lost or found dead. Surviving pet/pet rats showed marked retardation of postnatal growth, and their body weights were 41% (female rats) and 32% (male rats) of those of normal rats at the adult stage. The pet/pet rats exhibited proportional dwarfism, and their longitudinal bones were shorter than those of controls without skeletal malformations. Most organs of male pet/pet rats, especially the thymus, testis, adipose tissue surrounding the kidney, and accessory sex organs, weighed markedly less at 140 d of age than did those of their normal counterparts. The thymus of pet/pet rats was small with abnormal thymic follicles. Testes from pet/pet rats exhibited 2 patterns of abnormal histology. Spermatogenesis was present in testes that were only slightly anomalous, but the seminiferous tubules were reduced in diameter. In severely affected testes, most of the seminiferous tubules showed degeneration, and interstitial tissue was increased. Plasma growth hormone concentrations did not differ between pet/pet and normal male rats. The dwarf phenotype of pet/pet rats was inherited as an autosomal recessive trait. These results indicate that the pet/pet rat has a semilethal growth-hormone-independent dwarf phenotype that is accompanied by thymic and testicular anomalies and low birth weight. PMID:19149412

Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency

PubMed Central

Wong, Gabriel K.; Millar, David; Penny, Sarah; Heather, James M.; Mistry, Punam; Buettner, Nico; Bryon, Jane; Huissoon, Aarnoud P.

2016-01-01

Although common variable immunodeficiency (CVID) has long been considered as a group of primary Ab deficiencies, growing experimental data now suggest a global disruption of the entire adaptive immune response in a segment of patients. Oligoclonality of the TCR repertoire was previously demonstrated; however, the manner in which it relates to other B cell and T cell findings reported in CVID remains unclear. Using a combination approach of high-throughput TCRβ sequencing and multiparametric flow cytometry, we compared the TCR repertoire diversity between various subgroups of CVID patients according to their B cell immunophenotypes. Our data suggest that the reduction in repertoire diversity is predominantly restricted to those patients with severely reduced class-switched memory B cells and an elevated level of CD21lo B cells (Freiburg 1a), and may be driven by a reduced number of naive T cells unmasking underlying memory clonality. Moreover, our data indicate that this loss in repertoire diversity progresses with advancing age far exceeding the expected physiological rate. Radiological evidence supports the loss in thymic volume, correlating with the decrease in repertoire diversity. Evidence now suggests that primary thymic failure along with other well-described B cell abnormalities play an important role in the pathophysiology in Freiburg group 1a patients. Clinically, our findings emphasize the integration of combined B and T cell testing to identify those patients at the greatest risk for infection. Future work should focus on investigating the link between thymic failure and the severe reduction in class-switched memory B cells, while gathering longitudinal laboratory data to examine the progressive nature of the disease. PMID:27481850

The petit rat (pet/pet), a new semilethal mutant dwarf rat with thymic and testicular anomalies.

PubMed

Chiba, Junko; Suzuki, Katsushi; Suzuki, Hiroetsu

2008-12-01

The petit rat (pet/pet) is a recently discovered semilethal mutant dwarf. The neonatal pet/pet rats had a low body weight and small thymus and testis. During the first 3 d after birth, 50% of the male and 80% of the female pet/pet pups were lost or found dead. Surviving pet/pet rats showed marked retardation of postnatal growth, and their body weights were 41% (female rats) and 32% (male rats) of those of normal rats at the adult stage. The pet/pet rats exhibited proportional dwarfism, and their longitudinal bones were shorter than those of controls without skeletal malformations. Most organs of male pet/pet rats, especially the thymus, testis, adipose tissue surrounding the kidney, and accessory sex organs, weighed markedly less at 140 d of age than did those of their normal counterparts. The thymus of pet/pet rats was small with abnormal thymic follicles. Testes from pet/pet rats exhibited 2 patterns of abnormal histology. Spermatogenesis was present in testes that were only slightly anomalous, but the seminiferous tubules were reduced in diameter. In severely affected testes, most of the seminiferous tubules showed degeneration, and interstitial tissue was increased. Plasma growth hormone concentrations did not differ between pet/pet and normal male rats. The dwarf phenotype of pet/pet rats was inherited as an autosomal recessive trait. These results indicate that the pet/pet rat has a semilethal growth-hormone-independent dwarf phenotype that is accompanied by thymic and testicular anomalies and low birth weight.

T-cell antigenic sites involved in myasthenia gravis: correlations with antibody titre and disease severity.

PubMed

Berrih-Aknin, S; Cohen-Kaminsky, S; Lepage, V; Neumann, D; Bach, J F; Fuchs, S

1991-02-01

We have evaluated the ability of eight synthetic peptides corresponding to selected regions of the alpha-subunit from human (H) or Torpedo (T) acetylcholine receptor (AChR) to stimulate proliferative responses of peripheral blood lymphocytes (PBL) and thymic cells from patients with Myasthenia Gravis (MG) in comparison to healthy controls. Using PBL, two of the peptides were most reactive: in the 40 myasthenic patients tested, peptide 169-181 (H) induced significant proliferative responses in 10 patients and peptide 351-368 (H) in five, while there was no response in any of the 34 healthy controls tested. Interestingly, clear associations between proliferation to peptides and clinical data were observed. Indeed, among responding patients, all presented thymic hyperplasia and most showed a high anti-AChR Ab titre and/or a severe form of the disease. In addition, responses to AChR cytoplasmic sequences were observed only in severely affected patients. Correlation with HLA-DR haplotype, sought in a subgroup of patients, indicated that response to 169-181 (H) is associated with HLA-DR5 in the patients presenting a high anti-AChR antibody titre. Using thymic lymphocytes, few responses were obtained with the human peptides, suggesting that the frequency of autoreactive cells is lower than in the blood. Similar to PBL, responses to peptides were observed only with lymphocytes isolated from hyperplastic thymuses. The correlations observed between responses to peptides and clinical parameters underline the pathophysiological relevance of our data and indicate that pathogenic and nonpathogenic T-cell antigenic sites involved in the anti-AChR response could be identified by this approach.

Invasive plants may promote predator-mediated feedback that inhibits further invasion

PubMed Central

Smith, Lauren M; Schmitz, Oswald J

2015-01-01

Understanding the impacts of invasive species requires placing invasion within a full community context. Plant invaders are often considered in the context of herbivores that may drive invasion by avoiding invaders while consuming natives (enemy escape), or inhibit invasion by consuming invaders (biotic resistance). However, predators that attack those herbivores are rarely considered as major players in invasion. Invasive plants often promote predators, generally by providing improved habitat. Here, we show that predator-promoting invaders may initiate a negative feedback loop that inhibits invasion. By enabling top-down control of herbivores, predator-promoting invaders lose any advantage gained through enemy escape, indirectly favoring natives. In cases where palatable invaders encounter biotic resistance, predator promotion may allow an invader to persist, but not dominate. Overall, results indicate that placing invaders in a full community context may reveal reduced impacts of invaders compared to expectations based on simple plant–plant or plant–herbivore subsystems. PMID:26120430

Detection of a premature stop codon in the surface gene of hepatitis B virus from an HBsAg and antiHBc negative blood donor.

PubMed

Datta, Sibnarayan; Banerjee, Arup; Chandra, Partha K; Chakraborty, Subhasis; Basu, Subir Kumar; Chakravarty, Runu

2007-11-01

In blood donors, HBV infection is detected by the presence of serum hepatitis B surface antigen (HBsAg). However, some mutations in the surface gene region may result in altered or truncated HBsAg that can escape from immunoassay-based diagnosis. Such diagnostic escape mutants pose a potential risk for blood transfusion services. In the present study, we report a blood donor seronegative for HBsAg and antiHBc, but positive for antiHBs who was HBV DNA positive by PCR. Sequencing of the HBsAg gene revealed presence of a point mutation (T-A) at 207th nucleotide of the HBsAg ORF, which resulted in a premature stop codon at position 69. This results in a truncated HBsAg gene lacking the entire 'a' determinant region. However, follow-up of the donor after 2 years revealed clearance of HBV DNA from the serum. The case illustrates an unusual mutation, which causes HBsAg negativity. The finding emphasizes the importance of molecular assays in reducing the possibility of HBV transmission through blood transfusion. However, developing more sensitive serological assays, capable of detecting HBV mutants, is an alternative to expensive and complex amplification-based assays for developing countries.

Type three secretion system-mediated escape of Burkholderia pseudomallei into the host cytosol is critical for the activation of NFκB.

PubMed

Teh, Boon Eng; French, Christopher Todd; Chen, Yahua; Chen, Isabelle Gek Joo; Wu, Ting-Hsiang; Sagullo, Enrico; Chiou, Pei-Yu; Teitell, Michael A; Miller, Jeff F; Gan, Yunn-Hwen

2014-05-06

Burkholderia pseudomallei is the causative agent of melioidosis, a potentially fatal disease endemic in Southeast Asia and Northern Australia. This Gram-negative pathogen possesses numerous virulence factors including three "injection type" type three secretion systems (T3SSs). B. pseudomallei has been shown to activate NFκB in HEK293T cells in a Toll-like receptor and MyD88 independent manner that requires T3SS gene cluster 3 (T3SS3 or T3SSBsa). However, the mechanism of how T3SS3 contributes to NFκB activation is unknown. Known T3SS3 effectors are not responsible for NFκB activation. Furthermore, T3SS3-null mutants are able to activate NFκB almost to the same extent as wildtype bacteria at late time points of infection, corresponding to delayed escape into the cytosol. NFκB activation also occurs when bacteria are delivered directly into the cytosol by photothermal nanoblade injection. T3SS3 does not directly activate NFκB but facilitates bacterial escape into the cytosol where the host is able to sense the presence of the pathogen through cytosolic sensors leading to NFκB activation.

Tumor dormancy and cell signaling. V. Regrowth of the BCL1 tumor after dormancy is established.

PubMed

Vitetta, E S; Tucker, T F; Racila, E; Huang, Y W; Marches, R; Lane, N; Scheuermann, R H; Street, N E; Watanabe, T; Uhr, J W

1997-06-15

The majority of BALB/c mice immunized with the BCL1 lymphoma-derived idiotype (Id+) IgM and subsequently challenged with BCL1 tumor cells develop a state of tumor dormancy. The vast majority of dormant lymphoma cells are in cell cycle arrest, but there are also residual replicating cells. In the present studies, we attempted to define features of both the dormant lymphoma cells and the host that lead to escape from dormancy. Escape from dormancy occurs at a steady rate over a 2-year period, suggesting that it is a stochastic process. We found that, in the majority of mice, escape was due to the emergence of genetic variants that were no longer susceptible to the anti-Id-mediated induction of dormancy. Ten percent of these variants were Id-; the remainder were Id+ but could grow in the presence of anti-Id antibodies, suggesting that there were mutations in molecules involved in one or more mIg-mediated negative-signaling pathways. In two of five such escapees, alterations in either Syk, HS1, and/or Lyn were observed. In a small percentage of mice, a low titer of circulating anti-Id antibody before tumor challenge correlated with a subsequent, more rapid loss of dormancy.

Distinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing.

PubMed

Walker, Andreas; Skibbe, Kathrin; Steinmann, Eike; Pfaender, Stephanie; Kuntzen, Thomas; Megger, Dominik A; Groten, Svenja; Sitek, Barbara; Lauer, Georg M; Kim, Arthur Y; Pietschmann, Thomas; Allen, Todd M; Timm, Joerg

2016-01-01

Antiviral CD8(+) T cells are a key component of the adaptive immune response against HCV, but their impact on viral control is influenced by preexisting viral variants in important target epitopes and the development of viral escape mutations. Immunodominant epitopes highly conserved across genotypes therefore are attractive for T cell based prophylactic vaccines. Here, we characterized the CD8(+) T cell response against the highly conserved HLA-B*51-restricted epitope IPFYGKAI1373-1380 located in the helicase domain of NS3 in people who inject drugs (PWID) exposed predominantly to HCV genotypes 1a and 3a. Despite this epitope being conserved in both genotypes, the corresponding CD8(+) T cell response was detected only in PWID infected with genotype 3a and HCV-RNA negative PWID, but not in PWID infected with genotype 1a. In genotype 3a, the detection of strong CD8(+) T cell responses was associated with epitope variants in the autologous virus consistent with immune escape. Analysis of viral sequences from multiple cohorts confirmed HLA-B*51-associated escape mutations inside the epitope in genotype 3a, but not in genotype 1a. Here, a distinct substitution in the N-terminal flanking region located 5 residues upstream of the epitope (S1368P; P = 0.00002) was selected in HLA-B*51-positive individuals. Functional assays revealed that the S1368P substitution impaired recognition of target cells presenting the endogenously processed epitope. The results highlight that, despite an epitope being highly conserved between two genotypes, there are major differences in the selected viral escape pathways and the corresponding T cell responses. HCV is able to evolutionary adapt to CD8(+) T cell immune pressure in multiple ways. Beyond selection of mutations inside targeted epitopes, this study demonstrates that HCV inhibits epitope processing by modification of the epitope flanking region under T cell immune pressure. Selection of a substitution five amino acids upstream of the epitope underlines that efficient antigen presentation strongly depends on its larger sequence context and that blocking of the multistep process of antigen processing by mutation is exploited also by HCV. The pathways to mutational escape of HCV are to some extent predictable but are distinct in different genotypes. Importantly, the selected escape pathway of HCV may have consequences for the destiny of antigen-specific CD8(+) T cells. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Both positive and negative effects on immune responses by expression of a second class II MHC molecule.

PubMed

Ni, Peggy P; Wang, Yaming; Allen, Paul M

2014-11-01

It is perplexing why vertebrates express a limited number of major histocompatibility complex (MHC) molecules when theoretically, having a greater repertoire of MHC molecules would increase the number of epitopes presented, thereby enhancing thymic selection and T cell response to pathogens. It is possible that any positive effects would either be neutralized or outweighed by negative selection restricting the T cell repertoire. We hypothesize that the limit on MHC number is due to negative consequences arising from expressing additional MHC. We compared T cell responses between B6 mice (I-A(+)) and B6.E(+) mice (I-A(+), I-E(+)), the latter expressing a second class II MHC molecule, I-E(b), due to a monomorphic Eα(k) transgene that pairs with the endogenous I-Eβ(b) chain. First, the naive T cell Vβ repertoire was altered in B6.E(+) thymi and spleens, potentially mediating different outcomes in T cell reactivity. Although the B6 and B6.E(+) responses to hen egg-white lysozyme (HEL) protein immunization remained similar, other immune models yielded differences. For viral infection, the quality of the T cell response was subtly altered, with diminished production of certain cytokines by B6.E(+) CD4(+) T cells. In alloreactivity, the B6.E(+) T cell response was significantly dampened. Finally, we observed markedly enhanced susceptibility to experimental autoimmune encephalomyelitis (EAE) in B6.E(+) mice. This correlated with decreased percentages of nTreg cells, supporting the concept of Tregs exhibiting differential susceptibility to negative selection. Altogether, our data suggest that expressing an additional class II MHC can produce diverse effects, with more severe autoimmunity providing a compelling explanation for limiting the expression of MHC molecules. Copyright © 2014 Elsevier Ltd. All rights reserved.

The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation.

PubMed

Bardhan, Kankana; Anagnostou, Theodora; Boussiotis, Vassiliki A

2016-01-01

The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self-reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (T Regs ). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells.

The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation

PubMed Central

Bardhan, Kankana; Anagnostou, Theodora; Boussiotis, Vassiliki A.

2016-01-01

The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self-reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells. PMID:28018338

Myf5 and Myogenin in the development of thymic myoid cells - Implications for a murine in vivo model of myasthenia gravis.

PubMed

Hu, Bo; Simon-Keller, Katja; Küffer, Stefan; Ströbel, Philipp; Braun, Thomas; Marx, Alexander; Porubsky, Stefan

2016-03-01

Myasthenia gravis (MG) is caused by autoantibodies against the neuromuscular junction of striated muscle. Most MG patients have autoreactive T- and B-cells directed to the acetylcholine receptor (AChR). To achieve immunologic tolerance, developing thymocytes are normally eliminated after recognition of self-antigen-derived peptides. Presentation of muscle-specific antigens is likely achieved through two pathways: on medullary thymic epithelial cells and on medullary dendritic cells cross-presenting peptides derived from a unique population of thymic myoid cells (TMC). Decades ago, it has been hypothesized that TMC play a key role in the induction of immunological tolerance towards skeletal muscle antigens. However, an experimental model to address this postulate has not been available. To generate such a model, we tested the hypothesis that the development of TMC depends on myogenic regulatory factors. To this end, we utilized Myf5-deficient mice, which lack the first wave of muscle cells but form normal skeletal muscles later during development, and Myogenin-deficient mice, which fail to form differentiated myofibers. We demonstrate for the first time that Myf5- and Myogenin-deficient mice showed a partial or complete, respectively, loss of TMC in an otherwise regularly structured thymus. To overcome early postnatal lethality of muscle-deficient, Myogenin-knockout mice we transplanted Myogenin-deficient fetal thymuses into Foxn1(nu/nu) mice that lack their own thymus anlage. We found that the transplants are functional but lack TMC. In combination with established immunization strategies (utilizing AChR or Titin), this model should enable us in the future testing the hypothesis that TMC play an indispensable role in the development of central tolerance towards striated muscle antigens. Copyright © 2015 Elsevier Inc. All rights reserved.

Enhanced renewal of regulatory T cells in relation to CD4(+) conventional T lymphocytes in the peripheral compartment.

PubMed

Nogueira, Jeane de Souza; Canto, Fábio Barrozo do; Nunes, Caroline Fraga Cabral Gomes; Vianna, Pedro Henrique Oliveira; Paiva, Luciana de Souza; Nóbrega, Alberto; Bellio, Maria; Fucs, Rita

2016-02-01

CD4(+) Foxp3(+) regulatory T (Treg) cells are necessary for the maintenance of self-tolerance and T-cell homeostasis. This population is kept at stable frequencies in secondary lymphoid organs for the majority of the lifetime, despite permanent thymic emigration or in the face of thymic involution. Continuous competition is expected to occur between recently thymus-emigrated and resident Treg cells (either natural or post-thymically induced). In the present work, we analysed the renewal dynamics of Treg cells compared with CD4(+) Foxp3- conventional T cells (Tconv), using protocols of single or successive T-cell transfers into syngeneic euthymic or lymphopenic (nu/nu or RAG2(-/-)) mice, respectively. Our results show a higher turnover for Treg cells in the peripheral compartment, compared with Tconv cells, when B cell-sufficient euthymic or nude hosts are studied. This increased renewal within the Treg pool, shown by the greater replacement of resident Treg cells by donor counterparts, correlates with augmented rates of proliferation and is not modified following temporary environmental perturbations induced by inflammatory state or microbiota alterations. Notably, the preferential substitution of Treg lymphocytes was not observed in RAG2(-/-) hosts. We showed that limited B-cell replenishment in the RAG2(-/-) hosts decisively contributed to the altered peripheral T-cell homeostasis. Accordingly, weekly transfers of B cells to RAG2(-/-) hosts rescued the preferential substitution of Treg lymphocytes. Our study discloses a new aspect of T-cell homeostasis that depends on the presence of B lymphocytes to regulate the relative incorporation of recently arrived Treg and Tconv cells in the peripheral compartment. © 2015 John Wiley & Sons Ltd.

Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A

PubMed Central

Vallejo, Abbe N.; Michel, Joshua J.; Bale, Laurie K.; Lemster, Bonnie H.; Borghesi, Lisa; Conover, Cheryl A.

2009-01-01

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA−/− mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy, 18-month-old PAPPA−/− mice maintain discrete thymic cortex and medulla densely populated by CD4+CD8+ thymocytes that are capable of differentiating into single-positive CD4 and CD8 T cells. Old PAPPA−/− mice have high levels of T cell receptor excision circles, and have bone marrows enriched for subsets of thymus-seeding progenitors. PAPPA−/− mice have an overall larger pool of naive T cells, and also exhibit an age-dependent accumulation of CD44+CD43+ memory T cells similar to wild-type mice. However, CD43+ T cell subsets of old PAPPA−/− mice have significantly lower prevalence of 1B11 and S7, glycosylation isoforms known to inhibit T cell activation with normal aging. In bioassays of cell activation, splenic T cells of old PAPPA−/− mice have high levels of activation antigens and cytokine production, and also elicit Ig production by autologous B cells at levels equivalent to young wild-type mice. These data suggest an IGF-immune axis of healthy longevity. Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune homeostasis during postnatal development and aging. PMID:19549878

Prolonged CD4 T Cell Lymphopenia Increases Morbidity and Mortality after Renal Transplantation

PubMed Central

Courivaud, Cécile; Bamoulid, Jamal; Vivet, Bérengère; Chabroux, Aline; Deschamps, Marina; Rebibou, Jean-Michel; Ferrand, Christophe; Chalopin, Jean-Marc; Tiberghien, Pierre; Saas, Philippe

2010-01-01

Prolonged CD4 T cell lymphopenia after administration of polyclonal anti-thymocyte globulins increases the rate of posttransplantation morbidity, but whether impaired immune reconstitution affects survival is unknown. We studied the effect of CD4 T cell lymphopenia on survival in 302 consecutive prevalent renal transplant recipients and the role of thymic function in CD4 T cell reconstitution and posttransplantation outcomes in 100 consecutive incident renal transplant recipients. We followed the prevalent cohort for a mean duration of 92 months. Of these 302 patients, 81 (27%) had persistent CD4 T cell counts <300/mm3 and 36 (12%) died during follow-up. We observed a higher death rate in patients with CD4 T cell lymphopenia persisting for >1 year (24.1 versus 7.6%; P < 0.001). Furthermore, in Cox regression analysis, CD4 T cell lymphopenia associated with a nearly five-fold risk for death (adjusted hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.91 to 10.65; P = 0.001). In the incident cohort, we estimated thymic function by T cell receptor excision circles (TRECs) per 150,000 CD3+ cells, which predicted efficient CD4 T cell reconstitution. Higher pretransplantation TREC values associated with lower risks for cancer (adjusted HR 0.39; 95% CI 0.15 to 0.97; P = 0.046) and infection (HR 0.29; 95% CI 0.11 to 0.78; P = 0.013). In summary, prolonged polyclonal anti-thymocyte globulin–induced CD4 T cell lymphopenia is an independent risk factor for death. Determination of pretransplantation thymic function may identify patients at higher risk for CD4 T cell lymphopenia and posttransplantation morbidity, including cancer and infections. PMID:20203160

Prolonged CD4 T cell lymphopenia increases morbidity and mortality after renal transplantation.

PubMed

Ducloux, Didier; Courivaud, Cécile; Bamoulid, Jamal; Vivet, Bérengère; Chabroux, Aline; Deschamps, Marina; Rebibou, Jean-Michel; Ferrand, Christophe; Chalopin, Jean-Marc; Tiberghien, Pierre; Saas, Philippe

2010-05-01

Prolonged CD4 T cell lymphopenia after administration of polyclonal anti-thymocyte globulins increases the rate of posttransplantation morbidity, but whether impaired immune reconstitution affects survival is unknown. We studied the effect of CD4 T cell lymphopenia on survival in 302 consecutive prevalent renal transplant recipients and the role of thymic function in CD4 T cell reconstitution and posttransplantation outcomes in 100 consecutive incident renal transplant recipients. We followed the prevalent cohort for a mean duration of 92 months. Of these 302 patients, 81 (27%) had persistent CD4 T cell counts <300/mm3 and 36 (12%) died during follow-up. We observed a higher death rate in patients with CD4 T cell lymphopenia persisting for >1 year (24.1 versus 7.6%; P < 0.001). Furthermore, in Cox regression analysis, CD4 T cell lymphopenia associated with a nearly five-fold risk for death (adjusted hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.91 to 10.65; P = 0.001). In the incident cohort, we estimated thymic function by T cell receptor excision circles (TRECs) per 150,000 CD3+ cells, which predicted efficient CD4 T cell reconstitution. Higher pretransplantation TREC values associated with lower risks for cancer (adjusted HR 0.39; 95% CI 0.15 to 0.97; P = 0.046) and infection (HR 0.29; 95% CI 0.11 to 0.78; P = 0.013). In summary, prolonged polyclonal anti-thymocyte globulin-induced CD4 T cell lymphopenia is an independent risk factor for death. Determination of pretransplantation thymic function may identify patients at higher risk for CD4 T cell lymphopenia and posttransplantation morbidity, including cancer and infections.

Subcellular distribution of Lck during CD4 T-cell maturation in the thymic medulla regulates the T-cell activation threshold.

PubMed

Stephen, Tom Li; Wilson, Bridget S; Laufer, Terri M

2012-05-08

Mature peripheral T cells respond to foreign but not to self-antigens. During development in the thymus, deletion of high-affinity self-reactive immature thymocytes contributes to tolerance of mature T cells. However, double-positive thymocytes are positively selected to survive if they respond to self-peptide-MHC complexes; thus, there must be mechanisms to prevent overt reactivity to those same complexes in the periphery. "Developmental tuning" is the active process through which T-cell receptor (TCR)-associated signaling pathways of single-positive (SP) thymocytes are attenuated to respond appropriately to self-peptide-MHC complexes in the periphery. We previously showed that MHC class II expression in the thymic medulla was necessary to tune CD4(+) SP (CD4 SP) thymocytes. CD4 SP thymocytes from mice lacking medullary MHC class II expression had inappropriately enhanced proximal TCR signaling to low-affinity self-ligands that was associated with altered cellular distribution of the tyrosine kinase Lck. Now, we report that activation of both tuned and untuned CD4 SP thymocytes is Lck-dependent. Untuned CD4 SP cells contain a pool of Lck with increased basal phosphorylation that is not associated with the CD4 coreceptor. Phosphorylation of this pool of Lck decreases with tuning. Immunogold transmission electron microscopy of membrane sheets permitted direct visualization of Lck. In the absence of tuning, a significant proportion of Lck and the TCR subunit CD3ζ are expressed on the same protein island; this close association of Lck and the TCR probably explains the enhanced activation of untuned CD4 SP cells. Thus, changes in membrane topography during thymic maturation determine the set point for TCR responsiveness.

Pb exposure attenuates hypersensitivity in vivo by increasing regulatory T cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Liang; Zhao, Fang; Shen, Xuefeng

Pb is a common environmental pollutant affecting various organs. Exposure of the immune system to Pb leads to immunosuppression or immunodysregulation. Although previous studies showed that Pb exposure can modulate the function of helper T cells, Pb immunotoxicity remains incompletely understood. In this study, we investigated the effect of Pb exposure on T cell development, and the underlying mechanism of Pb-induced suppression of the delayed-type hypersensitivity (DTH) response in vivo. Sprague–Dawley rats were exposed to 300 ppm Pb-acetate solution via the drinking water for six weeks, and we found that Pb exposure significantly increased Pb concentrations in the blood bymore » 4.2-fold (p < 0.05) as compared to those in the control rats. In Pb-exposed rats, the amount of thymic CD4{sup +}CD8{sup −} and peripheral CD4{sup +} T cells was significantly reduced, whereas, CD8{sup +} population was not affected. In contrast to conventional CD4{sup +} T cells, Foxp3{sup +} regulatory T cells (Tregs) were increased in both the thymus and peripheral lymphoid organs of Pb-exposed rats. In line with the increase of Tregs, the DTH response of Pb-exposed rats was markedly suppressed. Depletion of Tregs reversed the suppression of DTH response by Pb-exposed CD4{sup +} T cells in an adoptive transfer model, suggesting a critical role of the increased Tregs in suppressing the DTH response. Collectively, this study revealed that Pb-exposure may upregulate Tregs, thereby leading to immunosuppression. -- Highlights: ► Pb exposure impaired CD4{sup +} thymic T cell development. ► Peripheral T lymphocytes were reduced following Pb exposure. ► Pb exposure increases thymic and peripheral Treg cells in rats. ► Tregs played a critical role in Pb-exposure-induced immune suppression.« less

[Comparison of the Masaoka-Koga Classification with the New TNM Staging of the IASLC/ITMIG for Thymoma and Thymic Carcinoma].

PubMed

Ried, Michael; Eicher, Maria-Magdalena; Neu, Reiner; Kraus, Dietmar; Inderhees, Sebastian; Marx, Alexander; Hofmann, Hans-Stefan

2018-05-18

The Masaoka-Koga classification describes the extent and spread of thymic epithelial malignancies. The objective of this study was to evaluate the Masaoka-Koga and the new TNM-staging system regarding differences in stage distributions, clinical implementation and therapeutic consequences. Retrospective analysis of all patients who underwent surgery between January 2005 and December 2015 for thymoma/thymic carcinoma in two centres for thoracic surgery. The final tumour stages were determined on the basis of preoperative imaging, surgical reports and histological findings. A total of 118 patients (male 51%) with a mean age of 56 ± 14.8 years were included. Indications for surgery were primary mediastinal tumour (n = 97), pleura dissemination (n = 15) or mediastinal recurrence (n = 7). Radical tumour resection was performed in 92% of patients (n = 109) within one operation, whereas 8% of patients (n = 9) underwent two operations. Surgical revision was necessary in 12 patients (10.1%) and in-hospital mortality was 1.7% (n = 2). Early Masaoka-Koga stages I (n = 34) and II (n = 16) shifted to the new UICC stage I (T1: n = 58). Locally advanced stages (Masaoka-Koga stage III n = 22 vs. UICC stage IIIA + IIIB n = 20) and metastasised stages (Masaoka-Koga stage IV n = 36 vs. UICC stage IV n = 39) remained very similar. The new TNM staging system gave rise to changes, especially in early stages (downstaging), but these had no therapeutic implications. Although advanced stages were very similar, the new TNM staging provides more clinically relevant differentiation. Georg Thieme Verlag KG Stuttgart · New York.

Measuring the Ability to Cope with Serious Illness

DTIC Science & Technology

1983-09-01

effort to negate a problem or situation; avoidance refers to acceptance of the reality of the threat, but there is deliberate effort not to ’think or... hypnosis or self- hypnosis (Kroger, 1977), mental imagery (Simonton, Simonton, and Creighton, 1978), and relaxation exercises (Jaffe, 1980). Escape/Distra...health and coping. Virtually none of the social network/social support measures were associated \\o;ith. any of the ratings, except people I.’ith

13. Photocopy of 1920 drawing titled: BUILDING 78, 3RD FLOOR ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

13. Photocopy of 1920 drawing titled: BUILDING 78, 3RD FLOOR BALCONY AND FIRE ESCAPES, including plans for skylight and North Elevation. HABS photograph is an 8x10' contact print made from a high contrast negative of an enlargement made from microfiche. Original is in the collection of Department of Public Works, Puget Sound Naval Shipyard, Bremerton, WA. - Puget Sound Naval Shipyard, Administration Building, Farragut Avenue, Bremerton, Kitsap County, WA

Regulatory and evolutionary signatures of sex-biased genes on both the X chromosome and the autosomes.

PubMed

Shen, Jiangshan J; Wang, Ting-You; Yang, Wanling

2017-11-02

Sex is an important but understudied factor in the genetics of human diseases. Analyses using a combination of gene expression data, ENCODE data, and evolutionary data of sex-biased gene expression in human tissues can give insight into the regulatory and evolutionary forces acting on sex-biased genes. In this study, we analyzed the differentially expressed genes between males and females. On the X chromosome, we used a novel method and investigated the status of genes that escape X-chromosome inactivation (escape genes), taking into account the clonality of lymphoblastoid cell lines (LCLs). To investigate the regulation of sex-biased differentially expressed genes (sDEG), we conducted pathway and transcription factor enrichment analyses on the sDEGs, as well as analyses on the genomic distribution of sDEGs. Evolutionary analyses were also conducted on both sDEGs and escape genes. Genome-wide, we characterized differential gene expression between sexes in 462 RNA-seq samples and identified 587 sex-biased genes, or 3.2% of the genes surveyed. On the X chromosome, sDEGs were distributed in evolutionary strata in a similar pattern as escape genes. We found a trend of negative correlation between the gene expression breadth and nonsynonymous over synonymous mutation (dN/dS) ratios, showing a possible pleiotropic constraint on evolution of genes. Genome-wide, nine transcription factors were found enriched in binding to the regions surrounding the transcription start sites of female-biased genes. Many pathways and protein domains were enriched in sex-biased genes, some of which hint at sex-biased physiological processes. These findings lend insight into the regulatory and evolutionary forces shaping sex-biased gene expression and their involvement in the physiological and pathological processes in human health and diseases.

ALTERED HISTOLOGY OF THE THYMUS AND SPLEEN IN CONTAMINANT-EXPOSED JUVENILE AMERICAN ALLIGATORS

EPA Science Inventory

Morphological difference in spleen and thymus are closely related to functional immune differences. Hormonal regulation of the immune system has been demonstrated in reptilian splenic and thymic tissue. Spleens and thymus were obtained from juvenile alligators at two reference si...

Wild Steelhead and introduced spring Chinook Salmon in the Wind River, Washington: Overlapping populations and interactions

USGS Publications Warehouse

Jezorek, I.G.; Connolly, P.J.

2010-01-01

We investigated interactions of introduced juvenile spring Chinook salmon Oncorhynchus tshawytscha with wild juvenile steelhead O. mykiss in the upper Wind River watershed (rkm 24.6 to rkm 43.8), Washington. Our objective was to determine if the presence of introduced spring Chinook salmon influenced populations of wild juvenile steelhead and if other biotic or abiotic factors influenced distribution and populations of these species. We snorkeled to assess distribution and abundance in one to six stream reaches per year during 2001 through 2007. Juvenile steelhead were found in each sampled reach each year, but juvenile Chinook salmon were not. The upstream extent of distribution of juvenile Chinook salmon varied from rkm 29.7 to 42.5. Our analyses suggest that juvenile Chinook salmon distribution was much influenced by flow during the spawning season. Low flow appeared to limit access of escaped adult Chinook salmon to upper stream reaches. Abundance of juvenile Chinook salmon was also influenced by base flow during the previous year, with base flow occurring post spawn in late August or early September. There were no relationships between juvenile Chinook salmon abundance and number of Chinook salmon spawners, magnitude of winter flow that might scour redds, or abundance of juvenile steelhead. Abundance of age-0 steelhead was influenced primarily by the number of steelhead spawners the previous year, and abundance of age-1 steelhead was influenced primarily by abundance of age-0 steelhead the previous year. Juvenile steelhead abundance did not show a relationship with base or peak flows, nor with number of escaped Chinook salmon adults during the previous year. We did not detect a negative influence of the relatively low abundance of progeny of escaped Chinook salmon on juvenile steelhead abundance. This low abundance of juvenile Chinook salmon was persistent throughout our study and is likely a result of hatchery management and habitat conditions. Should one or both change in the future, the potential for negative interactions with wild steelhead could change.

Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover.

PubMed

Westera, Liset; van Hoeven, Vera; Drylewicz, Julia; Spierenburg, Gerrit; van Velzen, Jeroen F; de Boer, Rob J; Tesselaar, Kiki; Borghans, José A M

2015-04-01

In healthy humans, lymphocyte populations are maintained at a relatively constant size throughout life, reflecting a balance between lymphocyte production and loss. Given the profound immunological changes that occur during healthy aging, including a significant decline in T-cell production by the thymus, lymphocyte maintenance in the elderly is generally thought to require homeostatic alterations in lymphocyte dynamics. Surprisingly, using in vivo (2) H2 O labeling, we find similar dynamics of most lymphocyte subsets between young adult and elderly healthy individuals. As the contribution of thymic output to T-cell production is only minor from young adulthood onward, compensatory increases in peripheral T-cell division rates are not required to maintain the T-cell pool, despite a tenfold decline in thymic output. These fundamental insights will aid the interpretation of further research into aging and clinical conditions related to disturbed lymphocyte dynamics. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Adrenergic nerve fibres and mast cells: correlation in rat thymus.

PubMed

Artico, Marco; Cavallotti, Carlo; Cavallotti, Daniela

2002-10-21

The interactions between adrenergic nerve fibres and mast cells (MCs) were studied in the thymus of adult and old rats by morphological methods and by quantitative analysis of images (QAIs). The whole thymus was drawn in adult (12 months old) rats: normal, sympathectomized or electrostimulated. Thymuses from the above-mentioned animals were weighed, measured and dissected. Thymic slices were stained with eosin orange for detection of microanatomical details and with Bodian's method for identification of the whole nerve fibres. Thymic MCs were stained with Astrablau. Histofluorescence microscopy was used for staining of adrenergic nerve fibres. Finally, all morphological results were submitted to the QAIs and statistical analysis of data. Our results suggest that after surgical sympathectomy, the greater part of adrenergic nerve fibres disappear while related MCs appear to show less evident fluorescence and few granules. On the contrary, electrostimulation of the cervical superior ganglion induced an increase in the fluorescence of adrenergic nerve fibres and of related MCs.

Ontogenic development of kidney, thymus and spleen and phenotypic expression of CD3 and CD4 receptors on the lymphocytes of cobia (Rachycentroncanadum).

PubMed

Klosterhoff, Marta C; Pereira Júnior, Joaber; Rodrigues, Ricardo V; Gusmão, Emeline P; Sampaio, Luís A; Tesser, Marcelo B; Romano, Luis A

2015-01-01

In the present study was evaluated the ontogenic of immunocompetent organs of cobia up to 53 days after hatching (dah) through histology and immunohistochemistry techniques. The kidney was the first lymphohematopoietic organ to appear, at 1 dah, followed by the spleen at 5 dah and the thymus at 7 dah. The first CD3 receptors on the lymphocytes were observed in 27% of the thymic tissue at 7 dah and in 99% at 53 dah. The phenotypic expression of CD3 receptors was registered in 10% of the kidney at 8 dah and in 32% at 53 dah. CD4 receptors were observed in 5% and 63% of the thymic area at 7 and 53 dah, respectively. In the kidney, T4 lymphocytes were first observed at 13 dah in 9% of the organ and in 28% at 53 dah, defining the functional development of the specific system associated with immunological memory capacity.

Chlorhexidine possesses unique cytotoxic actions in rat thymic lymphocytes: Its relation with electrochemical property of membranes.

PubMed

Nonami, Kayo; Saitoh, Shohei; Nishimura-Danjobara, Yumiko; Ishida, Shiro; Oyama, Yasuo

2016-12-01

Chlorhexidine (CHX) is an antibacterial agent used in various types of pharmaceutical products. Therefore, CHX is easily found around us. Owing to its positive charge, the electrochemical property of cell membranes was assumed to be a key point of cytotoxic action of CHX. Depolarization of membranes attenuated the cytotoxic action of CHX in rat thymic lymphocytes. CHX interfered with annexin V binding to membranes. Manipulations to induce exposure of phosphatidylserine on the outer membrane surface augmented the cytotoxic action of CHX, indicating that changes in the electrochemical property of membranes affected the cytotoxic action of CHX. Hence, CHX might kill cells physiologically undergoing apoptosis, resulting instead in necrotic cell death. However, the threshold CHX concentration in this in vitro study was slightly higher than blood CHX concentrations observed clinically. Therefore, these results may support the safety of CHX use although CHX possesses unique cytotoxic actions described in this study. Copyright © 2016 Elsevier B.V. All rights reserved.

Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids.

PubMed

Seet, Christopher S; He, Chongbin; Bethune, Michael T; Li, Suwen; Chick, Brent; Gschweng, Eric H; Zhu, Yuhua; Kim, Kenneth; Kohn, Donald B; Baltimore, David; Crooks, Gay M; Montel-Hagen, Amélie

2017-05-01

Studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPCs) through to mature T cells. Existing in vitro models induce T cell commitment from human HSPCs; however, differentiation into mature CD3 + TCR-αβ + single-positive CD8 + or CD4 + cells is limited. We describe here a serum-free, artificial thymic organoid (ATO) system that supports efficient and reproducible in vitro differentiation and positive selection of conventional human T cells from all sources of HSPCs. ATO-derived T cells exhibited mature naive phenotypes, a diverse T cell receptor (TCR) repertoire and TCR-dependent function. ATOs initiated with TCR-engineered HSPCs produced T cells with antigen-specific cytotoxicity and near-complete lack of endogenous TCR Vβ expression, consistent with allelic exclusion of Vβ-encoding loci. ATOs provide a robust tool for studying human T cell differentiation and for the future development of stem-cell-based engineered T cell therapies.

Free-hand ultrasound guidance permits safe and efficient minimally invasive intrathymic injections in both young and aged mice.

PubMed

Tuckett, Andrea Z; Zakrzewski, Johannes L; Li, Duan; van den Brink, Marcel R M; Thornton, Raymond H

2015-04-01

The goal of this study was to evaluate whether use of an aseptic free-hand approach to ultrasound-guided injection facilitates injection into the thymic gland in mice. We used this interventional radiology technique in young, aged and immunodeficient mice and found that the thymus was visible in all cases. The mean injection period was 8 seconds in young mice and 19 seconds in aged or immunodeficient mice. Injection accuracy was confirmed by intrathymic location of an injected dye or by in vivo bioluminescence imaging of injected luciferase-expressing cells. Accurate intrathymic injection was confirmed in 97% of cases. No major complications were observed. We conclude that an aseptic freehand technique for ultrasound-guided intrathymic injection is safe and accurate and reduces the time required for intrathymic injections. This method facilitates large-scale experiments and injection of individual thymic lobes and is clinically relevant. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Tissue specific distribution of iNKT cells impacts their cytokine response

PubMed Central

Lee, You Jeong; Wang, Haiguang; Starrett, Gabriel J.; Phuong, Vanessa; Jameson, Stephen C.; Hogquist, Kristin A.

2015-01-01

Summary Three subsets of invariant natural killer T (iNKT) cells have been identified, NKT1, NKT2 and NKT17, which produce distinct cytokines when stimulated, but little is known about their localization. Here, we have defined the anatomic localization and systemic distribution of these subsets and measured their cytokine production. Thymic NKT2 cells that produced interleukin-4 (IL-4) at steady state were located in the medulla and conditioned medullary thymocytes. NKT2 cells were abundant in the mesenteric lymph node (LN) of BALB/c mice and produced IL-4 in the T cell zone that conditioned other lymphocytes. Intravenous injection of α-galactosylceramide activated NKT1 cells with vascular access, but not LN or thymic NKT cells, resulting in systemic interferon-γ and IL-4 production, while oral α-galactosylceramide activated NKT2 cells in the mesenteric LN, resulting in local IL-4 release. These finding indicate that the localization of iNKT cells governs their cytokine response both at steady state and upon activation. PMID:26362265

Generation of mature T cells from human hematopoietic stem/progenitor cells in artificial thymic organoids

PubMed Central

Seet, Christopher S.; He, Chongbin; Bethune, Michael T.; Li, Suwen; Chick, Brent; Gschweng, Eric H.; Zhu, Yuhua; Kim, Kenneth; Kohn, Donald B.; Baltimore, David; Crooks, Gay M.; Montel-Hagen, Amélie

2017-01-01

Studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPCs) through to mature T cells. Existing in vitro models induce T cell commitment from human HSPCs; however, differentiation into mature CD3+TCRab+ single positive (SP) CD8+ or CD4+ cells is limited. We describe here a serum-free, artificial thymic organoid (ATO) system that supports highly efficient and reproducible in vitro differentiation and positive selection of conventional human T cells from all sources of HSPCs. ATO-derived T cells exhibited mature naïve phenotypes, a diverse TCR repertoire, and TCR-dependent function. ATOs initiated with TCR-engineered HSPCs produced T cells with antigen specific cytotoxicity and near complete lack of endogenous TCR Vβ expression, consistent with allelic exclusion of Vβ loci. ATOs provide a robust tool for studying human T cell development and stem cell based approaches to engineered T cell therapies. PMID:28369043

Diagnosis of Churg-Strauss Syndrome Presented With Neuroendocrine Carcinoma: A Case Report.

PubMed

Park, Dayun; Lee, Ho Jun; Lee, Kwang Hoon; Kwon, Bum Sun; Park, Jin-Woo; Nam, Ki Yeun; Lee, Kyoung Hwan

2017-06-01

Churg-Strauss syndrome (CSS) is a rare systemic vasculitis that affect small and medium-sized blood vessels and is accompanied by asthma, eosinophilia, and peripheral neuropathy. This report describes a case of a 52-year-old man who had a history of sinusitis, asthma, and thymus cancer and who had complained of bilateral lower extremity paresthesia and weakness for a month. Peripheral neuropathy was detected by electrodiagnostic studies. Resection of a mediastinal mass, which was diagnosed as thymic neuroendocrine carcinoma, was performed five months before his visit. After thymectomy, peripheral blood tests revealed a gradual increase in eosinophils. Two months after surgery, he was admitted to the hospital for dyspnea, and nodules of focal consolidation were found in his chest X-ray. One month later, pyoderma occurred in the right shin, and the skin biopsy showed extravascular eosinophilic infiltration. He was diagnosed with CSS after thymectomy, and we report a very rare case of CSS presented with thymic neuroendocrine carcinoma.

CD8+ recent thymic emigrants exhibit increased responses to low affinity ligands and improved access to peripheral sites of inflammation

PubMed Central

Berkley, Amy M.; Fink, Pamela J.

2014-01-01

To explore the TCR sensitivity of recent thymic emigrants (RTEs), we triggered T cells with altered peptide ligands (APLs). Upon peptide stimulation in vitro, RTEs exhibited increased TCR signal transduction, and following infection in vivo with APL-expressing bacteria, CD8 RTEs expanded to a greater extent in response to low affinity antigens than their mature T cell counterparts. RTEs skewed to short-lived effector cells in response to all APLs but were also characterized by diminished cytokine production. RTEs responding to infection expressed increased levels of VLA-4, with consequent improved entry into inflamed tissue and pathogen clearance. These positive outcomes were offset by the capacity of RTEs to elicit autoimmunity. Overall, salient features of CD8 RTE biology should inform strategies to improve neonatal vaccination and therapies for cancer and HIV, as RTEs make up a large proportion of the T cells in lymphodepleted environments. PMID:25172492

Recent thymic emigrants are tolerized in the absence of inflammation

PubMed Central

Friesen, Travis J.; Ji, Qingyong

2016-01-01

T cell development requires a period of postthymic maturation. Why this is the case has remained a mystery, particularly given the rigors of intrathymic developmental checkpoints, successfully traversed by only ∼5% of thymocytes. We now show that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which recent thymic emigrants (RTEs) encounter antigen. After encounter with TRAs in the absence of inflammation, RTEs exhibited defects in proliferation, diminished cytokine production, elevated expression of anergy-associated genes, and diminished diabetogenicity. These properties were mirrored in vitro by enhanced RTE susceptibility to regulatory T cell–mediated suppression. In the presence of inflammation, RTEs and mature T cells were, in contrast, equally capable of inducing diabetes, proliferating, and producing cytokines. Thus, recirculating RTEs encounter TRAs during a transitional developmental stage that facilitates tolerance induction, but inflammation converts antigen-exposed, tolerance-prone RTEs into competent effector cells. PMID:27139493

Rag Deletion in Peripheral T Cells Blocks TCR Revision

PubMed Central

Hale, J. Scott; Ames, Kristina T.; Boursalian, Tamar E.; Fink, Pamela J.

2010-01-01

Mature CD4+Vβ5+ T cells that recognize a peripherally expressed endogenous superantigen are tolerized either by deletion or T cell receptor (TCR) revision. In Vβ5 transgenic mice, this latter tolerance pathway results in the appearance of CD4+Vβ5−TCRβ+ T cells, coinciding with Rag1, Rag2, and TdT expression and the accumulation of Vβ-DJβ recombination intermediates in peripheral CD4+ T cells. Because post-thymic RAG-dependent TCR rearrangement has remained controversial, we sought to definitively determine whether TCR revision is an extrathymic process that occurs in mature peripheral T cells. We now show that Rag deletion in post-positive selection T cells in Vβ5 transgenic mice blocks TCR revision in vivo, and that mature peripheral T cells sorted to remove cells bearing endogenous TCRβ chains can express newly generated TCRβ molecules in adoptive hosts. These findings unambiguously demonstrate post-thymic, RAG-dependent TCR rearrangement and define TCR revision as a tolerance pathway that targets mature peripheral CD4+ T cells. PMID:20435935

Cutting edge: CD8+ recent thymic emigrants exhibit increased responses to low-affinity ligands and improved access to peripheral sites of inflammation.

PubMed

Berkley, Amy M; Fink, Pamela J

2014-10-01

To explore the TCR sensitivity of recent thymic emigrants (RTEs), we triggered T cells with altered peptide ligands (APLs). Upon peptide stimulation in vitro, RTEs exhibited increased TCR signal transduction, and following infection in vivo with APL-expressing bacteria, CD8 RTEs expanded to a greater extent in response to low-affinity Ags than did their mature T cell counterparts. RTEs skewed to short-lived effector cells in response to all APLs but also were characterized by diminished cytokine production. RTEs responding to infection expressed increased levels of VLA-4, with consequent improved entry into inflamed tissue and pathogen clearance. These positive outcomes were offset by the capacity of RTEs to elicit autoimmunity. Overall, salient features of CD8 RTE biology should inform strategies to improve neonatal vaccination and therapies for cancer and HIV, because RTEs make up a large proportion of the T cells in lymphodepleted environments. Copyright © 2014 by The American Association of Immunologists, Inc.

Cutting Edge: Enhanced Clonal Burst Size Corrects an Otherwise Defective Memory Response by CD8+ Recent Thymic Emigrants.

PubMed

Deets, Katherine A; Berkley, Amy M; Bergsbaken, Tessa; Fink, Pamela J

2016-03-15

The youngest peripheral T cells (recent thymic emigrants [RTEs]) are functionally distinct from naive T cells that have completed postthymic maturation. We assessed the RTE memory response and found that RTEs produced less granzyme B than their mature counterparts during infection but proliferated more and, therefore, generated equivalent target killing in vivo. Postinfection, RTE numbers contracted less dramatically than those of mature T cells, but RTEs were delayed in their transition to central memory, displaying impaired expression of CD62L, IL-2, Eomesodermin, and CXCR4, which resulted in impaired bone marrow localization. RTE-derived and mature memory cells expanded equivalently during rechallenge, indicating that the robust proliferative capacity of RTEs was maintained independently of central memory phenotype. Thus, the diminished effector function and delayed central memory differentiation of RTE-derived memory cells are counterbalanced by their increased proliferative capacity, driving the efficacy of the RTE response to that of mature T cells. Copyright © 2016 by The American Association of Immunologists, Inc.

Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1

PubMed Central

Landegren, Nils; Sharon, Donald; Freyhult, Eva; Hallgren, Åsa; Eriksson, Daniel; Edqvist, Per-Henrik; Bensing, Sophie; Wahlberg, Jeanette; Nelson, Lawrence M.; Gustafsson, Jan; Husebye, Eystein S.; Anderson, Mark S.; Snyder, Michael; Kämpe, Olle

2016-01-01

Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE’s selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance. PMID:26830021

Combined effects of a thymic peptide, thymopoietin and myasthenic patient sera in rat myotube culture.

PubMed

Eymard, B; Aimé, C; Cottin, C; Morel, E; Goldstein, G; Bach, J F; Berrih-Aknin, S

1992-10-01

We investigated in a rat myotube assay the combined effect of 26 myasthenic (MG) patient sera and a thymic peptide, thymopoietin (Tpo) which had previously been shown to bind Torpedo and human AChR and to compete with alpha-bungarotoxin (alpha-Bgt) binding. Cultures were first exposed to Tpo alone for 3 h (0.3, 7.5, 15 nM), then MG sera (5% final dilution) were added for an additional 18 h. Reduction in the amount of 125I-alpha-Bgt binding sites in the presence of various concentrations of Tpo were similar with control sera and in all the patients with low or undetectable anti-AChR Ab (11 cases). In cultures exposed to Tpo and sera with high anti-AChR Ab titre (15 cases), Tpo and anti-AChR Ab have an additive capacity to reduce the number of alpha-Bgt binding sites. The results are compatible with the hypothesis that anti-AChR Ab and Tpo could impair neuromuscular transmission by complementary mechanisms.

Hydroxyhydroquinone, a by-product of coffee bean roasting, increases intracellular Ca2+ concentration in rat thymic lymphocytes.

PubMed

Kamae, Risa; Nojima, Shoko; Akiyoshi, Kenji; Setsu, Shoki; Honda, Sari; Masuda, Toshiya; Oyama, Yasuo

2017-04-01

Hydroxyhydroquinone (HHQ) is generated during coffee bean roasting. A cup of coffee contains 0.1-1.7 mg of HHQ. The actions of HHQ on mammalian DNA were examined because HHQ is a metabolite of benzene, which causes leukemia. Currently, information on the cellular actions of HHQ is limited. We examined the effects of sublethal levels of HHQ on the concentration of intracellular Ca 2+ in rat thymic lymphocytes by using a flow cytometric technique with fluorescent probes. HHQ at 10 μM or more significantly elevated intracellular Ca 2+ levels by increasing the membrane permeability of divalent cations, resulting in hyperpolarization via the activation of Ca 2+ -dependent K + channels. HHQ-induced changes in the intracellular Ca 2+ concentration and membrane potential may affect the cell functions of lymphocytes. HHQ-reduced coffee may be preferable in order to avoid the possible adverse effects of HHQ. Copyright © 2017 Elsevier Ltd. All rights reserved.

Thymic stromal lymphopoietin-induced HOTAIR activation promotes endothelial cell proliferation and migration in atherosclerosis

PubMed Central

Peng, Yudong; Meng, Kai; Jiang, Lili; Zhong, Yucheng; Yang, Yong; Lan, Yin

2017-01-01

Endothelial cells’ (EC) injury is a major step for the pathological progression of atherosclerosis. Recent study demonstrated that thymic stromal lymphopoietin (TSLP) exerts a protective role in atherosclerosis. However, the effect of TSLP and the exact molecular mechanism involved in EC remains unknown. In the present study, we found that long noncoding RNA (lncRNA) HOTAIR was much lower in EC from atherosclerotic plaque. Functional assays showed that HOTAIR facilitated cell proliferation and migration, and suppressed apoptosis in EC. Moreover, we demonstrated that TSLP functions upstream of HOTAIR. We found that serum level of TSLP was decreased in atherosclerosis patients and serum TSLP level positively correlated with HOTAIR expression in EC. Further investigation demonstrated that TSLP activated HOTAIR transcription through PI3K/AKT-IRF1 pathway and then regulates the EC proliferation and migration. TSLP-HOTAIR axis also plays a protective role in low-density lipoprotein (ox-LDL)-induced EC injury. Taken together, TSLP-HOTAIR may be a potential therapy for EC dysfunction in atherosclerosis. PMID:28615347

Hydrodynamical Modeling of Hydrogen Escape from Rocky Planets

NASA Astrophysics Data System (ADS)

Barringer, Daniel; Zugger, M.; Kasting, J.

2013-01-01

Hydrogen escape affects both the composition of primitive atmospheres of terrestrial planets and the planet’s state of oxidation. On Mars, hydrogen escape played a critical role in how long the planet remained in a warm wet state amenable to life. For both solar and extrasolar planets, hydrogen-rich atmospheres are better candidates for originating life by way of Miller-Urey-type prebiotic synthesis. However, calculating the rate of atmospheric hydrogen escape is difficult, for a number of reasons. First, the escape can be controlled either by diffusion through the homopause or by conditions in the upper atmosphere, whichever is slower. Second, both thermal and non-thermal escape mechanisms are typically important. Third, thermal escape itself can be subdivided into Jeans escape (thin upper atmosphere), and hydrodynamic escape, and hydrodynamic escape can be further subdivided into transonic escape and slower subsonic escape, depending on whether the exobase occurs above or below the sonic point. Additionally, the rate of escape for real terrestrial planet atmospheres, which are not 100% hydrogen, depends upon the concentration of infrared coolants, and upon heating and photochemistry driven largely by extreme ultraviolet (EUV) radiation. We have modified an existing 1-D model of hydrodynamic escape (F. Tian et al., JGR, 2008) to work in the high- hydrogen regime. Calculations are underway to determine hydrogen escape rates as a function of atmospheric H2 mixing ratio and the solar EUV flux. We will compare these rates with the estimated upper limit on the escape rate based on diffusion. Initial results for early Earth and Mars will later be extended to rocky exoplanets.

Marek’s disease virus induces transient atrophy of cecal tonsils

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by an immunosupperessive alpha herpesvirus, Marek’s disease virus (MDV). Clinical signs of MD include bursal/thymic atrophy and neurological disorders. The cecal tonsils (CT) are the largest lymphoid aggregates of avia...

Time Intervals in Sequence Sampling, Not Data Modifications, Have a Major Impact on Estimates of HIV Escape Rates

PubMed Central

2018-01-01

The ability of human immunodeficiency virus (HIV) to avoid recognition by humoral and cellular immunity (viral escape) is well-documented, but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection compared to chronic infection. The rate of HIV escape was estimated with the help of simple mathematical models, and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, that early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. However, these conclusions were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a sampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements, with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses. PMID:29495443

Time Intervals in Sequence Sampling, Not Data Modifications, Have a Major Impact on Estimates of HIV Escape Rates.

PubMed

Ganusov, Vitaly V

2018-02-27

The ability of human immunodeficiency virus (HIV) to avoid recognition by humoral and cellular immunity (viral escape) is well-documented, but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection compared to chronic infection. The rate of HIV escape was estimated with the help of simple mathematical models, and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, that early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. However, these conclusions were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a sampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements, with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses.

Clinical Holistic Medicine: A Psychological Theory of Dependency to Improve Quality of Life

PubMed Central

Ventegodt, Søren; Morad, Mohammed; Kandel, Isack; Merrick, Joav

2004-01-01

In this paper, we suggest a psychological theory of dependency as an escape from feeling existential suffering and a poor quality of life. The ways in which human beings escape hidden existential pains are multiple. The wide range of dependency states seems to be the most common escape strategy used. If the patient can be guided into the hidden existential pain to feel, understand, and integrate it, we believe that dependency can be cured. The problem is that the patient must be highly motivated, sufficiently resourceful, and supported to want such a treatment that is inherently painful. Often, the family and surrounding world is suffering more than the dependent person himself, because the pattern of behavior the patient is dependent on makes him or her rather insensitive and unable to feel. If the patient is motivated, resourceful, and trusts his physician, recovery from even a severe state of dependency is not out of reach, if the holistic medical tools are applied wisely. The patient must find hidden resources to take action, then in therapy confront and feel old emotional pain, understand the source and inner logic of it, and finally learn to let go of negative attitudes and beliefs. In this way, the person can be healed and released of the emotional suffering and no longer be a slave to the dependency pattern. PMID:15349506

Course of life satisfaction in patients with depressive and addictive disorders after therapeutic intervention.

PubMed

Büssing, Arndt; Heusser, Peter; Mundle, Götz

2012-05-01

To analyse the course of life satisfaction during the clinic stay of patients with depressive and/or addictive disorders. In a cohort study, 199 patients with depressive and addictive diseases were asked to complete a series of questionnaires at the start and the end of their psychotherapeutic treatment (on average 4.2 ± 2.3 weeks later). The questionnaires were the Brief Multidimensional Life Satisfaction Scale (BMLSS), the Positive Life Construction/Contentedness/Well-Being Scale from the ERDA (Emotional/Rational Disease Acceptance) questionnaire, Beck's Depression Inventory and the revised Symptom Checklist (SCL-90-R). The psychotherapeutic interventions improved the clinical situation of the patients and resulted in strong effects with respect to positive life construction (d = 1.07) and moderate effects on life satisfaction (d = 0.71). Stronger effects were noted in patients with depressive disorders (d = 0.80) than in patients with addictive disorders (d = 0.69). Regression analyses revealed that pre-treatment life satisfaction can be explained negatively by an escape-avoidance strategy (Escape from Illness), and positively by positive life construction. In contrast, post-treatment life satisfaction can be explained negatively by psychological distress and depression, and positively by positive life construction and living with a partner. The hypothesis that life satisfaction changes are associated with the clinical situation of patients was confirmed. In particular, patients with depressive disorders profited from the psychotherapeutic interventions.

Cold Ion Escape from the Martian Ionosphere - 2005-2014

NASA Astrophysics Data System (ADS)

Fränz, Markus; Dubinin, Eduard; Andrews, David; Nilsson, Hans; Fedorov, Andrei

2015-04-01

It has always been challenging to observe the flux of ions with energies of less than 10eV escaping from the planetary ionospheres. We here report on new measurements of the ionospheric ion flows at Mars by the ASPERA-3 experiment on board Mars Express. The ion sensor IMA of this experiment has in principle a low-energy cut-off at 10eV but in negative spacecraft charging cold ions are lifted into the range of measurement but the field of view is restricted to about 4x360 deg. In a recent paper Nilsson et al. (Earth Planets Space, 64, 135, 2012) tried to use the method of long-time averaged distribution functions to overcome these constraints. In this paper we first use the same method to show that we get results consistent with this when using ASPERA-3 observations only. But then we can show that these results are inconsistent with observations of the local plasma density by the MARSIS radar instrument on board Mars Express. We demonstrate that the method of averaged distribution function can deliver the mean flow speed of the plasma but the low-energy cut-off does usually not allow to reconstruct the density. We then combine measurements of the cold ion flow speed with the plasma density observations of MARSIS to derive the cold ion flux. In an analysis of the combined nightside datasets we show that the main escape channel is along the shadow boundary on the tailside of Mars. At a distance of about 0.5 RM the flux settles at a constant value which indicates that about half of the transterminator ionospheric flow escapes from the planet. To derive the mean escape flux we include all combined observations of ASPERA-3 and MARSIS from 2005 to 2014. Possible mechanism to generate this flux can be the ionospheric pressure gradient between dayside and nightside or momentum transfer from the solar wind via the induced magnetic field since the flow velocity is in the Alfvénic regime.

Inhibition of chaotic escape from a potential well by incommensurate escape-suppressing excitations.

PubMed

Chacón, R; Martínez, J A

2002-03-01

Theoretical results are presented concerning the reduction of chaotic escape from a potential well by means of a harmonic parametric excitation that satisfies an ultrasubharmonic resonance condition with the escape-inducing excitation. The possibility of incommensurate escape-suppressing excitations is demonstrated by studying rational approximations to the irrational escape-suppressing frequency. The analytical predictions for the suitable amplitudes and initial phases of the escape-suppressing excitation are tested against numerical simulations based on a high-resolution grid of initial conditions. These numerical results indicate that the reduction of escape is reliably achieved for small amplitudes and at, and only at, the predicted initial phases. For the case of irrational escape-suppressing frequencies, the effective escape-reducing initial phases are found to lie close to the accumulation points of the set of suitable initial phases that are associated with the complete series of convergents up to the convergent giving the chosen rational approximation.

Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles.

PubMed

Wang, Ming; Zuris, John A; Meng, Fantao; Rees, Holly; Sun, Shuo; Deng, Pu; Han, Yong; Gao, Xue; Pouli, Dimitra; Wu, Qi; Georgakoudi, Irene; Liu, David R; Xu, Qiaobing

2016-03-15

A central challenge to the development of protein-based therapeutics is the inefficiency of delivery of protein cargo across the mammalian cell membrane, including escape from endosomes. Here we report that combining bioreducible lipid nanoparticles with negatively supercharged Cre recombinase or anionic Cas9:single-guide (sg)RNA complexes drives the electrostatic assembly of nanoparticles that mediate potent protein delivery and genome editing. These bioreducible lipids efficiently deliver protein cargo into cells, facilitate the escape of protein from endosomes in response to the reductive intracellular environment, and direct protein to its intracellular target sites. The delivery of supercharged Cre protein and Cas9:sgRNA complexed with bioreducible lipids into cultured human cells enables gene recombination and genome editing with efficiencies greater than 70%. In addition, we demonstrate that these lipids are effective for functional protein delivery into mouse brain for gene recombination in vivo. Therefore, the integration of this bioreducible lipid platform with protein engineering has the potential to advance the therapeutic relevance of protein-based genome editing.

Consequences of Learned Helplessness and Recognition of the State of Cognitive Exhaustion in Persons with Mild Intellectual Disability

PubMed Central

Gacek, Michał; Smoleń, Tomasz; Pilecka, Władysława

2017-01-01

Persons with intellectual disability are a group at risk of being exposed to overly demanding problem-solving situations, which may produce learned helplessness. The research was based on the informational model of learned helplessness. The consequences of exposure to an unsolvable task and the ability to recognize the symptoms of cognitive exhaustion were tested in 120 students with mild intellectual disability. After the exposure to the unsolvable task, persons in the experimental group obtained lower results than the control group in the escape/avoidance learning task, but a similar result was found in the divergent thinking fluency task. Also, participants in the experimental group had difficulties recognizing the symptoms of the cognitive exhaustion state. After a week’s time, the difference in escape/avoidance learning performance was still observed. The results indicate that exposure to unsolvable tasks may negatively influence the cognitive performance in persons with intellectual disability, although those persons may not identify the cognitive state related to lowered performance. PMID:28479937

Consequences of Learned Helplessness and Recognition of the State of Cognitive Exhaustion in Persons with Mild Intellectual Disability.

PubMed

Gacek, Michał; Smoleń, Tomasz; Pilecka, Władysława

2017-01-01

Persons with intellectual disability are a group at risk of being exposed to overly demanding problem-solving situations, which may produce learned helplessness . The research was based on the informational model of learned helplessness. The consequences of exposure to an unsolvable task and the ability to recognize the symptoms of cognitive exhaustion were tested in 120 students with mild intellectual disability. After the exposure to the unsolvable task, persons in the experimental group obtained lower results than the control group in the escape/avoidance learning task, but a similar result was found in the divergent thinking fluency task. Also, participants in the experimental group had difficulties recognizing the symptoms of the cognitive exhaustion state. After a week's time, the difference in escape/avoidance learning performance was still observed. The results indicate that exposure to unsolvable tasks may negatively influence the cognitive performance in persons with intellectual disability, although those persons may not identify the cognitive state related to lowered performance.

Community Detection in Signed Networks: the Role of Negative ties in Different Scales

PubMed Central

Esmailian, Pouya; Jalili, Mahdi

2015-01-01

Extracting community structure of complex network systems has many applications from engineering to biology and social sciences. There exist many algorithms to discover community structure of networks. However, it has been significantly under-explored for networks with positive and negative links as compared to unsigned ones. Trying to fill this gap, we measured the quality of partitions by introducing a Map Equation for signed networks. It is based on the assumption that negative relations weaken positive flow from a node towards a community, and thus, external (internal) negative ties increase the probability of staying inside (escaping from) a community. We further extended the Constant Potts Model, providing a map spectrum for signed networks. Accordingly, a partition is selected through balancing between abridgment and expatiation of a signed network. Most importantly, multi-scale spectrum of signed networks revealed how informative are negative ties in different scales, and quantified the topological placement of negative ties between dense positive ones. Moreover, an inconsistency was found in the signed Modularity: as the number of negative ties increases, the density of positive ties is neglected more. These results shed lights on the community structure of signed networks. PMID:26395815

Marek’s disease virus induced transient atrophy of cecal tonsils

USDA-ARS?s Scientific Manuscript database

Although bursal and thymic atrophy associated with Marek’s disease (MD) is well established and characterized, the effect of Marek's disease virus (MDV) infection on lymphoid aggregates within the gut-associated lymphoid tissue (GALT) is not known. The cecal tonsils (CT) are the two largest lympho...

Characterization of porcine CD205

USDA-ARS?s Scientific Manuscript database

Dendritic cells (DC) express a cell-surface receptor, CD205, that plays a role in antigen capture and delivery to the endocytic pathway. Besides DCs, high CD205 expression is also detected on thymic epithelial cells, but B cells, macrophages, and T cells have limited or no expression. CD205 has be...

ELEVATED OVARIAN AND THYMIC CELL APOPTOSIS IN WILD COTTON RATS INHABITING PETROCHEMICAL-CONTAMINATED TERRESTRIAL ECOSYSTEMS. (R826242)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Stronger effects of Roundup than its active ingredient glyphosate in damselfly larvae.

PubMed

Janssens, Lizanne; Stoks, Robby

2017-12-01

Pesticides are causing strong decreases in aquatic biodiversity at concentrations assumed safe by legislation. One reason for the failing risk assessment may be strong differences in the toxicity of the active ingredient of pesticides and their commercial formulations. Sublethal effects, especially those on behaviour, have been largely ignored in this context, yet can be equally important as lethal effects at the population and ecosystem levels. Here, we compared the toxicity of the herbicide Roundup and its active ingredient glyphosate on survival, but also on ecologically relevant sublethal traits (life history, behaviour and physiology) in damselfly larvae. Roundup was more toxic than glyphosate with negative effects on survival, behaviour and most of the physiological traits being present at lower concentrations (food intake, escape swimming speed) or even only present (survival, sugar and total energy content and muscle mass) following Roundup exposure. This confirms the toxicity of the surfactant POEA. Notably, also glyphosate was not harmless: a realistic concentration of 2mg/l resulted in reduced growth rate, escape swimming speed and fat content. Our results therefore indicate that the toxicity of Roundup cannot be fully attributed to its surfactant, thereby suggesting that also the new generation of glyphosate-based herbicides with other mixtures of surfactants likely will have adverse effects on non-target aquatic organisms. Ecotoxicological studies comparing the toxicity of active ingredients and their commercial formulations typically ignore behaviour while the here observed differential effects on behaviour likely will negatively impact damselfly populations. Our data highlight that risk assessment of pesticides ignoring sublethal effects may contribute to the negative effects of pesticides on aquatic biodiversity. Copyright © 2017 Elsevier B.V. All rights reserved.

MHC II-β chain gene expression studies define the regional organization of the thymus in the developing bony fish Dicentrarchus labrax (L.).

PubMed

Picchietti, S; Abelli, L; Guerra, L; Randelli, E; Proietti Serafini, F; Belardinelli, M C; Buonocore, F; Bernini, C; Fausto, A M; Scapigliati, G

2015-02-01

MHC II-β chain gene transcripts were quantified by real-time PCR and localised by in situ hybridization in the developing thymus of the teleost Dicentrarchus labrax, regarding the specialization of the thymic compartments. MHC II-β expression significantly rose when the first lymphoid colonization of the thymus occurred, thereafter increased further when the organ progressively developed cortex and medulla regions. The evolving patterns of MHC II-β expression provided anatomical insights into some mechanisms of thymocyte selection. Among the stromal cells transcribing MHC II-β, scattered cortical epithelial cells appeared likely involved in the positive selection, while those abundant in the cortico-medullary border and medulla in the negative selection. These latter most represent dendritic cells, based on typical localization and phenotype. These findings provide further proofs that efficient mechanisms leading to maturation of naïve T cells are operative in teleosts, strongly reminiscent of the models conserved in more evolved gnathostomes. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Depression in the elderly. Clinical aspects].

PubMed

Barbier, D

2001-02-24

DIFFICULT DIAGNOSIS: Depression in the elderly can take on many often misleading aspects. Sadness may be considered legitimate or "normal" for an elderly person. Depression may masquerade as an organic disorder where somatic complaints, pain and anxiety predominate. All these different clinical forms may mislead the clinician. THE MASK OF HYPOCHONDRIA: A tendency to hypochondria, found in more than one-half of all depressed elderly subjects, may be reinforced by bouts of complementary examinations. The patient is convinced of having an unrecognized organic disease. The mask of hypochondria must be considered with special care because it is a major risk factor for attempted and successful suicide. THE MASK OF DELUSIONS: Elderly patients often develop a state of melancolia-like depression with delusions. Delusions may be congruent with the predominant depressed mood, for example a guilt feeling for an act never committed, or inversely, non-congruent with the thymic state (persecution, negation delusin), for example Cotard syndrome where the patient is persuaded that his/her organs are malfunctioning or have disappeared. Despite these impressive mood disorders that often incite prescription of a neuroleptic, these elderly patients respond favorably to antidepressor treatment.

An evaluation of generalization of mands during functional communication training.

PubMed

Falcomata, Terry S; Wacker, David P; Ringdahl, Joel E; Vinquist, Kelly; Dutt, Anuradha

2013-01-01

The primary purpose of this study was to evaluate the generalization of mands during functional communication training (FCT) and sign language training across functional contexts (i.e., positive reinforcement, negative reinforcement). A secondary purpose was to evaluate a training procedure based on stimulus control to teach manual signs. During the treatment evaluation, we implemented sign language training in 1 functional context (e.g., positive reinforcement by attention) while continuing the functional analysis conditions in 2 other contexts (e.g., positive reinforcement by tangible item; negative reinforcement by escape). During the generalization evaluation, we tested for the generalization of trained mands across functional contexts (i.e., positive reinforcement; negative reinforcement) by implementing extinction in the 2 nontarget contexts. The results suggested that the stimulus control training procedure effectively taught manual signs and treated destructive behavior. Specific patterns of generalization of trained mands and destructive behavior also were observed. © Society for the Experimental Analysis of Behavior.

Targeting Tryptophan Catabolism: A Novel Method to Block Triple-Negative Breast Cancer Metastasis

DTIC Science & Technology

2016-04-01

in many immune cell types and its activation decreases T-cell activity leading to tumor immune escape. Since the rate limiting enzyme TDO2 increases...What were the major goals of the project? Our overall goals were to test the hypotheses that the ability to upregulate kynurenine via the enzyme TDO2...discipline(s) of the project? " o This research is strongly suggesting that TDO2 is likely the primary enzyme that catabolizes tryptophan that should

Negative reinforcement learning is affected in substance dependence.

PubMed

Thompson, Laetitia L; Claus, Eric D; Mikulich-Gilbertson, Susan K; Banich, Marie T; Crowley, Thomas; Krmpotich, Theodore; Miller, David; Tanabe, Jody

2012-06-01

Negative reinforcement results in behavior to escape or avoid an aversive outcome. Withdrawal symptoms are purported to be negative reinforcers in perpetuating substance dependence, but little is known about negative reinforcement learning in this population. The purpose of this study was to examine reinforcement learning in substance dependent individuals (SDI), with an emphasis on assessing negative reinforcement learning. We modified the Iowa Gambling Task to separately assess positive and negative reinforcement. We hypothesized that SDI would show differences in negative reinforcement learning compared to controls and we investigated whether learning differed as a function of the relative magnitude or frequency of the reinforcer. Thirty subjects dependent on psychostimulants were compared with 28 community controls on a decision making task that manipulated outcome frequencies and magnitudes and required an action to avoid a negative outcome. SDI did not learn to avoid negative outcomes to the same degree as controls. This difference was driven by the magnitude, not the frequency, of negative feedback. In contrast, approach behaviors in response to positive reinforcement were similar in both groups. Our findings are consistent with a specific deficit in negative reinforcement learning in SDI. SDI were relatively insensitive to the magnitude, not frequency, of loss. If this generalizes to drug-related stimuli, it suggests that repeated episodes of withdrawal may drive relapse more than the severity of a single episode. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Relationship of scores on the Escapism Scale of the MMPI to escape from minimum security federal custody.

PubMed

White, R B

1979-04-01

Investigated the ability of the Escapism (Ec) scale of the MMPI to differentiate between escape and non-escape minimum security federal prisoners. At the .05 level there was no difference between the scores of the two groups on the Ec scale or on comparisons of other correctional data, age, and ethnic composition. It appears that the Ec scale alone or in combination with other data will be a poor predictor of escape. Also, the rate of escape was so low as to make accurate prediction from any criteria extremely unlikely.

Mars atmospheric escape and evolution; interaction with the solar wind

NASA Astrophysics Data System (ADS)

Chassefière, Eric; Leblanc, François

2004-09-01

This tutorial deals with the question of atmospheric escape on Mars. After a brief introduction describing the general context of Mars escape studies, we will present in Section 2 a simplified theory of thermal escape, of both Jeans and hydrodynamic types. The phenomenon of hydrodynamic escape, still hypothetical and not proved to have ever existed on terrestrial planets, will be treated with the help of two well known examples: (i) the isotopic fractionation of xenon in Mars and Earth atmospheres, (ii) the paradox of missing oxygen in Venus atmosphere. In Section 3, a simplified approach of non-thermal escape will be developed, treating in a specific way the different kinds of escape (photochemical escape, ion sputtering, ion escape and ionospheric outflow). As a matter of illustration, some calculations of the relative contributions of these mechanisms, and of their time evolutions, will be given, and the magnitude of the total amount of atmosphere lost by non-thermal escape will be estimated. Section 4 will present the state of knowledge concerning the constraints derived from Mars isotopic geochemistry in terms of past escape and evolution. Finally, a few conclusions, which are more interrogations, will be proposed.

Seasonal variability of Martian ion escape through the plume and tail from MAVEN observations

NASA Astrophysics Data System (ADS)

Dong, Y.; Fang, X.; Brain, D. A.; McFadden, J. P.; Halekas, J. S.; Connerney, J. E. P.; Eparvier, F.; Andersson, L.; Mitchell, D.; Jakosky, B. M.

2017-04-01

We study the Mars Atmosphere and Volatile Evolution spacecraft observations of Martian planetary ion escape during two time periods: 11 November 2014 to 19 March 2015 and 4 June 2015 to 24 October 2015, with the focus on understanding the seasonal variability of Martian ion escape in response to the solar extreme ultraviolet (EUV) flux. We organize the >6 eV O+ ion data by the upstream electric field direction to estimate the escape rates through the plume and tail. To investigate the ion escape dependence on the solar EUV flux, we constrain the solar wind dynamic pressure and interplanetary magnetic filed strength and compare the ion escape rates through the plume and tail in different energy ranges under high and low EUV conditions. We found that the total >6 eV O+ escape rate increases from 2 to 3 × 1024 s-1 as the EUV irradiance increases by almost the same factor, mostly on the <1 keV tailward escape. The plume escape rate does not vary significantly with EUV. The relative contribution from the plume to the total escape varies between 30% and 20% from low to high EUV. Our results suggest that the Martian ion escape is sensitive to the seasonal EUV variation, and the contribution from plume escape becomes more important under low EUV conditions.

Diversity of the Lyman continuum escape fractions of high-z galaxies and its origins

NASA Astrophysics Data System (ADS)

Sumida, Takumi; Kashino, Daichi; Hasegawa, Kenji

2018-04-01

The Lyman continuum (LyC) escape fraction is a key quantity to determine the contribution of galaxies to cosmic reionization. It has been known that the escape fractions estimated by observations and numerical simulations show a large diversity. However, the origins of the diversity are still uncertain. In this work, to understand what quantities of galaxies are responsible for controlling the escape fraction, we numerically evaluate the escape fraction by performing ray-tracing calculation with simplified disc galaxy models. With a smooth disc model, we explore the dependence of the escape fraction on the disposition of ionizing sources and find that the escape fraction varies up to ˜3 orders of magnitude. It is also found that the halo mass dependence of disc scale height determines whether the escape fraction increases or decreases with halo mass. With a clumpy disc model, it turns out that the escape fraction increases as the clump mass fraction increases because the density in the inter-clump region decreases. In addition, we find that clumpiness regulates the escape fraction via two ways when the total clump mass dominates the total gas mass; the escape fraction is controlled by the covering factor of clumps if the clumps are dense sufficient to block LyC photons, otherwise the clumpiness works to reduce the escape fraction by increasing the total number of recombination events in a galaxy.

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

Escape as Reinforcement and Escape Extinction in the Treatment of Feeding Problems

ERIC Educational Resources Information Center

LaRue, Robert H.; Stewart, Victoria; Piazza, Cathleen C.; Volkert, Valerie M.; Patel, Meeta R.; Zeleny, Jason

2011-01-01

Given the effectiveness of putative escape extinction as treatment for feeding problems, it is surprising that little is known about the effects of escape as reinforcement for appropriate eating during treatment. In the current investigation, we examined the effectiveness of escape as reinforcement for mouth clean (a product measure of…

Decompression illness in goats following simulated submarine escape: 1993-2006.

PubMed

Seddon, F M; Thacker, J C; Fisher, A S; Jurd, K M; White, M G; Loveman, G A M

2014-01-01

The United Kingdom Ministry of Defence commissioned work to define the relationship between the internal pressure of a distressed submarine (DISSUB), the depth from which escape is made and the risk of decompression illness (DCI). The program of work used an animal model (goat) to define these risks and this paper reports the incidence and type of DCI observed. A total of 748 pressure exposures comprising saturation only, escape only or saturation followed by escape were conducted in the submarine escape simulator between 1993 and 2006. The DCI following saturation exposures was predominantly limb pain, whereas following escape exposures the DCI predominantly involved the central nervous system and was fast in onset. There was no strong relationship between the risk of DCI and the range of escape depths investigated. The risk of DCI incurred from escape following saturation was greater than that obtained by combining the risks for the independent saturation only, and escape only, exposures. The output from this program of work has led to improved advice on the safety of submarine escape.

Dendritic Cell Therapy, Cryosurgery, and Pembrolizumab in Treating Patients With Non-Hodgkin Lymphoma

ClinicalTrials.gov

2018-05-15

Aggressive Non-Hodgkin Lymphoma; Indolent Non-Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Recurrent T-Cell Non-Hodgkin Lymphoma; Small Lymphocytic Lymphoma

IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

USDA-ARS?s Scientific Manuscript database

CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal...

Minimal change disease in a patient with myasthenia gravis: A case report.

PubMed

Tsai, Jun-Li; Tsai, Shang-Feng

2016-09-01

Myasthenia gravis superimposed with proteinuria is a very rare disorder with only 39 cases reported so far. Of these cases, the most commonly associated disorder is minimal change disease. Myasthenia gravis and minimal change disease are both related to the dysfunction of T lymphocytes and hence the 2 disorders may be connected. Here we report the first case on a patient diagnosed with myasthenia gravis concurrently with the minimal change disease, and it was presented in the absence of thymoma or thymic hyperplasia. Treatment for myasthenia gravis also lowered proteinuria of minimal change disease. He ever experienced good control for myasthenia gravis and minimal change disease. However, pneumonia related septic shock occurred to him and finally he was dead. Minimal change disease is generally considered to occur subsequent to the onset of myasthenia gravis with causal association. After extensive literature review, we noted only 47.8% minimal change disease had occurred after the onset of myasthenia gravis. Minimal change disease mostly occurs in children and if diagnosed in adults, clinicians should search for a potential cause such as myasthenia gravis and other associated thymic disorders.

What happens in the thymus does not stay in the thymus: how T cells recycle the CD4+-CD8+ lineage commitment transcriptional circuitry to control their function

PubMed Central

Vacchio, Melanie S.; Bosselut, Rémy

2016-01-01

MHC-restricted CD4+ and CD8+ T cell are at the core of most adaptive immune responses. Although these cells carry distinct functions, they arise from a common precursor during thymic differentiation, in a developmental sequence that matches CD4 and CD8 expression and functional potential with MHC restriction. While the transcriptional control of CD4+-CD8+ lineage choice in the thymus is now better understood, less was known about what maintains the CD4+- and CD8+-lineage integrity of mature T cells. In this review, we discuss the mechanisms that establish in the thymus, and maintain in post-thymic cells, the separation of these lineages. We focus on recent studies that address the mechanisms of epigenetic control of Cd4 expression and emphasize how maintaining a transcriptional circuitry nucleated around Thpok and Runx proteins, the key architects of CD4+-CD8+ lineage commitment in the thymus, is critical for CD4+ T cell helper functions. PMID:27260768

Molecular dynamics study of lipid bilayers modeling the plasma membranes of mouse hepatocytes and hepatomas.

PubMed

Andoh, Yoshimichi; Aoki, Noriyuki; Okazaki, Susumu

2016-02-28

Molecular dynamics (MD) calculations of lipid bilayers modeling the plasma membranes of normal mouse hepatocytes and hepatomas in water have been performed under physiological isothermal-isobaric conditions (310.15 K and 1 atm). The changes in the membrane properties induced by hepatic canceration were investigated and were compared with previous MD calculations included in our previous study of the changes in membrane properties induced by murine thymic canceration. The calculated model membranes for normal hepatocytes and hepatomas comprised 23 and 24 kinds of lipids, respectively. These included phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, lysophospholipids, and cholesterol. We referred to previously published experimental values for the mole fraction of the lipids adopted in the present calculations. The calculated structural and dynamic properties of the membranes such as lateral structure, order parameters, lateral self-diffusion constants, and rotational correlation times all showed that hepatic canceration causes plasma membranes to become more ordered laterally and less fluid. Interestingly, this finding contrasts with the less ordered structure and increased fluidity of plasma membranes induced by thymic canceration observed in our previous MD study.

Inhibitory effects of nicotine derived from cigarette smoke on thymic stromal lymphopoietin production in epidermal keratinocytes.

PubMed

Dong, Jiangxu; Segawa, Ryosuke; Mizuno, Natsumi; Hiratsuka, Masahiro; Hirasawa, Noriyasu

2016-04-01

Thymic stromal lymphopoietin (TSLP) is regarded as the main factor responsible for the pathogenesis of atopic dermatitis (AD). Cigarette smoke is an aggravating factor for allergies, but has been reported to decrease the risk of AD. In the present study, we evaluated the role of nicotine, the main constituent in cigarette smoke extract, and its underlying mechanism of action in the regulation of TSLP expression. We found that nicotine significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced TSLP expression in BALB/c mice and the mouse keratinocyte cell line PAM212. Nicotine inhibition of TSLP production was abolished by pretreatments with α7 nicotinic acetylcholine receptor (α7 nAChR) antagonists, AMP-activated protein kinase (AMPK) inhibitor, and phosphoinositide 3-kinase (PI3K) inhibitors. The same inhibitors abolished inhibition of nuclear factor-κB (NF-κB) activation by nicotine. These results suggest that nicotine inhibits the expression of TSLP by suppressing the activation of NF-κB through the α7 nAChR-PI3K-AMPK signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

The frequency of occurrence and nature of recombinant feline leukemia viruses in the induction of multicentric lymphoma by infection of the domestic cat with FeLV-945.

PubMed

Ahmad, Shamim; Levy, Laura S

2010-08-01

During feline leukemia virus (FeLV) infection in the domestic cat, viruses with a novel envelope gene arise by recombination between endogenous FeLV-related elements and the exogenous infecting species. These recombinant viruses (FeLV-B) are of uncertain disease association, but have been linked to the induction of thymic lymphoma. To assess the role of FeLV-B in the induction of multicentric lymphoma and other non-T-cell disease, the frequency of occurrence and nature of FeLV-B were examined in diseased tissues from a large collection of FeLV-infected animals. Diseased tissues were examined by Southern blot and PCR amplification to detect the presence of FeLV-B. Further analysis was performed to establish the recombination junctions and infectivity of FeLV-B in diseased tissues. The results confirmed the frequent association of FeLV-B with thymic lymphoma but showed infrequent generation, low levels and lack of infectivity of FeLV-B in non-T-cell diseases including multicentric lymphoma.

The role of the thymus in allogeneic hematopoietic stem cell transplantation.

PubMed

Krenger, Werner; Holländer, Georg A

2010-07-19

Allogeneic haematopoietic stem cell transplantation (HSCT) is used to treat an increasing number of congenital and acquired disorders of the haematopoietic system. Even though cytoreductive conditioning regimens vary in intensity, all clinically used protocols invariably cause side effects that compromise transiently or long-term the response of the natural and the adaptive immune systems. However, in the context of the reconstruction of immunity, the generation of naïve T cells constitutes a slow process, and requires a functionally competent thymus. Unfortunately, regular thymic function is frequently suppressed by transplant-related toxicities. Most notably, graft-versus-host disease (GVHD) causes a state of posttransplantation immune deficiency. Here we discuss preclinical allogeneic HSCT models and clinical observations that have contributed to a detailed understanding of the cellular and molecular mechanisms responsible for the thymic dysfunction caused by acute GVHD. An in-depth knowledge of the mechanisms that control regular thymopoiesis and, conversely, affect thymus function is expected to provide the factual basis for the design of innovative therapies to recover T-cell numbers and function following allogeneic HSCT.

Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci.

PubMed

Berkley, Amy M; Hendricks, Deborah W; Simmons, Kalynn B; Fink, Pamela J

2013-06-15

Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery and exhibit phenotypic and functional characteristics distinct from those of their more mature counterparts in the naive peripheral T cell pool. We show in this study that the Il2 and Il4 promoter regions of naive CD4(+) RTEs are characterized by site-specific hypermethylation compared with those of both mature naive (MN) T cells and the thymocyte precursors of RTEs. Thus, RTEs do not merely occupy a midpoint between the thymus and the mature T cell pool, but represent a distinct transitional T cell population. Furthermore, RTEs and MN T cells exhibit distinct CpG DNA methylation patterns both before and after activation. Compared with MN T cells, RTEs express higher levels of several enzymes that modify DNA methylation, and inhibiting methylation during culture allows RTEs to reach MN T cell levels of cytokine production. Collectively, these data suggest that the functional differences that distinguish RTEs from MN T cells are influenced by epigenetic mechanisms and provide clues to a mechanistic basis for postthymic maturation.

Recent thymic emigrants are tolerized in the absence of inflammation.

PubMed

Friesen, Travis J; Ji, Qingyong; Fink, Pamela J

2016-05-30

T cell development requires a period of postthymic maturation. Why this is the case has remained a mystery, particularly given the rigors of intrathymic developmental checkpoints, successfully traversed by only ∼5% of thymocytes. We now show that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which recent thymic emigrants (RTEs) encounter antigen. After encounter with TRAs in the absence of inflammation, RTEs exhibited defects in proliferation, diminished cytokine production, elevated expression of anergy-associated genes, and diminished diabetogenicity. These properties were mirrored in vitro by enhanced RTE susceptibility to regulatory T cell-mediated suppression. In the presence of inflammation, RTEs and mature T cells were, in contrast, equally capable of inducing diabetes, proliferating, and producing cytokines. Thus, recirculating RTEs encounter TRAs during a transitional developmental stage that facilitates tolerance induction, but inflammation converts antigen-exposed, tolerance-prone RTEs into competent effector cells. © 2016 Friesen et al.

The 3’-Jα Region of the TCRα Locus Bears Gene Regulatory Activity in Thymic and Peripheral T Cells

PubMed Central

Kučerová-Levisohn, Martina; Knirr, Stefan; Mejia, Rosa I.; Ortiz, Benjamin D.

2015-01-01

Much progress has been made in understanding the important cis-mediated controls on mouse TCRα gene function, including identification of the Eα enhancer and TCRα locus control region (LCR). Nevertheless, previous data have suggested that other cis-regulatory elements may reside in the locus outside of the Eα/LCR. Based on prior findings, we hypothesized the existence of gene regulatory elements in a 3.9-kb region 5’ of the Cα exons. Using DNase hypersensitivity assays and TCRα BAC reporter transgenes in mice, we detected gene regulatory activity within this 3.9-kb region. This region is active in both thymic and peripheral T cells, and selectively affects upstream, but not downstream, gene expression. Together, these data indicate the existence of a novel cis-acting regulatory complex that contributes to TCRα transgene expression in vivo. The active chromatin sites we discovered within this region would remain in the locus after TCRα gene rearrangement, and thus may contribute to endogenous TCRα gene activity, particularly in peripheral T cells, where the Eα element has been found to be inactive. PMID:26177549

ZAP-70 Restoration in Mice by In Vivo Thymic Electroporation

PubMed Central

Kissenpfennig, Adrien; Poulin, Lionel Franz; Leserman, Lee; Marche, Patrice N.; Jouvin-Marche, Evelyne; Berger, François; Nguyen, Catherine

2008-01-01

Viral and non-viral vectors have been developed for gene therapy, but their use is associated with unresolved problems of efficacy and safety. Efficient and safe methods of DNA delivery need to be found for medical application. Here we report a new monopolar system of non-viral electro-gene transfer into the thymus in vivo that consists of the local application of electrical pulses after the introduction of the DNA. We assessed the proof of concept of this approach by correcting ZAP-70 deficient severe combined immunodeficiency (SCID) in mice. The thymic electro-gene transfer of the pCMV-ZAP-70-IRES-EGFP vector in these mice resulted in rapid T cell differentiation in the thymus with mature lymphocytes detected by three weeks in secondary lymphoid organs. Moreover, this system resulted in the generation of long-term functional T lymphocytes. Peripheral reconstituted T cells displayed a diversified T cell receptor (TCR) repertoire, and were responsive to alloantigens in vivo. This process applied to the thymus could represent a simplified and effective alternative for gene therapy of T cell immunodeficiencies. PMID:18446234

Molecular dynamics study of lipid bilayers modeling the plasma membranes of mouse hepatocytes and hepatomas

NASA Astrophysics Data System (ADS)

Andoh, Yoshimichi; Aoki, Noriyuki; Okazaki, Susumu

2016-02-01

Molecular dynamics (MD) calculations of lipid bilayers modeling the plasma membranes of normal mouse hepatocytes and hepatomas in water have been performed under physiological isothermal-isobaric conditions (310.15 K and 1 atm). The changes in the membrane properties induced by hepatic canceration were investigated and were compared with previous MD calculations included in our previous study of the changes in membrane properties induced by murine thymic canceration. The calculated model membranes for normal hepatocytes and hepatomas comprised 23 and 24 kinds of lipids, respectively. These included phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, lysophospholipids, and cholesterol. We referred to previously published experimental values for the mole fraction of the lipids adopted in the present calculations. The calculated structural and dynamic properties of the membranes such as lateral structure, order parameters, lateral self-diffusion constants, and rotational correlation times all showed that hepatic canceration causes plasma membranes to become more ordered laterally and less fluid. Interestingly, this finding contrasts with the less ordered structure and increased fluidity of plasma membranes induced by thymic canceration observed in our previous MD study.

Generation and characterization of Tbx1-AmCyan1 transgenic reporter mouse line that selectively labels developing thymus primordium.

PubMed

Kimura, Wataru; Sharkar, Mohammad Tofael Kabir; Sultana, Nishat; Islam, Mohammod Johirul; Uezato, Tadayoshi; Miura, Naoyuki

2013-06-01

Thymus development is a complicated process that includes highly dynamic morphological changes and reciprocal tissue interactions between endoderm-derived epithelial cells of the anterior foregut and neural crest-derived mesenchymal cells. We generated and characterized a Tbx1-AmCyan1 reporter transgenic mouse to visualize thymus precursor cells during early embryonic development. In transgenic embryos, AmCyan1 fluorescence was specifically detected in the endoderm of the developing 3rd and 4th pharyngeal pouches and later in thymus epithelium until E14.5. Cells expressing AmCyan1 that were isolated based on AmCyan1 fluorescence expressed endodermal, thymic, and parathyroid markers, but they did not express neural crest or endothelial markers; these findings indicated that this transgenic mouse strain could be used to collect thymic or parathyroid precursor cells or both. We also showed that in nude mice, which exhibit defects in thymus development, the thymus precursors were clearly labeled with AmCyan1. In summary, these AmCyan1-fluorescent transgenic mice are useful for investigating early thymus development.

CCR4+T cell recruitment to the skin in mycosis fungoides: potential contributions by thymic stromal lymphopoietin and interleukin-16.

PubMed

Tuzova, Marina; Richmond, Jillian; Wolpowitz, Deon; Curiel-Lewandrowski, Clara; Chaney, Keri; Kupper, Thomas; Cruikshank, William

2015-02-01

Mycosis fungoides (MF) is characterized by skin accumulation of CCR4+CCR7- effector memory T cells; however the mechanism for their recruitment is not clearly identified. Thymic Stromal Lymphopoietin (TSLP) is a keratinocyte-derived cytokine that triggers Th2 immunity and is associated with T cell recruitment to the skin in atopic dermatitis. Interleukin-16 (IL-16) is a chemoattractant and growth factor for CD4+T cells. We hypothesized that TSLP and IL-16 could contribute to recruitment of malignant T cells in MF. We found elevated TSLP and IL-16 in very early stage patients' plasma and skin biopsies, prior to elevation in CCL22. Both TSLP and IL-16 induced migratory responses of CCR4+TSLPR+CD4+CCR7-CD31+cells, characteristic of malignant T cells in the skin. Co-stimulation also resulted in significant proliferative responses. We conclude that TSLP and IL-16, expressed at early stages of disease, function to recruit malignant T cells to the skin and contribute to their enhanced proliferation.

PDYN rs2281285 Variant Association with Drinking to Avoid Emotional or Somatic Discomfort

PubMed Central

Preuss, Ulrich W.; Winham, Stacey J.; Biernacka, Joanna M.; Geske, Jennifer R.; Bakalkin, Georgy; Koller, Gabriele; Zill, Peter; Soyka, Michael; Karpyak, Victor M.

2013-01-01

Introduction One of the proposed psychobiological pathways of craving attributes the desire for drinking in the context of tension, discomfort or unpleasant emotions, to “negative” (or “relief”) craving. The aim of this study was to replicate a previously reported association of the PDYN rs2281285 variant with negative craving using a different phenotyping approach. Methods The TaqMan® Genotyping Assay was used to genotype the rs2281285 variant in 417 German alcohol-dependent subjects. The presence of negative/relief craving was assessed by asking if participants ever ingested alcohol to avoid unwanted emotional or somatic discomfort. Results The minor allele of rs2281285 was associated with an increased risk of drinking to avoid/escape unwanted emotional or somatic events (OR = 2.29, 95% CI = 1.08–4.85, p = 0.0298). Discussion Despite the use of a different phenotyping approach to the measurement of negative craving, our results confirm the association between negative craving and PDYN rs2281285. Genetic markers of negative craving may help to identify subgroups of alcohol-dependent individuals vulnerable to relapse in the context of negative emotions or somatic discomfort, leading to the development of specifically tailored treatment strategies. PMID:24223163

Risks incurred by hydrogen escaping from containers and conduits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swain, M.R.; Grilliot, E.S.

1998-08-01

This paper is a discussion of a method for hydrogen leak classification. Leaks are classified as; gas escapes into enclosed spaces, gas escapes into partially enclosed spaces (vented), and gas escapes into unenclosed spaces. Each of the three enclosure classifications is further divided into two subclasses; total volume of hydrogen escaped and flow rate of escaping hydrogen. A method to aid in risk assessment determination in partially enclosed spaces is proposed and verified for several enclosure geometries. Examples are discussed for additional enclosure geometries.

Hydrodynamic escape from planetary atmospheres

NASA Astrophysics Data System (ADS)

Tian, Feng

Hydrodynamic escape is an important process in the formation and evolution of planetary atmospheres. Due to the existence of a singularity point near the transonic point, it is difficult to find transonic steady state solutions by solving the time-independent hydrodynamic equations. In addition to that, most previous works assume that all energy driving the escape flow is deposited in one narrow layer. This assumption not only results in less accurate solutions to the hydrodynamic escape problem, but also makes it difficult to include other chemical and physical processes in the hydrodynamic escape models. In this work, a numerical model describing the transonic hydrodynamic escape from planetary atmospheres is developed. A robust solution technique is used to solve the time dependent hydrodynamic equations. The method has been validated in an isothermal atmosphere where an analytical solution is available. The hydrodynamic model is applied to 3 cases: hydrogen escape from small orbit extrasolar planets, hydrogen escape from a hydrogen rich early Earth's atmosphere, and nitrogen/methane escape from Pluto's atmosphere. Results of simulations on extrasolar planets are in good agreement with the observations of the transiting extrasolar planet HD209458b. Hydrodynamic escape of hydrogen from other hypothetical close-in extrasolar planets are simulated and the influence of hydrogen escape on the long-term evolution of these extrasolar planets are discussed. Simulations on early Earth suggest that hydrodynamic escape of hydrogen from a hydrogen rich early Earth's atmosphere is about two orders magnitude slower than the diffusion limited escape rate. A hydrogen rich early Earth's atmosphere could have been maintained by the balance between the hydrogen escape and the supply of hydrogen into the atmosphere by volcanic outgassing. Origin of life may have occurred in the organic soup ocean created by the efficient formation of prebiotic molecules in the hydrogen rich early Earth's atmosphere. Simulations show that hydrodynamic escape of nitrogen from Pluto is able to remove a ~3 km layer of ice over the age of the solar system. The escape flux of neutral nitrogen may interact with the solar wind at Pluto's orbit and may be detected by the New Horizon mission.

Creating Engaging Escape Rooms for the Classroom

ERIC Educational Resources Information Center

Nicholson, Scott

2018-01-01

Escape rooms are "live-action team-based games where players discover clues, solve puzzles, and accomplish tasks in one or more rooms in order to accomplish a specific goal (usually escaping from the room) in a limited amount of time." Escape Rooms are one type of Escape Game, which are narrative-based challenges that use puzzles, tasks,…

MAVEN in situ measurements of photochemical escape of oxygen from Mars

NASA Astrophysics Data System (ADS)

Lillis, Robert; Deighan, Justin; Fox, Jane; Bougher, Stephen; Lee, Yuni; Cravens, Thomas; Rahmati, Ali; Mahaffy, Paul; Benna, Mehdi; Groller, Hannes; Jakosky, Bruce

2016-04-01

One of the primary goals of the MAVEN mission is to characterize rates of atmospheric escape from Mars at the present epoch and relate those escape rates to solar drivers. One of the known escape processes is photochemical escape, where a) an exothermic chemical reaction in the atmosphere results in an upward-traveling neutral particle whose velocity exceeds planetary escape velocity and b) the particle is not prevented from escaping through subsequent collisions. At Mars, photochemical escape of oxygen is expected to be a significant channel for atmospheric escape, particularly in the early solar system when extreme ultraviolet (EUV) fluxes were much higher. Thus characterizing this escape process and its variability with solar drivers is central to understanding the role escape to space has played in Mars' climate evolution. We use near-periapsis (<400 km altitude) data from three MAVEN instruments: the Langmuir Probe and Waves (LPW) instrument measures electron density and temperature, the Suprathermal And Thermal Ion Composition (STATIC) experiment measures ion temperature and the Neutral Gas and Ion Mass Spectrometer (NGIMS) measures neutral and ion densities. For each profile of in situ measurements, we make several calculations, each as a function of altitude. The first uses electron and temperatures and simulates the dissociative recombination of both O2+ and CO2+ to calculate the probability distribution for the initial energies of the resulting hot oxygen atoms. The second is a Monte Carlo hot atom transport model that takes that distribution of initial O energies and the measured neutral density profiles and calculates the probability that a hot atom born at that altitude will escape. The third takes the measured electron and ion densities and electron temperatures and calculates the production rate of hot O atoms. We then multiply together the profiles of hot atom production and escape probability to get profiles of the production rate of escaping atoms. We integrate with respect to altitude to give us the escape flux of hot oxygen atoms for that periapsis pass. We have sufficient coverage in solar zenith angle (SZA) to estimate total escape rates for two intervals with the obvious assumption that escape rates are the same at all points with the same SZA. We estimate total escape rates of 3.5-5.8 x 1025 s-1 for Ls = 289° to 319° and 1.6-2.6 x 1025 s-1 for Ls = 326° to 348°. The latter is the most directly comparable to previous model-based estimates and is roughly in line with several of them. Total photochemical loss over Mars history is not very useful to calculate from such escape fluxes derived over a limited area and under limited conditions. A thicker atmosphere and much higher solar EUV in the past may change the dynamics of escape dramatically. In the future, we intend to use 3-D Monte Carlo models of global atmospheric escape, in concert with our in situ and remote measurements, to fully characterize photochemical escape under current conditions and carefully extrapolate back in time using further simulations with new boundary conditions.

Clinical and pathological aspects of microscopic thymoma with myasthenia gravis and review of published reports.

PubMed

Fukuhara, Mitsuro; Higuchi, Mitsunori; Owada, Yuki; Inoue, Takuya; Watanabe, Yuzuru; Yamaura, Takumi; Muto, Satoshi; Hasegawa, Takeo; Suzuki, Hiroyuki

2017-06-01

Microscopic thymomas, defined as epithelial proliferations smaller than 1 mm in diameter, characteristically occur in patients with myasthenia gravis without macroscopic thymic epithelial tumors. However, some clinical and pathological aspects of this entity are still unclear. This retrospective study includes five consecutive patients who had undergone extended thymectomy for myasthenia gravis at our institution from April 2007 to March 2016 and in whom microscopic thymomas were diagnosed by histopathological examination of the resected specimens. During the same period, we performed 32 extended transsternal thymothymectomies/thymectomies in patients with myasthenia gravis, including the above five cases. We here review 18 cases of microscopic thymoma, including our five cases and 13 previously reported cases. The incidence of previously undiagnosed microscopic thymoma in patients undergoing thymectomy for myasthenia gravis in our institution is 15.2%. Serum preoperative anti-acetylcholine receptor antibody (anti-AchR Ab) titers were abnormally high in all of our five cases h (74.4±53.3 nmol/L) and decreased significantly after surgery (11.7±13.5 nmol/L, P=0.037). We divided our cases into the following three groups: microscopic thymoma group (Group M), thymoma group (Group T) and non-thymic tumor group (Group N). The mean preoperative anti-AchR Ab titers of these groups were 74.4, 26.5, and 368 nmol/L, respectively. All these values decreased postoperatively. The mean anti-AchR Ab titer was significantly higher in Group M than in Group T (P=0.034). All five cases in Group M were found by post-operative pathological examination to have multifocal type A thymomas. Microscopic thymomas tend to be multifocal type A thymomas. Anti-AchR Ab titers decreased significantly in all groups. It is very important to both perform complete extended thymectomies in patients with myasthenia gravis and pathological examination of thin slices of thymic tissue to maximize detection of microscopic thymomas.