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Sample records for cells chronically adapted

  1. Transcriptional and functional adaptations of human endothelial cells to physiological chronic low oxygen.

    Science.gov (United States)

    Jiang, Yi-Zhou; Wang, Kai; Li, Yan; Dai, Cai-Feng; Wang, Ping; Kendziorski, Christina; Chen, Dong-Bao; Zheng, Jing

    2013-05-01

    Endothelial cells chronically reside in low-O2 environments in vivo (2%-13% O2), which are believed to be critical for cell homeostasis. To elucidate the roles of this physiological chronic normoxia in human endothelial cells, we examined transcriptomes of human umbilical vein endothelial cells (HUVECs), proliferation and migration of HUVECs in response to fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA), and underlying signaling mechanisms under physiological chronic normoxia. Immediately after isolation, HUVECs were cultured steadily under standard cell culture normoxia (SCN; 21% O2) or physiological chronic normoxia (PCN; 3% O2) up to 25 days. We found that PCN up-regulated 41 genes and down-regulated 21 genes, 90% of which differed from those previously reported from HUVECs cultured under SCN and exposed to acute low O2. Gene ontology analysis indicated that PCN-regulated genes were highly related to cell proliferation and migration, consistent with the results from benchtop assays that showed that PCN significantly enhanced FGF2- and VEGFA-stimulated cell proliferation and migration. Interestingly, preexposing the PCN cells to 21% O2 up to 5 days did not completely diminish PCN-enhanced cell proliferation and migration. These PCN-enhanced cell proliferations and migrations were mediated via augmented activation of MEK1/MEK2/ERK1/ERK2 and/or PI3K/AKT1. Importantly, these PCN-enhanced cellular responses were associated with an increase in activation of VEGFR2 but not FGFR1, without altering their expression. Thus, PCN programs endothelial cells to undergo dramatic changes in transcriptomes and sensitizes cellular proliferative and migratory responses to FGF2 and VEGFA. These PCN cells may offer a unique endothelial model, more closely mimicking the in vivo states.

  2. Fetal exposure to a diabetic intrauterine environment resulted in a failure of cord blood endothelial progenitor cell adaptation against chronic hypoxia

    Science.gov (United States)

    Dincer, U Deniz

    2015-01-01

    Gestational diabetes mellitus (GDM) has long-term health consequences, and fetal exposure to a diabetic intrauterine environment increases cardiovascular risk for her adult offspring. Some part of this could be related to their endothelial progenitor cells (EPCs). Understanding the vessel-forming ability of human umbilical cord blood (HUCB)-derived endothelial colony-forming cells (ECFCs) against pathological stress such as GDM response to hypoxia could generate new therapeutic strategies. This study aims to investigate the role of chronic hypoxia in EPCs functional and vessel-forming ability in GDM subjects. Each ECFC was expressed in endothelial and pro-angiogenic specific markers, namely endothelial nitric oxide synthase (eNOS), platelet (PECAM-1) endothelial cell adhesion molecule 1, vascular endothelial-cadherin CdH5 (Ca-dependent cell adhesion molecule), vascular endothelial growth factor A, (VEGFA) and insulin-like growth factor 1 (IGF1). Chronic hypoxia did not affect CdH5, but PECAM1 MRNA expressions were increased in control and GDM subjects. Control hypoxic and GDM normoxic VEGFA MRNA expressions and hypoxia-inducible factor 1-alpha (HIF1α) protein expressions were significantly increased in HUCB ECFCs. GDM resulted in most failure of HUCB ECFC adaptation and eNOS protein expressions against chronic hypoxia. Chronic hypoxia resulted in an overall decline in HUCB ECFCs’ proliferative ability due to reduction of clonogenic capacity and diminished vessel formation. Furthermore, GDM also resulted in most failure of cord blood ECFC adaptation against chronic hypoxic environment. PMID:25565870

  3. Oxidative Stress Adaptation with Acute, Chronic and Repeated Stress

    OpenAIRE

    Pickering, Andrew. M.; Vojtovich, Lesya; Tower, John; Davies, Kelvin J. A.

    2012-01-01

    Oxidative stress adaptation or hormesis is an important mechanism by which cells and organisms respond to, and cope with, environmental and physiological shifts in the level of oxidative stress. Most studies of oxidative stress adaption have been limited to adaptation induced by acute stress. In contrast, many if not most environmental and physiological stresses are either repeated or chronic. In this study we find that both cultured mammalian cells, and the fruit fly Drosophila melanogaster,...

  4. Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells.

    Science.gov (United States)

    Kobayashi, S; Conforti, L; Zhu, W H; Beitner-Johnson, D; Millhorn, D E

    1999-11-01

    We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize and undergo Ca2+ influx through voltage-dependent Ca2+ channels in response to moderate hypoxia and that intracellular free Ca2+ is modulated by activation of dopamine D2 receptors in this cell type. The present study shows that D2 (quinpirole-mediated) inhibition of a voltage-dependent Ca2+ current (ICa) in PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia (24 h at 10% O2). Pretreatment of cells with pertussis toxin abolished D2-mediated inhibition of ICa. The D2-induced inhibition of ICa did not depend on protein kinase A (PKA), as it persisted both in the presence of a specific PKA inhibitor (PKI) and in PKA-deficient PC12 cells. Prolonged exposure to hypoxia (24 h) significantly reduced the level of Gi/o alpha immunoreactivity, but did not alter G beta levels. Furthermore, dialysis of recombinant G(o) alpha protein through the patch pipette restored the inhibitory effect of quinpirole in cells chronically exposed to hypoxia. We conclude that the attenuation of the D2-mediated inhibition of ICa by chronic hypoxia is caused by impaired receptor-G protein coupling, due to reduced levels of G(o) alpha protein. This attenuated feedback modulation of ICa by dopamine may allow for a more sustained Ca2+ influx and enhanced cellular excitation during prolonged hypoxia. PMID:10591061

  5. Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells

    OpenAIRE

    Kobayashi, Shuichi; Conforti, Laura; Zhu Dana Beitner-Johnson, Wylie H.; Millhorn, David E.

    1999-01-01

    We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize and undergo Ca2+ influx through voltage-dependent Ca2+ channels in response to moderate hypoxia and that intracellular free Ca2+ is modulated by activation of dopamine D2 receptors in this cell type. The present study shows that D2 (quinpirole-mediated) inhibition of a voltage-dependent Ca2+ current (ICa) in PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia (24 h at 10% O2). Pretreatm...

  6. Adaptations to chronic rapamycin in mice

    Directory of Open Access Journals (Sweden)

    Sherry G. Dodds

    2016-05-01

    Full Text Available Rapamycin inhibits mechanistic (or mammalian target of rapamycin (mTOR that promotes protein production in cells by facilitating ribosome biogenesis (RiBi and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level. Here, we report our observations of chronic eRapa treatment on mTORC1 signaling and RiBi in mouse colon and visceral adipose. As expected, chronic eRapa treatment decreased detection of phosphorylated mTORC1/S6K substrate, ribosomal protein (rpS6 in colon and fat. However, in colon, contrary to expectations, there was an upregulation of 18S rRNA and some ribosomal protein genes (RPGs suggesting increased RiBi. Among RPGs, eRapa increases rpl22l1 mRNA but not its paralog rpl22. Furthermore, there was an increase in the cap-binding protein, eIF4E relative to its repressor 4E-BP1 suggesting increased translation. By comparison, in fat, there was a decrease in the level of 18S rRNA (opposite to colon, while overall mRNAs encoding ribosomal protein genes appeared to increase, including rpl22, but not rpl22l1 (opposite to colon. In fat, there was a decrease in eIF4E relative to actin (opposite to colon but also an increase in the eIF4E/4E-BP1 ratio likely due to reductions in 4E-BP1 at our lower eRapa dose (similar to colon. Thus, in contrast to predictions of decreased protein production seen in cell-based studies, we provide evidence that colon from chronically treated mice exhibited an adaptive ‘pseudo-anabolic’ state, which is only partially present in fat, which might relate to differing tissue levels of rapamycin, cell-type-specific responses, and/or strain differences.

  7. Neural control of chronic stress adaptation

    OpenAIRE

    James eHerman

    2013-01-01

    Stress initiates adaptive processes that allow the organism to physiologically cope with prolonged or intermittent exposure to real or perceived threats. A major component of this response is repeated activation of glucocorticoid secretion by the hypothalamo-pituitary-adrenocortical (HPA) axis, which promotes redistribution of energy in a wide range of organ systems, including the brain. Prolonged or cumulative increases in glucocorticoid secretion can reduce benefits afforded by enhanced s...

  8. δ-OPIOID RECEPTOR ADAPTATION IN NEUROBLASTOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    D-M,Chuang; M.Belchers; J.Barg; J.Rowinski; G.Clark; C.A.Gloeckner; A.Ho; X-M.Gao; C.J.Coscia

    1993-01-01

    The mechanisms underlying tolerance and dependence arising from chronic opioid exposure are poorly understood. However, the development of neuroblastoma and neurohybrid cell culturea, has provided a simplified model for the atudy of opioid receptor adaptation. Using neuroblastoma NG108-15 cells,

  9. Chronic Inflammation and γδ T Cells.

    Science.gov (United States)

    Fay, Nathan S; Larson, Emily C; Jameson, Julie M

    2016-01-01

    The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programed to mobilize the host innate and adaptive immune responses. Included among these immune cells are gamma delta T lymphocytes (γδ T cells) that are unique in their T cell receptor usage, location, and functions in the body. Stress reception by γδ T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces γδ T cell activation. Once activated, γδ T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon γδ T cell activation. Pathogenesis of many chronic inflammatory diseases involves γδ T cells; some of which are exacerbated by their presence, while others are improved. γδ T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial γδ T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts γδ T cell function. Future studies will be important to understand how this balance is achieved. PMID:27303404

  10. Chronic Inflammation and  T Cells

    Directory of Open Access Journals (Sweden)

    Nathan S Fay

    2016-05-01

    Full Text Available The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programmed to mobilize the host innate and adaptive immune responses. Included among these immune cells are  T cells that are unique in their TCR usage, location, and functions in the body. Stress reception by  T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces  T cell activation. Once activated,  T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon  T cell activation. Pathogenesis of many chronic inflammatory diseases involve  T cells; some of which are exacerbated by their presence, while others are improved.  T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial  T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts  T cell function. Future studies will be important to understand how this balance is achieved.

  11. How to adapt the pulmonary rehabilitation programme to patients with chronic respiratory disease other than COPD

    OpenAIRE

    Holland, Anne E.; Karin Wadell; Spruit, Martijn A

    2013-01-01

    Dyspnoea, fatigue, reduced exercise tolerance, peripheral muscle dysfunction and mood disorders are common features of many chronic respiratory disorders. Pulmonary rehabilitation successfully treats these manifestations in chronic obstructive pulmonary disease (COPD) and emerging evidence suggests that these benefits could be extended to other chronic respiratory conditions, although adaptations to the standard programme format may be required. Whilst the benefits of exercise training are we...

  12. Dynamic Adaptive Remote Health Monitoring for Patients with Chronic Disease

    OpenAIRE

    Suh, Myung-kyung

    2012-01-01

    Chronic diseases are the leading causes of death and disability in the United States. More than 70% of deaths among Americans are caused by chronic diseases and more than 133 million Americans have at least one chronic disease. Due to the prevalence of chronic disease-related issues, it is prudent to seek out methodologies that would facilitate the prevention, monitoring, and feedback for patients with chronic diseases.This dissertation describes WANDA (Weight and Activity with Other Vital Si...

  13. How to adapt the pulmonary rehabilitation programme to patients with chronic respiratory disease other than COPD.

    Science.gov (United States)

    Holland, Anne E; Wadell, Karin; Spruit, Martijn A

    2013-12-01

    Dyspnoea, fatigue, reduced exercise tolerance, peripheral muscle dysfunction and mood disorders are common features of many chronic respiratory disorders. Pulmonary rehabilitation successfully treats these manifestations in chronic obstructive pulmonary disease (COPD) and emerging evidence suggests that these benefits could be extended to other chronic respiratory conditions, although adaptations to the standard programme format may be required. Whilst the benefits of exercise training are well established in asthma, pulmonary rehabilitation can also provide evidence-based interventions including breathing techniques and self-management training. In interstitial lung disease, a small number of trials show improved exercise capacity, symptoms and quality of life following pulmonary rehabilitation, which is a positive development for patients who may have few treatment options. In pulmonary arterial hypertension, exercise training is safe and effective if patients are stable on medical therapy and close supervision is provided. Pulmonary rehabilitation for bronchiectasis, including exercise training and airway clearance techniques, improves exercise capacity and quality of life. In nonsmall cell lung cancer, a comprehensive interdisciplinary approach is required to ensure the success of pulmonary rehabilitation following surgery. Pulmonary rehabilitation programmes provide important and underutilised opportunities to improve the integrated care of people with chronic respiratory disorders other than COPD. PMID:24293474

  14. How to adapt the pulmonary rehabilitation programme to patients with chronic respiratory disease other than COPD

    Directory of Open Access Journals (Sweden)

    Anne E. Holland

    2013-12-01

    Full Text Available Dyspnoea, fatigue, reduced exercise tolerance, peripheral muscle dysfunction and mood disorders are common features of many chronic respiratory disorders. Pulmonary rehabilitation successfully treats these manifestations in chronic obstructive pulmonary disease (COPD and emerging evidence suggests that these benefits could be extended to other chronic respiratory conditions, although adaptations to the standard programme format may be required. Whilst the benefits of exercise training are well established in asthma, pulmonary rehabilitation can also provide evidence-based interventions including breathing techniques and self-management training. In interstitial lung disease, a small number of trials show improved exercise capacity, symptoms and quality of life following pulmonary rehabilitation, which is a positive development for patients who may have few treatment options. In pulmonary arterial hypertension, exercise training is safe and effective if patients are stable on medical therapy and close supervision is provided. Pulmonary rehabilitation for bronchiectasis, including exercise training and airway clearance techniques, improves exercise capacity and quality of life. In nonsmall cell lung cancer, a comprehensive interdisciplinary approach is required to ensure the success of pulmonary rehabilitation following surgery. Pulmonary rehabilitation programmes provide important and underutilised opportunities to improve the integrated care of people with chronic respiratory disorders other than COPD.

  15. Beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    2016-01-01

    Pregnancy is associated with a compensatory increase in beta cell mass. It is well established that somatolactogenic hormones contribute to the expansion both indirectly by their insulin antagonistic effects and directly by their mitogenic effects on the beta cells via receptors for prolactin...... and growth hormone expressed in rodent beta cells. However, the beta cell expansion in human pregnancy seems to occur by neogenesis of beta cells from putative progenitor cells rather than by proliferation of existing beta cells. Claes Hellerström has pioneered the research on beta cell growth for decades......, but the mechanisms involved are still not clarified. In this review the information obtained in previous studies is recapitulated together with some of the current attempts to resolve the controversy in the field: identification of the putative progenitor cells, identification of the factors involved...

  16. Adult stem cells for chronic lung diseases.

    Science.gov (United States)

    Mora, Ana L; Rojas, Mauricio

    2013-10-01

    Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are chronic, progressive and lethal lung diseases. The incidence of IPF and COPD increases with age, independent of exposure to common environmental risk factors. At present, there is limited understanding of the relationship between ageing and the development of chronic lung diseases. One hypothesis is that chronic injury drives to exhaustion the local and systemic repair responses in the lung. These changes are accentuated during ageing where there is a progressive accumulation of senescent cells. Recently, stem cells have emerged as a critical reparative mechanism for lung injury. In this review, we discuss the repair response of bone marrow-derived mesenchymal stem cells (B-MSC) after lung injury and how their function is affected by ageing. Our own work has demonstrated a protective role of B-MSC in several animal models of acute and chronic lung injury. We recently demonstrated the association, using animal models, between age and an increase in the susceptibility to develop severe injury and fibrosis. At the same time, we have identified functional differences between B-MSC isolated from young and old animals. Further studies are required to understand the functional impairment of ageing B-MSC, ultimately leading to a rapid stem cell depletion or fatigue, interfering with their ability to play a protective role in lung injury. The elucidation of these events will help in the development of rational and new therapeutic strategies for COPD and IPF. PMID:23648014

  17. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    Energy Technology Data Exchange (ETDEWEB)

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Ngalame, Ntube N. Olive; Waalkes, Michael P., E-mail: waalkes@niehs.nih.gov

    2013-12-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. - Highlights: • Chronic cadmium exposure induces cancer cell characteristics in human lung cells. • This provides an in vitro model of cadmium-induced human lung cell transformation. • This occurred with general and lung specific changes typical for cancer cells. • These findings add insight to the

  18. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    International Nuclear Information System (INIS)

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. - Highlights: • Chronic cadmium exposure induces cancer cell characteristics in human lung cells. • This provides an in vitro model of cadmium-induced human lung cell transformation. • This occurred with general and lung specific changes typical for cancer cells. • These findings add insight to the relationship

  19. Stromal control of chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Seke Etet PF

    2013-09-01

    Full Text Available Paul Faustin Seke Etet,1 Armel Herve Nwabo Kamdje,2 Jeremie Mbo Amvene,2 Yousef Aldebasi,3 Mohammed Farahna,1 Lorella Vecchio41Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 2Department of Medicine, University of Ngaoundere, Ngaoundere, Cameroon; 3Department of Optometry, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 4Laboratory of Cytometry, Institute of Molecular Genetics, CNR, University of Pavia, Pavia, ItalyAbstract: In the ongoing efforts to develop therapies against chronic lymphocytic leukemia (CLL, stromal factors allowing malignant cells to escape spontaneous and chemotherapy-mediated apoptosis, giving way to relapses, have been abundantly investigated. Bone marrow adherent cell types, collectively referred to as stromal cells, appear to be key players in such escape, mainly because CLL malignant cells, which rapidly undergo spontaneous apoptosis when cultured in vitro, survive, migrate, and resist cytotoxic agents in co-culture with bone marrow stromal cells. CLL displays variable clinical courses according to well-defined prognostic factors induced on malignant B-cells (CLL cells or expressed by the transformed bone marrow stromal microenvironment. Particularly, a critical pathogenic role is played by proinflammatory factors, adhesion molecules, and signaling molecules involved in cell fate and stemness, such as Notch, Wnt, sonic Hedgehog, phosphoinositide 3-kinase (PI3K, protein kinase B (Akt, and the B-cell CLL/lymphoma 2 (Bcl-2 family of regulator proteins. As herein discussed, these molecules probably form a complex network favoring CLL cell survival, proliferation, and chemoresistance to anticancer therapy. Characterizing the sets of signaling pathways involved in the interactions between stromal cells and CLL cells may provide new tools for CLL clinical phenotyping and for re-sensitizing chemotherapy resistant cells

  20. Adapting chronic care models for diabetes care delivery inlow-and-middle-income countries: A review

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    A contextual review of models for chronic care was doneto develop a context-adapted chronic care model-basedservice delivery model for chronic conditions includingdiabetes. The Philippines was used as the setting ofa low-to-middle-income country. A context-basednarrative review of existing models for chronic carewas conducted. A situational analysis was done at thegrassroots level, involving the leaders and members ofthe community, the patients, the local health system andthe healthcare providers. A second analysis making useof certain organizational theories was done to explore onimproving feasibility and acceptability of organizing carefor chronic conditions. The analyses indicated that carefor chronic conditions may be introduced, consideringthe needs of people with diabetes in particular andthe community in general as recipients of care, andthe issues and factors that may affect the healthcareworkers and the health system as providers of thiscare. The context-adapted chronic care model-basedservice delivery model was constructed accordingly.Key features are incorporation of chronic care in thehealth system's services; assimilation of chronic caredelivery with the other responsibilities of the healthcareworkers but with redistribution of certain tasks; andensuring that the recipients of care experience thewhole spectrum of basic chronic care that includes educationand promotion in the general population, riskidentification, screening, counseling including self-caredevelopment, and clinical management of the chroniccondition and any co-morbidities, regardless of level ofcontrol of the condition. This way, low-to-middle incomecountries can introduce and improve care for chronicconditions without entailing much additional demand ontheir limited resources.

  1. Adaptive leadership framework for chronic illness: framing a research agenda for transforming care delivery.

    Science.gov (United States)

    Anderson, Ruth A; Bailey, Donald E; Wu, Bei; Corazzini, Kirsten; McConnell, Eleanor S; Thygeson, N Marcus; Docherty, Sharron L

    2015-01-01

    We propose the Adaptive Leadership Framework for Chronic Illness as a novel framework for conceptualizing, studying, and providing care. This framework is an application of the Adaptive Leadership Framework developed by Heifetz and colleagues for business. Our framework views health care as a complex adaptive system and addresses the intersection at which people with chronic illness interface with the care system. We shift focus from symptoms to symptoms and the challenges they pose for patients/families. We describe how providers and patients/families might collaborate to create shared meaning of symptoms and challenges to coproduce appropriate approaches to care. PMID:25647829

  2. Salmonella Typhimurium undergoes distinct genetic adaption during chronic infections of mice

    DEFF Research Database (Denmark)

    Søndberg, Emilie; Jelsbak, Lotte

    2016-01-01

    Background Typhoid fever caused by Salmonella enterica serovar Typhi (S. Typhi) is a severe systemic human disease and endemic in regions of the world with poor drinking water quality and sewage treatment facilities. A significant number of patients become asymptomatic life-long carriers of S....... In the current study genetic adaptation during experimental chronic S. Typhimurium infections of mice, an established model of chronic typhoid fever, was probed as an approach for studying the molecular mechanisms of host-adaptation during long-term host-association. Results Individually sequence-tagged wild......, the kdgR-SNP was confirmed to confer selective advantage during chronic infections and constitute a true patho-adaptive mutation. Together, the results provide evidence for rapid genetic adaptation to the host of S. Typhimurium and validate experimental evolution in the context of host infection...

  3. Pancreatic Stellate Cells and Chronic Alcoholic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Raffaele Pezzilli

    2007-03-01

    Full Text Available Chronic pancreatitis is a disease often characterized by recurrent episodes of abdominal pain accompanied by progressive pancreatic exocrine and endocrine insufficiency [1] and it sometimes requires multiple hospitalizations. Obstructive jaundice, duodenal stenosis, left-sided portal hypertension, pseudocyst and mass formation, and pancreatic carcinoma may occur as complications of chronic pancreatitis. The disease is frequently the result of chronic alcohol abuse, even if other factors such as genetic alterations, autoimmune disorders, and obstructive disease of the biliary tract and the pancreas may cause the disease [2]. Medical therapy is the treatment of choice for most patients and it is based on substitutive therapy for either exocrine or endocrine insufficiency and on analgesics for pain control. In the presence of intractable pain, surgical management is the main option [3] even if, in recent years, other therapeutic options such as endoscopic therapy [4], thoracoscopic splanchnicectomy [5], and extracorporeal shockwave lithotripsy have been applied in clinical practice [6]. From a pathological point of view, chronic pancreatitis is characterized by irregular sclerosis with destruction and loss of the exocrine parenchyma, and complete replacement of acinar, ductal and endocrine tissue by fibrotic tissue. It has recently been reported that acute alcoholic pancreatitis develops in a pancreas already affected by chronic pancreatitis [7]. In 1982, Watari et al. [8] reported the presence of vitamin A-containing cells in the vitamin A-fed rat pancreas. These were later described and characterized as stellate cells in the rat and the human pancreas [9, 10]. Pancreatic stellate cells are morphologically similar to hepatic stellate cells. They bear long cytoplasmic processes and are situated close to the pancreatic acini. In the quiescent state, these cells contain lipid droplets, store vitamin A and express markers such as desmin, glial

  4. Epigenetic Regulation of Adaptive NK Cell Diversification.

    Science.gov (United States)

    Tesi, Bianca; Schlums, Heinrich; Cichocki, Frank; Bryceson, Yenan T

    2016-07-01

    Natural killer (NK) cells were previously considered to represent short-lived, innate lymphocytes. However, mouse models have revealed expansion and persistence of differentiated NK cell subsets in response to cytomegalovirus (CMV) infection, paralleling antigen-specific T cell differentiation. Congruently, analyses of humans have uncovered CMV-associated NK cell subsets characterized by epigenetic diversification processes that lead to altered target cell specificities and functional capacities. Here, focusing on responses to viruses, we review similarities and differences between mouse and human adaptive NK cells, identifying molecular analogies that may be key to transcriptional reprogramming and functional alterations. We discuss possible molecular mechanisms underlying epigenetic diversification and hypothesize that processes driving epigenetic diversification may represent a more widespread mechanism for fine-tuning and optimization of cellular immunity.

  5. Chronic pain and the adaptive significance of positive emotions.

    Science.gov (United States)

    Ong, Anthony D; Zautra, Alex J; Reid, M Carrington

    2015-04-01

    The February-March 2014 special issue of the American Psychologist featured articles summarizing select contributions from the field of psychology to the assessment and treatment of chronic pain. The articles examined a range of psychosocial and family factors that influence individual adjustment and contribute to disparities in pain care. The reviews also considered the psychological correlates and neurophysiological mechanisms of specific pain treatments, including cognitive-behavioral therapy, hypnosis, acceptance and commitment therapy, mindfulness, and meditation. Although a number of articles emphasized the role that negative states of mind play in pain outcomes, positive emotions were given only brief mention. Here, we provide a rationale for the inclusion of positive emotions in chronic pain research. PMID:25844656

  6. Dynamical Adaptation in Terrorist Cells/Networks

    DEFF Research Database (Denmark)

    Hussain, Dil Muhammad Akbar; Ahmed, Zaki

    2010-01-01

    Typical terrorist cells/networks have dynamical structure as they evolve or adapt to changes which may occur due to capturing or killing of a member of the cell/network. Analytical measures in graph theory like degree centrality, betweenness and closeness centralities are very common and have long...... history of their successful use in revealing the importance of various members of the network. However, modeling of covert, terrorist or criminal networks through social graph dose not really provide the hierarchical structure which exist in these networks as these networks are composed of leaders...

  7. Astrocytic adaptation during cerebral angiogenesis follows the new vessel formation induced through chronic hypoxia in adult mouse cortex

    Science.gov (United States)

    Masamoto, Kazuto; Kanno, Iwao

    2014-03-01

    We examined longitudinal changes of the neuro-glia-vascular unit during cerebral angiogenesis induced through chronic hypoxia in the adult mouse cortex. Tie2-GFP mice in which the vascular endothelial cells expressed green fluorescent proteins (GFP) were exposed to chronic hypoxia, while the spatiotemporal developments of the cortical capillary sprouts and the neighboring astrocytic remodeling were characterized with repeated two-photon microscopy. The capillary sprouts appeared at early phases of the hypoxia adaptation (1-2 weeks), while the morphological changes of the astrocytic soma and processes were not detected in this phase. In the later phases of the hypoxia adaptation (> 2 weeks), the capillary sprouts created a new connection with existing capillaries, and its neighboring astrocytes extended their processes to the newly-formed vessels. The findings show that morphological adaptation of the astrocytes follow the capillary development during the hypoxia adaptation, which indicate that the newly-formed vessels provoke cellular interactions with the neighboring astrocytes to strengthen the functional blood-brain barrier.

  8. Angioimmunoblastic T Cell Lymphoma Mimicking Chronic Urticaria

    Directory of Open Access Journals (Sweden)

    Mohleen Kang

    2016-01-01

    Full Text Available Angioimmunoblastic T cell lymphoma (AITL is a rare but distinct type of T cell lymphoma with an aggressive course and high mortality. Most patients are diagnosed late in the disease and usually present with generalized lymphadenopathy. A minority have skin lesions at the time of diagnosis, more commonly in the form of nonspecific maculopapular rash with or without pruritus. We report a rare case of AITL presenting with chronic, recurrent angioedema and urticaria-like lesions and no palpable peripheral adenopathy. Primary Care physicians, dermatologists, and allergists must maintain a high index of suspicion for cutaneous manifestations of lymphoma, especially if the skin lesions are refractory to standard treatment. Timely diagnosis is essential to improve survival.

  9. Neurodevelopmental Status and Adaptive Behaviors in Preschool Children with Chronic Kidney Disease

    Science.gov (United States)

    Duquette, Peter J.; Hooper, Stephen R.; Icard, Phil F.; Hower, Sarah J.; Mamak, Eva G.; Wetherington, Crista E.; Gipson, Debbie S.

    2009-01-01

    This study examines the early neurodevelopmental function of infants and preschool children who have chronic kidney disease (CKD). Fifteen patients with CKD are compared to a healthy control group using the "Mullen Scales of Early Learning" (MSEL) and the "Vineland Adaptive Behavior Scale" (VABS). Multivariate analysis reveals significant…

  10. P. aeruginosa in the paranasal sinuses and transplanted lungs have similar adaptive mutations as isolates from chronically infected CF lungs

    DEFF Research Database (Denmark)

    Ciofu, Oana; Johansen, Helle Krogh; Aanaes, Kasper;

    2013-01-01

    BACKGROUND: Pseudomonas aeruginosa cells are present as biofilms in the paranasal sinuses and the lungs of chronically infected cystic fibrosis (CF) patients. Since different inflammatory responses and selective antibiotic pressures are acting in the sinuses compared with the lungs, we compared...... the adaptive profiles of mucoid and non-mucoid isolates from the two locations. METHODS: We studied the genetic basis of phenotypic diversification and gene expression profiles in sequential lung and sinus P. aeruginosa isolates from four chronically infected CF patients, including pre- and post-lung...... transplantation isolates. RESULTS: The same phenotypes caused by similar mutations and similar gene expression profiles were found in mucoid and non-mucoid isolates from the paranasal sinuses and from the lungs before and after transplantation. CONCLUSION: Bilateral exchange of P. aeruginosa isolates between...

  11. Adaptation of Problem-Solving Skills Training (PSST) for Parent Caregivers of Youth with Chronic Pain.

    Science.gov (United States)

    Palermo, Tonya M; Law, Emily F; Essner, Bonnie; Jessen-Fiddick, Tricia; Eccleston, Christopher

    2014-09-01

    Research on the experience of parents caring for a child with chronic pain indicates that high levels of parental role stress, feelings of frustration over an inability to help, and psychological distress are common. Moreover, parental distress adversely influences child adjustment to chronic pain. Therefore, intervening with parents of youth with chronic pain may, in turn, result in positive outcomes for children in their ability to engage in positive coping strategies, reduce their own distress, and to function competently in their normal daily lives. Our aim was to adapt an intervention, Problem-Solving Skills Training, previously proven effective in reducing parental distress in other pediatric illness conditions to the population of caregivers of youth with chronic pain. In the first phase, the intervention was adapted based on expert review of the literature and review of parent responses on a measure of pain-related family impact. In the second phase, the intervention was tested in a small group of parents to evaluate feasibility, determined by response to treatment content, ratings of acceptability, and ability to enroll and deliver the treatment visits. This phase included piloting the PSST intervention and all outcome measures at pre-treatment and immediately post-treatment. In an exploratory manner we examined change in parent distress and child physical function and depression from pre- to post-treatment. Findings from this feasibility study suggest that PSST can be implemented with parents of youth with chronic pain, and they find the treatment acceptable.

  12. E. coli cells adaptation to solar environment

    Energy Technology Data Exchange (ETDEWEB)

    Favre, A. [Institute J. Monod, Paris (France)

    1997-12-31

    Full text. Photo mutagenesis of E.coli cells exposed to solar light results essentially from the combined effect of its U V C, U V B and U V A components. The high photo mutagenic efficiency of UVC is known to be hampered when the cells have been pre illuminated with near UV light. Near UV light triggers the growth delay effect at sublethal fluences ( and reveals poorly mutagenic). The chromophore leading to this growth lag effect is a rare nucleoside, 4-thio uridine s4U, present only in position 8 of E. coli tRNAs. Upon photo activation s4U led to formation of an intramolecular 8-13 crosslink in a number of tRNA species, including tRNAphe and tRNApro. These two crosslinked Trna species can no more be efficiently acylated by their corresponding tRNa ligases and accumulate on the uncharged from thus preventing protein synthesis, and effect amplified by the so called stringent response. Accordingly nuvA mutant cells no more exhibit growth delay UVC induced mutagenesis involves activation of the inducible error-prone SOS system which requires protein synthesis. By compacting the level of expression of the SOS gene sfiA (using a sfiA:lacZ fusion) in wild-type and nuvA mutant cells submitted to combined UVC, UVA radiations, we have demonstrated that indeed 4-thio uridine behaves as an anti photo mutagenic device. Adaptation of E. coli cell to its solar environment will be discussed in the light of this finding

  13. An intestinal microRNA modulates the homeostatic adaptation to chronic oxidative stress in C. elegans

    Science.gov (United States)

    Kato, Masaomi; Kashem, Mohammed Abul; Cheng, Chao

    2016-01-01

    Adaptation to an environmental or metabolic perturbation is a feature of the evolutionary process. Recent insights into microRNA function suggest that microRNAs serve as key players in a robust adaptive response against stress in animals through their capacity to fine-tune gene expression. However, it remains largely unclear how a microRNA-modulated downstream mechanism contributes to the process of homeostatic adaptation. Here we show that loss of an intestinally expressed microRNA gene, mir-60, in the nematode C. elegans promotes an adaptive response to chronic – a mild and long-term – oxidative stress exposure. The pathway involved appears to be unique since the canonical stress-responsive factors, such as DAF-16/FOXO, are dispensable for mir-60 loss to enhance oxidative stress resistance. Gene expression profiles revealed that genes encoding lysosomal proteases and those involved in xenobiotic metabolism and pathogen defense responses are up-regulated by the loss of mir-60. Detailed genetic studies and computational microRNA target prediction suggest that endocytosis components and a bZip transcription factor gene zip-10, which functions in innate immune response, are directly modulated by miR-60 in the intestine. Our findings suggest that the mir-60 loss facilitates adaptive response against chronic oxidative stress by ensuring the maintenance of cellular homeostasis. PMID:27623524

  14. Salmonella Typhimurium undergoes distinct genetic adaption during chronic infections of mice

    DEFF Research Database (Denmark)

    Søndberg, Emilie; Jelsbak, Lotte

    2016-01-01

    , the kdgR-SNP was confirmed to confer selective advantage during chronic infections and constitute a true patho-adaptive mutation. Together, the results provide evidence for rapid genetic adaptation to the host of S. Typhimurium and validate experimental evolution in the context of host infection......Background Typhoid fever caused by Salmonella enterica serovar Typhi (S. Typhi) is a severe systemic human disease and endemic in regions of the world with poor drinking water quality and sewage treatment facilities. A significant number of patients become asymptomatic life-long carriers of S...... type strains of S. Typhimurium 4/74 were used to establish chronic infections of 129X1/SvJ mice. Over the course of infections, S. Typhimurium bacteria were isolated from feces and from livers and spleens upon termination of the experiment. In all samples dominant clones were identified and select...

  15. Chronic adaptations of lung function in breath-hold diving fishermen

    OpenAIRE

    Cristiane Diniz; Tiago Farias; Mayane Pereira; Caio Pires; Luciana Gonçalves; Patrícia Coertjens; Marcelo Coertjens

    2014-01-01

    Objectives: The aim of this study was to verify and analyze the existence of chronic adaptations of lung function in freediving fishermen whose occupation is artisanal fishing. Material and Methods: This was a cross-sectional study involving 11 breath-hold diving fishermen and 10 non-breath-hold diving fishermen (control) from the village of Bitupitá in the municipality of Barroquinha (Ceará - Brazil). Anthropometric measurements, chest and abdominal circumferences as well as spirometric and ...

  16. B cells mediate chronic allograft rejection independently of antibody production.

    Science.gov (United States)

    Zeng, Qiang; Ng, Yue-Harn; Singh, Tripti; Jiang, Ke; Sheriff, Khaleefathullah A; Ippolito, Renee; Zahalka, Salwa; Li, Qi; Randhawa, Parmjeet; Hoffman, Rosemary A; Ramaswami, Balathiripurasundari; Lund, Frances E; Chalasani, Geetha

    2014-03-01

    Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells. Mice that were deficient for antibodies but not B cells experienced the same chronic allograft vasculopathy (CAV), which is a pathognomonic feature of chronic rejection, as WT mice; however, mice that were deficient for both B cells and antibodies were protected from CAV. B cells contributed to CAV by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice, in which B cells were present but could not present antigen, both T cell responses and CAV were markedly reduced. These findings establish that chronic rejection can occur in the complete absence of antibodies and that B cells contribute to this process by supporting T cell responses through antigen presentation and maintenance of lymphoid architecture.

  17. B cells mediate chronic allograft rejection independently of antibody production.

    Science.gov (United States)

    Zeng, Qiang; Ng, Yue-Harn; Singh, Tripti; Jiang, Ke; Sheriff, Khaleefathullah A; Ippolito, Renee; Zahalka, Salwa; Li, Qi; Randhawa, Parmjeet; Hoffman, Rosemary A; Ramaswami, Balathiripurasundari; Lund, Frances E; Chalasani, Geetha

    2014-03-01

    Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells. Mice that were deficient for antibodies but not B cells experienced the same chronic allograft vasculopathy (CAV), which is a pathognomonic feature of chronic rejection, as WT mice; however, mice that were deficient for both B cells and antibodies were protected from CAV. B cells contributed to CAV by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice, in which B cells were present but could not present antigen, both T cell responses and CAV were markedly reduced. These findings establish that chronic rejection can occur in the complete absence of antibodies and that B cells contribute to this process by supporting T cell responses through antigen presentation and maintenance of lymphoid architecture. PMID:24509079

  18. Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Person, Rachel J.; Olive Ngalame, Ntube N.; Makia, Ngome L.; Bell, Matthew W.; Waalkes, Michael P.; Tokar, Erik J., E-mail: tokare@niehs.nih.gov

    2015-07-01

    Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. - Highlights: • Chronic arsenic exposure transforms a human peripheral lung epithelia cell line. • Cells acquire characteristics in common with human lung adenocarcinoma cells. • These transformed cells provide a

  19. Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

    International Nuclear Information System (INIS)

    Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. - Highlights: • Chronic arsenic exposure transforms a human peripheral lung epithelia cell line. • Cells acquire characteristics in common with human lung adenocarcinoma cells. • These transformed cells provide a

  20. Progress Report for "Developing a Proactive Framework for Adaptive Management of Chronic Wasting Disease on the National Elk Refuge"

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Hobbs, Monello, and Kauffman have been granted funds to develop a Bayesian state space model to support adaptive management of Chronic Wasting Disease (CWD) in the...

  1. Regulation of the adaptive immune system by innate lymphoid cells

    OpenAIRE

    Hepworth, Matthew R.; Sonnenberg, Gregory F.

    2014-01-01

    Innate lymphoid cells (ILCs) are a group of lymphocytes that promote rapid cytokine-dependent innate immunity, inflammation and tissue repair. In addition, a growing body of evidence suggests ILCs can influence adaptive immune cell responses. During fetal development a subset of ILCs orchestrate the generation and maturation of secondary lymphoid tissues. Following birth, ILCs continue to modulate adaptive immune cell responses indirectly through interactions with stromal cells in lymphoid ti...

  2. [Chronic B-cell lymphoproliferative disorders with hairy cells].

    Science.gov (United States)

    Troussard, Xavier; Cornet, Édouard

    2015-01-01

    The standardized blood smear examination is the first step in the diagnosis of a B-cell chronic lymphoproliferative disorder and can guide further investigations. In the laboratory, the identification of hairy cells on blood smear is a matter of daily practice. Hairy cell proliferations represent heterogeneous entities and their respective diagnoses can be difficult. If hairy cell leukemia (HCL) and splenic marginal zone lymphoma (SMZL) represent separate entities, the variant form of HCL (HCLv) and splenic diffuse red pulp small B-cell lymphoma (SDRPL) remain provisional entities in the 2008 WHO classification. We discuss the main clinical and biological characteristics of these four entities and appropriate means to characterize, identify and distinguish from each other; standardized blood smear examination, multiparameter flow cytometry analysis, analysis of the repertoire of immunoglobulins heavy chains genes and their mutational status (mutated or unmutated profile), molecular analyses: BRAF gene V600E mutation in HCL and MAP2K1 gene mutations in HCLv. We also discuss the main therapeutic aspects with emphasis on the new targeted drugs that enter into force in the therapeutic arsenal. PMID:25858127

  3. Adaptive changes in the acute haemodynamic effects of cilazapril during chronic treatment. Comparison with long-term clinical effect

    DEFF Research Database (Denmark)

    Larsen, J; Sykulski, R; Jensen, G;

    1996-01-01

    OBJECTIVE: To study the adaptive changes in the acute haemodynamic response to ACE inhibition during chronic treatment in CHF. METHODS: The acute and chronic effects of oral cilazapril (CLZ) treatment, an ACE-inhibitor with prolonged duration on haemodynamic measures (PCWP, PAP, RAP, CI and SVR) ...

  4. Adaptation to alkalosis induces cell cycle delay and apoptosis in cortical collecting duct cells: role of Aquaporin-2.

    Science.gov (United States)

    Rivarola, Valeria; Flamenco, Pilar; Melamud, Luciana; Galizia, Luciano; Ford, Paula; Capurro, Claudia

    2010-08-01

    Collecting ducts (CD) not only constitute the final site for regulating urine concentration by increasing apical membrane Aquaporin-2 (AQP2) expression, but are also essential for the control of acid-base status. The aim of this work was to examine, in renal cells, the effects of chronic alkalosis on cell growth/death as well as to define whether AQP2 expression plays any role during this adaptation. Two CD cell lines were used: WT- (not expressing AQPs) and AQP2-RCCD(1) (expressing apical AQP2). Our results showed that AQP2 expression per se accelerates cell proliferation by an increase in cell cycle progression. Chronic alkalosis induced, in both cells lines, a time-dependent reduction in cell growth. Even more, cell cycle movement, assessed by 5-bromodeoxyuridine pulse-chase and propidium iodide analyses, revealed a G2/M phase cell accumulation associated with longer S- and G2/M-transit times. This G2/M arrest is paralleled with changes consistent with apoptosis. All these effects appeared 24 h before and were always more pronounced in cells expressing AQP2. Moreover, in AQP2-expressing cells, part of the observed alkalosis cell growth decrease is explained by AQP2 protein down-regulation. We conclude that in CD cells alkalosis causes a reduction in cell growth by cell cycle delay that triggers apoptosis as an adaptive reaction to this environment stress. Since cell volume changes are prerequisite for the initiation of cell proliferation or apoptosis, we propose that AQP2 expression facilitates cell swelling or shrinkage leading to the activation of channels necessary to the control of these processes. PMID:20432437

  5. Kicking off adaptive immunity: the discovery of dendritic cells

    OpenAIRE

    Katsnelson, Alla

    2006-01-01

    In 1973, Ralph Steinman and Zanvil Cohn discovered an unusual looking population of cells with an unprecedented ability to activate naive T cells. Dubbed “dendritic cells,” these cells are now known as the primary instigators of adaptive immunity.

  6. Adaptive changes in basal metabolic rate and thermogenesis in chronic undernutrition

    International Nuclear Information System (INIS)

    Metabolic adaptation during chronic undernutrition represents a complex integration of several processes which affect the total energy expenditure of the individual. Basal metabolic rate (BMR) is reduced; reductions in BMR per unit fat free mass (FFM) is difficult to demonstrate. BMR changes in undernutrition reflect the low body weight as well as alterations in the composition of the FFM; more specifically changes in the ratio of viscera to muscle compartments of the FFM. Thermogenic responses to norepinephrine are transiently suppressed but recover rapidly on repeated stimulation. Dietary thermogenesis is enhanced possible the result of increases in tissue synthesis within the body. Changes in BMR and thermogenesis suggestive of an increase in metabolic efficiency is thus difficult to demonstrate in chronic undernutrition. (author). 15 refs, 2 figs, 7 tabs

  7. Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections.

    Science.gov (United States)

    Winstanley, Craig; O'Brien, Siobhan; Brockhurst, Michael A

    2016-05-01

    Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification. PMID:26946977

  8. Stem cells and chronic wound healing: state of the art

    Directory of Open Access Journals (Sweden)

    Leavitt T

    2016-03-01

    Full Text Available Tripp Leavitt, Michael S Hu, Clement D Marshall, Leandra A Barnes, Michael T Longaker, H Peter Lorenz Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA Abstract: Currently available treatments for chronic wounds are inadequate. A clearly effective therapy does not exist, and treatment is often supportive. This is largely because the cellular and molecular processes underlying failure of wound repair are still poorly understood. With an increase in comorbidities, such as diabetes and vascular disease, as well as an aging population, the incidence of these intractable wounds is expected to rise. As such, chronic wounds, which are already costly, are rapidly growing as a tremendous burden to the health-care system. Stem cells have garnered much interest as a therapy for chronic wounds due to their inherent ability to differentiate into multiple lineages and promote regeneration. Herein, we discuss the types of stem cells used for chronic wound therapy, as well as the proposed means by which they do so. In particular, we highlight mesenchymal stem cells (including adipose-derived stem cells, endothelial progenitor cells, and induced pluripotent stem cells. We include the results of recent in vitro and in vivo studies in both animal models and human clinical trials. Finally, we discuss the current studies to improve stem cell therapies and the limitations of stem cell-based therapeutics. Stem cells promise improved therapies for healing chronic wounds, but further studies that are well-designed with standardized protocols are necessary for fruition. Keywords: stem cells, chronic wounds, cell therapy, wound healing

  9. ER stress in pancreatic beta cells: the thin red line between adaptation and failure.

    Science.gov (United States)

    Eizirik, Decio L; Cnop, Miriam

    2010-01-01

    Secretory cells, such as pancreatic beta cells, face the challenge of increasing protein synthesis severalfold during acute or chronic stimulation. This poses a burden on the endoplasmic reticulum (ER), the organelle where proinsulin synthesis and folding takes place. Thus, beta cells use various adaptive mechanisms to adjust the functional capacity of the ER to the prevailing demand. These check-and-balance mechanisms are collectively known as the unfolded protein response (UPR). It remains unclear how UPR signaling is ultimately regulated and what delineates the boundaries between a physiological and a pathological response. New discoveries point to the divergent effects of acute and chronic metabolic fluxes and chemical ER stressors on the formation of complexes among UPR transducers, scaffold proteins, and phosphatases. These and other findings provide a first glimpse on how different signals trigger diverging UPR outcomes. PMID:20179270

  10. Genetic features of B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Stilgenbauer, S; Lichter, P; Döhner, H

    2000-03-01

    The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently

  11. [Adapted Physical Activity for patients with chronic diseases in a therapeutic community].

    Science.gov (United States)

    Bouricha, Rémy; Thöni, Gilles; Raffard, Laurence; Cochet, Laurence; Saucourt, Vincent; Tirode, Véronique

    2015-01-01

    The French therapeutic communities ("Appartements de Coordination Therapeutique (ACT)") are mostly members of the "National Federation of Accommodation for HIV+ and other chronic diseases. They provide accommodation for people living with chronic conditions (HIV hepatitis, cancers...) and in a situation of high psychosocial frailty. As a result of their coordinated multidisciplinary intervention, these structures provide the required support to access health care and facilitate social inclusion. They are designed to provide an appropriate response to people with cumulative medical and social conditions (chronic diseases, precariousness, addictions and other comorbidities). Our innovative local experiment integrates Adapted Physical Activities (APA) into the global medical and social follow-up, in line with the patient's individual health care project. The characteristics of each APA project (nature of the activities proposed, intensity, duration, frequency, individual vs. team activity and accompanying methods) are defined on an individual basis, according to the user's motivations and inputs from the support team (medical, psychological and social coordination). The follow-up ensured by our APA professionals allows the residents to participate in a regular and attractive physical activity and could contribute to their social inclusion. The multidisciplinary approach proposed by ACTs determines the beneficial effects observed in such vulnerable patients. PMID:26168635

  12. Adaptive response in frogs chronically exposed to low doses of ionizing radiation in the environment

    International Nuclear Information System (INIS)

    Using the micronucleus assay, decreased levels of DNA damage were found after high dose ionizing radiation exposure of liver cells taken from frogs inhabiting a natural environment with above-background levels of ionizing radiation, compared to cells taken from frogs inhabiting background areas. The data obtained from a small number of animals suggest that stress present in the above-background environment could induce an adaptive response to ionizing radiation. This study did not reveal harmful effects of exposure to low levels of radioactivity. On the contrary, stress present in the above-background area may serve to enhance cellular defense mechanisms. - Highlights: → Frogs were collected from background and higher tritium level habitats. → The micronucleus assay was conducted on liver cells obtained from the frogs. → No detrimental effects were noted in frogs exposed to elevated tritium. → Adaptive responses were observed in frogs exposed to elevated tritium.

  13. Adaptive response in frogs chronically exposed to low doses of ionizing radiation in the environment

    Energy Technology Data Exchange (ETDEWEB)

    Audette-Stuart, M., E-mail: stuartm@aecl.ca [Environmental Technologies Branch, Atomic Energy of Canada Limited, Chalk River Laboratories, Chalk River, Ontario, K0J 1P0 (Canada); Kim, S.B.; McMullin, D.; Festarini, A.; Yankovich, T.L.; Carr, J.; Mulpuru, S. [Environmental Technologies Branch, Atomic Energy of Canada Limited, Chalk River Laboratories, Chalk River, Ontario, K0J 1P0 (Canada)

    2011-06-15

    Using the micronucleus assay, decreased levels of DNA damage were found after high dose ionizing radiation exposure of liver cells taken from frogs inhabiting a natural environment with above-background levels of ionizing radiation, compared to cells taken from frogs inhabiting background areas. The data obtained from a small number of animals suggest that stress present in the above-background environment could induce an adaptive response to ionizing radiation. This study did not reveal harmful effects of exposure to low levels of radioactivity. On the contrary, stress present in the above-background area may serve to enhance cellular defense mechanisms. - Highlights: > Frogs were collected from background and higher tritium level habitats. > The micronucleus assay was conducted on liver cells obtained from the frogs. > No detrimental effects were noted in frogs exposed to elevated tritium. > Adaptive responses were observed in frogs exposed to elevated tritium.

  14. H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection

    Directory of Open Access Journals (Sweden)

    Arnold Isabelle C

    2011-11-01

    Full Text Available Abstract Persistent infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high gastric cancer risk, but has also been linked to protection from allergic, chronic inflammatory and autoimmune diseases. In the course of tens of thousands of years of co-existence with its human host, H. pylori has evolved elaborate adaptations that allow it to persist in the hostile environment of the stomach in the face of a vigorous innate and adaptive immune response. For this review, we have identified several key immune cell types and signaling pathways that appear to be preferentially targeted by the bacteria to establish and maintain persistent infection. We explore the mechanisms that allow the bacteria to avoid detection by innate immune cells via their pattern recognition receptors, to escape T-cell mediated adaptive immunity, and to reprogram the immune system towards tolerance rather than immunity. The implications of the immunomodulatory properties of the bacteria for the prevention of allergic and auto-immune diseases in chronically infected individuals are also discussed.

  15. Epistasis and maternal effects in experimental adaptation to chronic nutritional stress in Drosophila.

    Science.gov (United States)

    Vijendravarma, R K; Kawecki, T J

    2013-12-01

    Based on ecological and metabolic arguments, some authors predict that adaptation to novel, harsh environments should involve alleles showing negative (diminishing return) epistasis and/or that it should be mediated in part by evolution of maternal effects. Although the first prediction has been supported in microbes, there has been little experimental support for either prediction in multicellular eukaryotes. Here we use a line-cross design to study the genetic architecture of adaptation to chronic larval malnutrition in a population of Drosophila melanogaster that evolved on an extremely nutrient-poor larval food for 84 generations. We assayed three fitness-related traits (developmental rate, adult female weight and egg-to-adult viability) under the malnutrition conditions in 14 crosses between this selected population and a nonadapted control population originally derived from the same base population. All traits showed a pattern of negative epistasis between alleles improving performance under malnutrition. Furthermore, evolutionary changes in maternal traits accounted for half of the 68% increase in viability and for the whole of 8% reduction in adult female body weight in the selected population (relative to unselected controls). These results thus support both of the above predictions and point to the importance of nonadditive effects in adaptive microevolution.

  16. Hematopoietic Stem and Immune Cells in Chronic HIV Infection

    Directory of Open Access Journals (Sweden)

    Jielin Zhang

    2015-01-01

    Full Text Available Hematopoietic stem cell (HSC belongs to multipotent adult somatic stem cells. A single HSC can reconstitute the entire blood system via self-renewal, differentiation into all lineages of blood cells, and replenishment of cells lost due to attrition or disease in a person’s lifetime. Although all blood and immune cells derive from HSC, immune cells, specifically immune memory cells, have the properties of HSC on self-renewal and differentiation into lineage effector cells responding to the invading pathogens. Moreover, the interplay between immune memory cell and viral pathogen determines the course of a viral infection. Here, we state our point of view on the role of blood stem and progenitor cell in chronic HIV infection, with a focus on memory CD4 T-cell in the context of HIV/AIDS eradication and cure.

  17. Hematopoietic Stem and Immune Cells in Chronic HIV Infection.

    Science.gov (United States)

    Zhang, Jielin; Crumpacker, Clyde

    2015-01-01

    Hematopoietic stem cell (HSC) belongs to multipotent adult somatic stem cells. A single HSC can reconstitute the entire blood system via self-renewal, differentiation into all lineages of blood cells, and replenishment of cells lost due to attrition or disease in a person's lifetime. Although all blood and immune cells derive from HSC, immune cells, specifically immune memory cells, have the properties of HSC on self-renewal and differentiation into lineage effector cells responding to the invading pathogens. Moreover, the interplay between immune memory cell and viral pathogen determines the course of a viral infection. Here, we state our point of view on the role of blood stem and progenitor cell in chronic HIV infection, with a focus on memory CD4 T-cell in the context of HIV/AIDS eradication and cure. PMID:26300920

  18. Renal cell carcinoma in a setting of chronic lithium toxicity

    OpenAIRE

    Zardawi, Ibrahim; Nagonkar, Santoshi; Patel, Purvish

    2013-01-01

    Patient: Female, 72 Final Diagnosis: Renal cell carcinoma Symptoms: — Medication: — Clinical Procedure: — Specialty: Oncology Objective: Challenging differential diagnosis Background: Lithium salts are widely used in the treatment of affective disorders of the bipolar type. Lithium is a nephrotoxic substance which can cause both acute and chronic renal disease, including cyst formation. Cysts appear to predispose the kidney to renal cell carcinoma. Case Report: A case of renal cell carcinoma ...

  19. Adaptive response to chronic mild ethanol stress involves ROS, sirtuins and changes in chromosome dosage in wine yeasts.

    Science.gov (United States)

    Adamczyk, Jagoda; Deregowska, Anna; Skoneczny, Marek; Skoneczna, Adrianna; Kwiatkowska, Aleksandra; Potocki, Leszek; Rawska, Ewa; Pabian, Sylwia; Kaplan, Jakub; Lewinska, Anna; Wnuk, Maciej

    2016-05-24

    Industrial yeast strains of economic importance used in winemaking and beer production are genomically diverse and subjected to harsh environmental conditions during fermentation. In the present study, we investigated wine yeast adaptation to chronic mild alcohol stress when cells were cultured for 100 generations in the presence of non-cytotoxic ethanol concentration. Ethanol-induced reactive oxygen species (ROS) and superoxide signals promoted growth rate during passages that was accompanied by increased expression of sirtuin proteins, Sir1, Sir2 and Sir3, and DNA-binding transcription regulator Rap1. Genome-wide array-CGH analysis revealed that yeast genome was shaped during passages. The gains of chromosomes I, III and VI and significant changes in the gene copy number in nine functional gene categories involved in metabolic processes and stress responses were observed. Ethanol-mediated gains of YRF1 and CUP1 genes were the most accented. Ethanol also induced nucleolus fragmentation that confirms that nucleolus is a stress sensor in yeasts. Taken together, we postulate that wine yeasts of different origin may adapt to mild alcohol stress by shifts in intracellular redox state promoting growth capacity, upregulation of key regulators of longevity, namely sirtuins and changes in the dosage of genes involved in the telomere maintenance and ion detoxification. PMID:27074556

  20. Adaptive response to chronic mild ethanol stress involves ROS, sirtuins and changes in chromosome dosage in wine yeasts.

    Science.gov (United States)

    Adamczyk, Jagoda; Deregowska, Anna; Skoneczny, Marek; Skoneczna, Adrianna; Kwiatkowska, Aleksandra; Potocki, Leszek; Rawska, Ewa; Pabian, Sylwia; Kaplan, Jakub; Lewinska, Anna; Wnuk, Maciej

    2016-05-24

    Industrial yeast strains of economic importance used in winemaking and beer production are genomically diverse and subjected to harsh environmental conditions during fermentation. In the present study, we investigated wine yeast adaptation to chronic mild alcohol stress when cells were cultured for 100 generations in the presence of non-cytotoxic ethanol concentration. Ethanol-induced reactive oxygen species (ROS) and superoxide signals promoted growth rate during passages that was accompanied by increased expression of sirtuin proteins, Sir1, Sir2 and Sir3, and DNA-binding transcription regulator Rap1. Genome-wide array-CGH analysis revealed that yeast genome was shaped during passages. The gains of chromosomes I, III and VI and significant changes in the gene copy number in nine functional gene categories involved in metabolic processes and stress responses were observed. Ethanol-mediated gains of YRF1 and CUP1 genes were the most accented. Ethanol also induced nucleolus fragmentation that confirms that nucleolus is a stress sensor in yeasts. Taken together, we postulate that wine yeasts of different origin may adapt to mild alcohol stress by shifts in intracellular redox state promoting growth capacity, upregulation of key regulators of longevity, namely sirtuins and changes in the dosage of genes involved in the telomere maintenance and ion detoxification.

  1. Immunohistochemical analysis of Langerhans cells in chronic gingivitis using anti-CD1a antibody

    Directory of Open Access Journals (Sweden)

    Shweta Jaitley

    2014-01-01

    Full Text Available Background: The Langerhans cells (LCs are dendritic cells (DCs which belong to the group of antigen presenting cells (APCs. Their function is to recognize the antigen, capture it, and present it to the T lymphocytes; thus initiating an early immune response. The antigen presenting functional LCs may play an important part in initiation and development of gingivitis. The aim of this study was to analyze the density, intraepithelial distribution, and morphology of LCs in gingival epithelium among different age groups with chronic gingivitis and to compare it with that of normal gingiva. Materials and Methods: Immunohistochemistry (IHC was performed to study LCs in normal gingival epithelium (n = 10 and gingival epithelium in chronic gingivitis (n = 30 using anti-CD1a antibody. Mann Whitney U test was performed to compare the density of LCs in normal gingiva with chronic gingivitis. The distribution of LCs in various layers of the epithelium within the three age groups was analyzed using Kruskal-Wallis test. P value less than 0.05 was considered as significant. Results: The density of LCs in chronic gingivitis was significantly higher then that of normal gingiva. Comparing different age groups, the younger individuals had more number of LCs which were located in the superficial layers of gingival epithelium. In chronic gingivitis, higher number of LCs were located in deeper layers when compared with that of normal gingiva. Three morphological types of CD1a positive LCs were observed in normal gingiva, out of which the density of LCs with branched dendritic processes was highest in normal gingiva. Conclusion: The LCs showed variable number, location, and morphology which indicated their adaptation for function in chronic gingivitis.

  2. Chronic adaptations of lung function in breath-hold diving fishermen

    Directory of Open Access Journals (Sweden)

    Cristiane Diniz

    2014-04-01

    Full Text Available Objectives: The aim of this study was to verify and analyze the existence of chronic adaptations of lung function in freediving fishermen whose occupation is artisanal fishing. Material and Methods: This was a cross-sectional study involving 11 breath-hold diving fishermen and 10 non-breath-hold diving fishermen (control from the village of Bitupitá in the municipality of Barroquinha (Ceará - Brazil. Anthropometric measurements, chest and abdominal circumferences as well as spirometric and respiratory muscle strength tests were conducted according to the specifications of the American Thoracic Society/European Respiratory Society (ATS/ERS. In order to compare the measured values versus the predicted values, Student t test was used in the case of parametric test and Wilcoxon test in the case of nonparametric test. To compare the inter-group means Student t test was used for parametric test and Mann-Whitney test for the nonparametric one. The level of significance was set at α = 5%. Results: The forced vital capacity (FVC (4.9±0.6 l vs. 4.3±0.4 l and forced expiratory volume in 1 s (FEV1 (4.0±0.5 l vs. 3.6±0.3 l were, respectively, higher in the group of divers compared to the control group (p ≤ 0.05. Furthermore, in the group of free divers, the measured FVC, FEV1 and FEV1/FVC ratios were significantly greater than the predicted ones. No differences were found between the measured respiratory pressures. Conclusions: These results indicate that breath-hold diving seems to produce chronic adaptations of the respiratory system, resulting in elevated lung volumes with no airway obstruction.

  3. Participation of mast cells in chronic otitis media

    Directory of Open Access Journals (Sweden)

    Tomasz Durko

    2011-10-01

    Full Text Available In the pathogenesis of chronic otitis media (COM, much attention is paid to the molecular mechanisms of local inflammatory reactions in which mast cells (MCs may be involved due to their role not only in allergic but also inflammatory processes. The aim of this study was to assess the density of mast cells in chronic otitis media in relationship to different clinical courses of COM, bacterial infections and types of disease. The MCs expression was measured immunohistochemically in paraffin-embedded granulation tissue specimens taken during surgery, by staining with a monoclonal antibody against tryptase. The density of tryptase-positive mast cells was lower in tissue samples from the group with a good clinical course than in those from the group with poor healing and recurrence (p = 0.006. There were no differences between the groups of patients with granulomatous and cholesteatomatous chronic otitis media (p = 0.66 or between the groups of patients with and without bacterial infection (p = 0.30, although the density of mast cells was lower for those with Pseudomonas aeruginosa/Proteus sp./ /Staphyloccocus MRSA infection. In conclusion, the expression of mast cells in chronic otitis media granulation tissue was found to differ depending on the clinical course of the disease, but not on bacterial infection or type of COM. This may suggest that mast cells contribute to the maintenance of the inflammatory process, but not to antibacterial defense in chronic otitis media. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 3, pp. 479–485

  4. Regulatory T Cells in Chronic Hepatitis B Virus Infection

    NARCIS (Netherlands)

    J.N. Stoop (Jeroen Nicolaas)

    2007-01-01

    textabstractWorldwide 400 million people suffer from chronic hepatitis B virus (HBV) infection and approximately 1 million people die annually from HBV-related disease. To clear HBV, an effective immune response, in which several cell types and cytokines play a role, is important. It is known that p

  5. Characterization of bortezomib-adapted I-45 mesothelioma cells

    Directory of Open Access Journals (Sweden)

    Peddaboina Chander

    2010-05-01

    Full Text Available Abstract Background Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy. Results The present study reports the development of I-45-BTZ-R, a bortezomib-resistant cell line, from the bortezomib-sensitive mesothelioma cell line I-45. I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin, 5-fluorouracil, and doxorubicin. Moreover, the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit β5 (PSMB5 as compared to parental I-45 cells. I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity, but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib. Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response (UPR in the bortezomib-adapted cells, while higher doses induced UPR with concomitant cell death, as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum (ER stress-related pro-apoptotic protein CHOP. In addition, bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53, Mcl-1S, and noxa in the bortezomib-adapted cells. Conclusion These results suggest that UPR evasion, together with reduced pro-apoptotic gene induction, accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R.

  6. B-cell-mediated strategies to fight chronic allograft rejection

    Directory of Open Access Journals (Sweden)

    Ali H Dalloul

    2013-12-01

    Full Text Available Solid organs have been transplanted for decades. Since the improvement in graft selection and in medical and surgical procedures, the likelihood of graft function after one year is now close to 90%. Nonetheless even well-matched recipients continue to need medications for the rest of their lives hence adverse side effects and enhanced morbidity. Understanding Immune rejection mechanisms, is of increasing importance since the greater use of living-unrelated donors and genetically unmatched individuals. Chronic rejection is devoted to T-cells, however the role of B-cells in rejection has been appreciated recently by the observation that B-cell depletion improve graft survival. By contrast however, B-cells can be beneficial to the grafted tissue. This protective effect is secondary to either the secretion of protective antibodies or the induction of B-cells that restrain excessive inflammatory responses, chiefly by local provision of IL-10, or inhibit effector T-cells by direct cellular interactions. As a proof of concept B-cell-mediated infectious transplantation tolerance could be achieved in animal models, and evidence emerged that the presence of such B-cells in transplanted patients correlate with a favorable outcome. Among these populations, regulatory B-cells constitute a recently described population. These cells may develop as a feedback mechanism to prevent uncontrolled reactivity to antigens and inflammatory stimuli. The difficult task for the clinician, is to quantify the respective ratios and functions of tolerant vs effector B-cells within a transplanted organ, at a given time point in order to modulate B-cell-directed therapy. Several receptors at the B-cell membrane as well as signaling molecules, can now be targeted for this purpose. Understanding the temporal expansion of regulatory B-cells in grafted patients and the stimuli that activate them will help in the future to implement specific strategies aimed at fighting chronic

  7. Contrast Adaptation Decreases Complexity in Retinal Ganglion Cell Spike Train

    Institute of Scientific and Technical Information of China (English)

    WANG Guang-Li; HUANG Shi-Yong; ZHANG Ying-Ying; LIANG Pei-Ji

    2007-01-01

    @@ The difference in temporal structures of retinal ganglion cell spike trains between spontaneous activity and firing activity after contrast adaptation is investigated. The Lempel-Ziv complexity analysis reveals that the complexity of the neural spike train decreases after contrast adaptation. This implies that the behaviour of the neuron becomes ordered, which may carry relevant information about the external stimulus. Thus, during the neuron activity after contrast adaptation, external information could be encoded in forms of some certain patterns in the temporal structure of spike train that is significantly different, compared to that of the spike train during spontaneous activity, although the firing rates in spontaneous activity and firing activity after contrast adaptation are sometime similar.

  8. Apoptosis pathway of liver cells in chronic hepatitis

    Institute of Scientific and Technical Information of China (English)

    Nai-Ling Chen; Zhen-Qiu Zhou; Ling Bai; Lin Li; Pei-Lan Chen; Chang Zhang; Chao-Ying Liu; Tao Deng; Hao Chen; Ke-Ming Jia

    2004-01-01

    AIM: To study the pathway of apoptosis in chronic liver disease and the role of mitochondria in programmed cell death.METHODS: Liver biopsy specimens from 72 cases of chronic hepatitis and 29 cases of post hepatitis cirrhosis were studied. The pro-apoptotic protein Fas, FasL, Bax and the anti-apoptotic protein Bcl-2, Bcl-xL, Bcl-2α were studied immunohistochemically by SP method. Specimens from 15 cases of chronic hepatitis and post hepatitis cirrhosis were examined for their ultramicrostructures with special attention to their mitochondrial changes. Specimens from 3 normal adults (demised in traffic accidents) were used as control.RESULTS: The expression of proapoptotic proteins (Fas,FasL, Bax) in hepatocytes was significantly higher in the chronic hepatitis group than in the cirrhosis group (P<0.001).In the study of ultramicrostructure 364 hepatocytes were examined, from 12 cases of chronic hepatitis (including 10mild cases, 1 moderate case and 1 severe case). Out of 364 hepatocytes 40 (11.0%) hepatocytes were found with various kinds of destruction in their mitochondria. Rupture of the outer membrane of mitochondria and the leakage of matrix from the intermembrane space were definitely demonstrated. The ultramicrostructural changes of mitochondria in the chronic hepatitis group were statistically higher than that in normal adults control group (χ2=4.32, P<0.05).CONCLUSION: The result of the study was in support of the current view that the apoptotic process in chronic hepatitis patients were largely along the intrinsic pathway (mitochondrial pathway), given that the intrinsic and extrinsic pathways could interlinked (converged) at some point on their progression, also it is impossible at present to exclude the possibility that the two pathways could be chosen by hepatocytes in parallel simultaneously.

  9. Natural Killer Cell Functional Dichotomy: a Feature of Chronic Viral Hepatitis ?

    Directory of Open Access Journals (Sweden)

    Mario Umberto Mondelli

    2012-11-01

    Full Text Available NK cells are involved in innate immune responses to viral infections either via direct cytotoxicity which destroys virus-infected cells or production of immunoregulatory cytokines which modulate adaptive immunity and directly inhibit virus replication. These functions are mediated by different NK subpopulations, with cytotoxicity being generally performed by CD56dim NK cells, whereas CD56bright NK cells are mainly involved in cytokine secretion. NK functional defects are usually combined so that impaired degranulation is often associated with deficient cytokine production. Innate immunity is thought to be relevant in the control of hepatitis virus infections such as HBV and HCV, and recent findings reproducibly indicate that NK cells in chronic viral hepatitis are characterized by a functional dichotomy, featuring a conserved or enhanced cytotoxicity and a reduced production of IFN-gamma and TNF-alfa. In chronic HCV infection this appears to be caused by altered IFN-alfa signaling resulting from increased STAT1 phosphorylation, which polarizes NK cells toward cytotoxicity, and a concomitantly reduced IFN-alfa induced STAT4 phosphorylation yielding reduced IFN-gamma mRNA levels. These previously unappreciated findings are compatible on the one hand with the inability to clear HCV and HBV from the liver and on the other they may contribute to understand why these patients are often resistant to interferon (IFNalfa-based therapies.

  10. Cell cycle control after DNA damage: arrest, recovery and adaptation

    International Nuclear Information System (INIS)

    DNA damage triggers surveillance mechanisms, the DNA checkpoints, that control the genome integrity. The DNA checkpoints induce several responses, either cellular or transcriptional, that favor DNA repair. In particular, activation of the DNA checkpoints inhibits cell cycle progression in all phases, depending on the stage when lesions occur. These arrests are generally transient and cells ultimately reenter the cell division cycle whether lesions have been repaired (this process is termed 'recovery') or have proved un-repairable (this option is called 'adaptation'). The mechanisms controlling cell cycle arrests, recovery and adaptation are largely conserved among eukaryotes, and much information is now available for the yeast Saccharomyces cerevisiae, that is used as a model organism in these studies. (author)

  11. Splicing Regulation: A Molecular Device to Enhance Cancer Cell Adaptation

    Directory of Open Access Journals (Sweden)

    Vittoria Pagliarini

    2015-01-01

    Full Text Available Alternative splicing (AS represents a major resource for eukaryotic cells to expand the coding potential of their genomes and to finely regulate gene expression in response to both intra- and extracellular cues. Cancer cells exploit the flexible nature of the mechanisms controlling AS in order to increase the functional diversity of their proteome. By altering the balance of splice isoforms encoded by human genes or by promoting the expression of aberrant oncogenic splice variants, cancer cells enhance their ability to adapt to the adverse growth conditions of the tumoral microenvironment. Herein, we will review the most relevant cancer-related splicing events and the underlying regulatory mechanisms allowing tumour cells to rapidly adapt to the harsh conditions they may face during the occurrence and development of cancer.

  12. Autologous Bone Marrow Mononuclear Cells Intrathecal Transplantation in Chronic Stroke

    Directory of Open Access Journals (Sweden)

    Alok Sharma

    2014-01-01

    Full Text Available Cell therapy is being widely explored in the management of stroke and has demonstrated great potential. It has been shown to assist in the remodeling of the central nervous system by inducing neurorestorative effect through the process of angiogenesis, neurogenesis, and reduction of glial scar formation. In this study, the effect of intrathecal administration of autologous bone marrow mononuclear cells (BMMNCs is analyzed on the recovery process of patients with chronic stroke. 24 patients diagnosed with chronic stroke were administered cell therapy, followed by multidisciplinary neurorehabilitation. They were assessed on functional independence measure (FIM objectively, along with assessment of standing and walking balance, ambulation, and hand functions. Out of 24 patients, 12 improved in ambulation, 10 in hand functions, 6 in standing balance, and 9 in walking balance. Further factor analysis was done. Patients of the younger groups showed higher percentage of improvement in all the areas. Patients who underwent cell therapy within 2 years after the stroke showed better changes. Ischemic type of stroke had better recovery than the hemorrhagic stroke. This study demonstrates the potential of autologous BMMNCs intrathecal transplantation in improving the prognosis of functional recovery in chronic stage of stroke. Further clinical trials are recommended. This trial is registered with NCT02065778.

  13. Mast cells in allergy and autoimmunity: implications for adaptive immunity.

    Science.gov (United States)

    Gregory, Gregory D; Brown, Melissa A

    2006-01-01

    As in the fashion industry, trends in a particular area of scientific investigation often are fleeting but then return with renewed and enthusiastic interest. Studies of mast cell biology are good examples of this. Although dogma once relegated mast cells almost exclusively to roles in pathological inflammation associated with allergic disease, these cells are emerging as important players in a number of other physiological processes. Consequently, they are quickly becoming the newest "trendy" cell, both within and outside the field of immunology. As sources of a large array of pro- and anti-inflammatory mediators, mast cells also express cell surface molecules with defined functions in lymphocyte activation and trafficking. Here, we provide an overview of the traditional and newly appreciated contributions of mast cells to both innate and adaptive immune responses.

  14. Mutual interaction of Basophils and T cells in chronic inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Marika eSarfati

    2015-08-01

    Full Text Available Basophils are, together with mast cells, typical innate effector cells of allergen-induced IgE-dependent allergic diseases. Both cell types express the high affinity receptor for IgE (FcεR1, release histamine, inflammatory mediators and cytokines following FcεR1 cross-linking. Basophils are rare granulocytes in blood, lymphoid and non-lymphoid tissues and the difficulties to detect and isolate these cells has hampered the study of their biology and the understanding of their possible role in pathology. Furthermore, the existence of other FcεR1-expressing cells, including professional Ag-presenting dendritic cells, generated some controversy regarding the ability of basophils to express MHC Class II molecules, present Ag and drive naïve T cell differentiation into Th2 cells. The focus of this review is to present the recent advances on the interactions between basophils and peripheral blood and tissue memory Th1, Th2 and Th17 cells, as well as their potential role in IgE-independent non allergic chronic inflammatory disorders, including human inflammatory bowel diseases. Basophils interactions with the innate players of IgE-dependent allergic inflammation, particularly innate lymphoid cells, will also be considered. The previously unrecognized function for basophils in skewing adaptive immune responses opens novel perspectives for the understanding of their contribution to the pathogenesis of inflammatory diseases.

  15. Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection.

    Science.gov (United States)

    Gaudieri, Silvana; Rauch, Andri; Park, Lawrence P; Freitas, Elizabeth; Herrmann, Susan; Jeffrey, Gary; Cheng, Wendy; Pfafferott, Katja; Naidoo, Kiloshni; Chapman, Russell; Battegay, Manuel; Weber, Rainer; Telenti, Amalio; Furrer, Hansjakob; James, Ian; Lucas, Michaela; Mallal, Simon A

    2006-11-01

    Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level. PMID:17071929

  16. Effector Cells and Mechanisms in Chronic Spontaneous Urticaria

    OpenAIRE

    Borzova, Elena

    2014-01-01

    Background: Chronic spontaneous urticaria (CSU) is characterised by weals, angioedema, or both, which occur for six weeks or more. Itchy, red and raised weals in CSU are thought to occur as a result of skin mast cell activation, local vasodilatation and increased vascular permeability which are the cardinal features of the disease. Serum histamine-releasing activity and abnormal basophil function were implicated in the pathophysiology of CSU. We hypothesized that severe and/or persistent CSU ...

  17. The role of Cajal cells in chronic prostatitis.

    Science.gov (United States)

    Haki Yuksel, Ozgur; Urkmez, Ahmet; Verit, Ayhan

    2016-01-01

    Types of prostatitis can be defined as groups of syndromes in adult men associated with infectious and noninfectious causes characterized frequently by lower abdominal and perineal signs and diverse clinical symptoms and complications. Etiopathogenesis of chronic prostatitis is not well defined. Moreover, its treatment outcomes are not satisfactory. Presence of c-kit positive interstitial cells in human prostate is already known. It has been demonstrated that these cells can be pacemaker cells which trigger spontaneous slow-wave electrical activity in the prostate and can be responsible for the transport of glandular secretion from acinar cells into major and minor prostatic ducts and finally into urethra. In the light of all these data, when presence of a possible inflammatory pathology is thought to involve prostate that secretes and has a reservoir which drains its secretion (for prostate, prostatic urethra), two points are worth mentioning. Impairment of secretion mechanism and collection of secretion within the organ with reflux of the microbial material from its reservoir back into prostate gland. Both of these potential conditions can be explained by ductal neuromuscular mechanism, which induces secretion. We think that in this neuromuscular mechanism interstitial Cajal cells have an important role in chronic prostatitis. Our hypothesis is that curability of prostatitis is correlated with the number of Cajal cells not subjected to apoptosis. PMID:27377090

  18. Inspiratory muscle training in patients with chronic obstructive pulmonary disease: structural adaptation and physiologic outcomes.

    Science.gov (United States)

    Ramirez-Sarmiento, Alba; Orozco-Levi, Mauricio; Guell, Rosa; Barreiro, Esther; Hernandez, Nuria; Mota, Susana; Sangenis, Merce; Broquetas, Joan M; Casan, Pere; Gea, Joaquim

    2002-12-01

    The present study was aimed at evaluating the effects of a specific inspiratory muscle training protocol on the structure of inspiratory muscles in patients with chronic obstructive pulmonary disease. Fourteen patients (males, FEV1, 24 +/- 7% predicted) were randomized to either inspiratory muscle or sham training groups. Supervised breathing using a threshold inspiratory device was performed 30 minutes per day, five times a week, for 5 consecutive weeks. The inspiratory training group was subjected to inspiratory loading equivalent to 40 to 50% of their maximal inspiratory pressure. Biopsies from external intercostal muscles and vastus lateralis (control muscle) were taken before and after the training period. Muscle samples were processed for morphometric analyses using monoclonal antibodies against myosin heavy chain isoforms I and II. Increases in both the strength and endurance of the inspiratory muscles were observed in the inspiratory training group. This improvement was associated with increases in the proportion of type I fibers (by approximately 38%, p < 0.05) and in the size of type II fibers (by approximately 21%, p < 0.05) in the external intercostal muscles. No changes were observed in the control muscle. The study demonstrates that inspiratory training induces a specific functional improvement of the inspiratory muscles and adaptive changes in the structure of external intercostal muscles. PMID:12406842

  19. Intestinal adaptations in chronic kidney disease and the influence of gastric bypass surgery.

    Science.gov (United States)

    Hatch, Marguerite

    2014-09-01

    Studies have shown that compensatory adaptations in gastrointestinal oxalate transport can impact the amount of oxalate excreted by the kidney. Hyperoxaluria is a major risk factor in the formation of kidney stones, and oxalate is derived from both the diet and the liver metabolism of glyoxylate. Although the intestine generally absorbs oxalate from dietary sources and can contribute as much as 50% of urinary oxalate, enteric oxalate elimination plays a significant role when renal function is compromised. While the mechanistic basis for these changes in the direction of intestinal oxalate movements in chronic renal failure involves an upregulation of angiotensin II receptors in the large intestine, enteric secretion/excretion of oxalate can also occur by mechanisms that are independent of angiotensin II. Most notably, the commensal bacterium Oxalobacter sp. interacts with the host enterocyte and promotes the movement of oxalate from the blood into the lumen, resulting in the beneficial effect of significantly lowering urinary oxalate excretion. Changes in the passive permeability of the intestine, such as in steatorrhoea and following gastric bypass, also promote oxalate absorption and hyperoxaluria. In summary, this report highlights the two-way physiological signalling between the gut and the kidney, which may help to alleviate the consequences of certain kidney diseases. PMID:24951497

  20. Pilot study: bone marrow stem cells as a treatment for dogs with chronic spinal cord injury

    OpenAIRE

    Sarmento, Carlos Alberto Palmeira; Rodrigues, Marcio Nogueira; Bocabello, Renato Zonzini; Mess, Andrea Maria; Miglino, Maria Angelica

    2014-01-01

    Background Chronic Spinal Cord injury is a common, severe, and medically untreatable disease. Since the functional outcomes of acute and experimental chronic spinal cord injury have been shown to improve with stem cell therapy, a case study was conducted to test if the application of stem cell also regenerates chronic SCI dysfunction. Transplantation of foetal bone marrow stem cells was applied in seven dogs with chronic spinal cord injury. Magnetic resonance images and assessments of symptom...

  1. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2016-04-26

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma,; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

  2. Chronic exposure of juvenile rats to environmental noise impairs hippocampal cell proliferation in adulthood

    Directory of Open Access Journals (Sweden)

    Fernando Jáuregui-Huerta

    2011-01-01

    Full Text Available Increasing evidence indicates that chronic exposure to environmental noise may permanently affect the central nervous system. The aim of this study was to evaluate the long-term effects of early exposure to environmental noise on the hippocampal cell proliferation of the adult male rat. Early-weaned Wistar rats were exposed for 15 days to a rats′ audiogram-fitted adaptation to a noisy environment. Two months later, the rats were injected with the cellular proliferation marker 5΄bromodeoxiuridine (BrdU, and their brains were processed for immunohistochemical analysis. Coronal sections were immunolabeled with anti-BrdU antibodies to identify new-born cells in dentate gyrus (DG, cornu amonis areas CA1 and CA3. In addition, blood samples were obtained to evaluate corticosterone serum levels after noise exposure. All data are expressed as mean΁standard deviation. For mean comparisons between groups, we used the Student t test. We found an increase in corticosterone serum levels after environmental noise exposure. Interestingly, noise-exposed rats showed a long-term reduction of proliferating cells in the hippocampal formation, as compared to controls. These findings indicate that chronic environmental noise exposure at young ages produces persistent non-auditory impairment that modifies cell proliferation in the hippocampal formation.

  3. Dendritic cells: The warriors upfront-turned defunct in chronic hepatitis C infection

    Institute of Scientific and Technical Information of China (English)

    Meenakshi; Sachdeva; Yogesh; K; Chawla; Sunil; K; Arora

    2015-01-01

    Hepatitis C virus(HCV) infection causes tremendousmorbidity and mortality with over 170 million people infected worldwide. HCV gives rise to a sustained, chronic disease in the majority of infected individuals owing to a failure of the host immune system to clear the virus. In general, an adequate immune response is elicited by an efficient antigen presentation by dendritic cells(DCs), the cells that connect innate and adaptive immune system to generate a specific immune response against a pathogen. However, HCV seems to dysregulate the activity of DCs, making them less proficient antigen presenting cells for the optimal stimulation of virusspecific T cells, hence interfering with an optimal antiviral immune response. There are discordant reports on the functional status of DCs in chronic HCV infection(CHC), from no phenotypic or functional defects to abnormal functions of DCs. Furthermore, the molecular mechanisms behind the impairment of DC function are even so not completely elucidated during CHC. Understanding the mechanisms of immune dysfunction would help in devising strategies for better management of the disease at the immunological level and help to predict the prognosis of the disease in the patients receiving antiviral therapy. In this review, we have discussed the outcomes of the interaction of DCs with HCV and the mechanisms of DC impairment during HCV infection with its adverse effects on the immune response in the infected host.

  4. Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

    Science.gov (United States)

    2016-07-18

    B-Cell Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  5. Within-host co-evolution of chronic viruses and the adaptive immune system

    Science.gov (United States)

    Nourmohammad, Armita

    We normally think of evolution occurring in a population of organisms, in response to their external environment. Rapid evolution of cellular populations also occurs within our bodies, as the adaptive immune system works to eliminate infection. Some pathogens, such as HIV, are able to persist in a host for extended periods of time, during which they also evolve to evade the immune response. In this talk I will introduce an analytical framework for the rapid co-evolution of B-cell and viral populations, based on the molecular interactions between them. Since the co-evolution of antibodies and viruses is perpetually out of equilibrium, I will show how to quantify the amount of adaptation in each of the two populations by analysis of their co-evolutionary history. I will discuss the consequences of competition between lineages of antibodies, and characterize the fate of a given lineage dependent on the state of the antibody and viral populations. In particular, I will discuss the conditions for emergence of highly potent broadly neutralizing antibodies, which are now recognized as critical for designing an effective vaccine against HIV.

  6. Freshwater molluscs from volcanic areas as model organisms to assess adaptation to metal chronic pollution

    Energy Technology Data Exchange (ETDEWEB)

    Zaldibar, Benat [Biologia Zelularra eta Histologia laborategia, Zoologia eta Animalien Biologia Zelularra Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea, 644 P.K. E-48080 Bilbo, Basque Country (Spain); Rodrigues, Armindo [Cirn e Departamento Biologia, Universidade dos Acores, R. Mae de Deus, APT 1422, PT-9501-855 Ponta Delgada (Portugal); Lopes, Marco [Cirn e Departamento Biologia, Universidade dos Acores, R. Mae de Deus, APT 1422, PT-9501-855 Ponta Delgada (Portugal); Amaral, Andre [Cirn e Departamento Biologia, Universidade dos Acores, R. Mae de Deus, APT 1422, PT-9501-855 Ponta Delgada (Portugal); Marigomez, Ionan [Biologia Zelularra eta Histologia laborategia, Zoologia eta Animalien Biologia Zelularra Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea, 644 P.K. E-48080 Bilbo, Basque Country (Spain); Soto, Manu [Biologia Zelularra eta Histologia laborategia, Zoologia eta Animalien Biologia Zelularra Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea, 644 P.K. E-48080 Bilbo, Basque Country (Spain)]. E-mail: manu.soto@ehu.es

    2006-12-01

    Cellular biomarkers of exposure and biological effects were measured in digestive gland of snails (Physa acuta) sampled in sites with and without active volcanism in Sao Miguel Island (Azores). Metal content in digestive cell lysosomes was determined by image analysis after autometallography (AMG) as volume density of autometallographed black silver deposits (Vv{sub BSD}). Lysosomal structural changes (lysosomal volume, surface and numerical densities - Vv{sub LYS,} Sv{sub LYS} and Nv{sub LYS-}, and surface-to-volume ratio - S/V{sub LYS}-) were quantified by image analysis, after demonstration of {beta}-glucuronidase activity, on digestive gland cryotome sections. Additional chemical analyses (atomic absorption spectrophotometry) were done in the digestive gland of snails. The highest metal concentrations were found in snails from the active volcanic site, which agreed with high intralysomal Vv{sub BSD}. Digestive cell lysosomes in snails inhabiting sites with active volcanism resembled a typical stress situation (enlarged and less numerous lysosomes). In conclusion, the biomarkers used in this work can be applied to detect changes in metal bioavailability due to chronic exposure to metals (volcanism), in combination with chemical analyses.

  7. REGULATORY T-CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Giovanni D'arena

    2012-08-01

    Full Text Available Regulatory T-cells (Tregs constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL. Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosis, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in either cancer and autoimmune disorders.

  8. Docosahexaenoic acid induces apoptosis in primary chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Romain Guièze

    2015-12-01

    Full Text Available Chronic lymphocytic leukemia is an indolent disorder with an increased infectious risk remaining one of the main causes of death. Development of therapies with higher safety profile is thus a challenging issue. Docosahexaenoic acid (DHA, 22:6 is an omega-3 fatty acid, a natural compound of normal cells, and has been shown to display antitumor potency in cancer. We evaluated the potential in vitro effect of DHA in primary CLL cells. DHA induces high level of in vitro apoptosis compared to oleic acid in a dose-dependent and time-dependent manner. Estimation of IC50 was only of 4.813 μM, which appears lower than those reported in solid cancers. DHA is highly active on CLL cells in vitro. This observation provides a rationale for further studies aiming to understand its mechanisms of action and its potent in vivo activity.

  9. Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells

    International Nuclear Information System (INIS)

    Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines. Our findings suggest that chronic inhibition of tumor cell-derived VEGF

  10. The antimicrobial/elastase inhibitor elafin regulates lung dendritic cells and adaptive immunity.

    Science.gov (United States)

    Roghanian, Ali; Williams, Steven E; Sheldrake, Tara A; Brown, Tom I; Oberheim, Karen; Xing, Zhou; Howie, Sarah E M; Sallenave, Jean-Michel

    2006-05-01

    Infections with bacteria and viruses such as adenovirus are a feature of chronic lung diseases such as chronic obstructive pulmonary diseases (COPD), and may be instrumental in the generation of disease exacerbations. We have previously shown in acute models that elafin (a lung natural chemotactic molecule for macrophages and neutrophils, with potent antimicrobial and neutrophil elastase inhibitor activity) is upregulated in infection and modulates innate immunity. Here we present data using two independent systems of elafin overexpression in vivo (recombinant adenovirus [Ad-elafin] and an elafin transgenic mouse line) to examine the function of elafin in adaptive immunity. We show that elafin increases the number (immunofluorescence) and activation status (flow cytometric measurement) of CD11c+/MHCII+ lung dendritic cells in vivo. Analysis of cytokines produced by spleen and lung cells, and of antibodies measured in serum and bronchoalveolar lavage fluid, shows that the immunity induced is biased toward a type 1 response (production of IL-12, IFN-gamma, and IgG2a). Furthermore, elafin overexpression protected mice against further challenge with Ad-LacZ, as assessed by antibody levels and neutralization titer, as well as LacZ expression in lung tissue. Thus, the pleiotropic molecule elafin has significant potential in modulating antigen-presenting cell numbers and activity, and could be beneficial in mucosal protective strategies. PMID:16424380

  11. Peculiarities of death and regeneration of pancreas cells at early stages of alcoholic chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    N. Y. Oshmyanska

    2014-10-01

    Full Text Available The study has been conducted on 39 white laboratory male rats which formed 5 groups: experimental occlusal pancreatitis caused by ligation of the main pancreatic duct (n = 6, experimental alcoholic pancreatitis caused by oral intake of alcohol (n = 6, against the background of an excess (n = 6 or deficiency (n = 6 of nitric oxide, as well as a control group (n = 15. This study provides the detailed description of the processes of death and regeneration in the islets of Langerhans, typical for early stages of the disease. The expression of the proliferation markers (PCNA and Neurogenin-3 has been analyzed using histological and immunohistochemical methods along with the changes of morphological structure, that led to initiation of the alcoholic chronic pancreatitis against the background of imbalance in NO-ergic regulatory system caused by an excess or deficiency of nitric oxide. It has been found that ligation of the pancreatic duct in the experiment reconstructedthe circumstances of chronic pancreatitis in rats and caused the activation of fibrosis and regeneration of endocrine and exocrine tissue. Compared with occlusion, the effects of ethanol on the pancreas also manifested in the activation of fibrogenesis, but the structural changes were negligible and could unlikely lead to advanced fibrosis and chronic pancreatitis in the future. On the other side, an imbalance of NO-system in alcoholic rats leads to disruption of the zymogens secretion in the acinar cells and dilatation of the capillary network in islets. Uneven distribution of zymogen granules may lead to their intracellular activation as evidenced by the deformation of acini and focal apoptosis without inflammatory response. In this case, violation of the key adaptive responses in the pancreas makes it more vulnerable to the effects of ethanol, its metabolites, and other environmental factors, and may increase the probability of chronic pancreatitis development. At the same time

  12. Red cell ferritin and iron stores in chronic granulocytic leukemia

    International Nuclear Information System (INIS)

    Basic red cell ferritin was investigated in 28 patients with different phases of chronic granulocytic leukemia (GCL). Red cell ferritin was significantly decreased in remission after busulphan treatment and significantly elevated in the blast crisis as compared to healthy controls. Bone marrow stainable iron was decreased or absent in 86% of patients in the initial phase at the time of diagnosis and in 92% of those in remission. Red cell ferritin correlated with serum ferritin, however, serum ferritin level remained above normal range during all phases of the disease. A negative correlation between red cell ferritin and hemoglobin (Hb) (r = -0.605, p < 0.001) suggested that red cell ferritin level reflected the rate of iron utilization for heme synthesis. Decrease red cell iron observed in the remission may be explained by regression of dyserythropoiesis and by restoration of normal Hb synthesis after busulphan treatment. A progressive dyserythropoiesis in the blast crisis may lead to an increased red cell ferritin level. (author)

  13. A multilevel structural equation modeling analysis of vulnerabilities and resilience resources influencing affective adaptation to chronic pain.

    Science.gov (United States)

    Sturgeon, John A; Zautra, Alex J; Arewasikporn, Anne

    2014-02-01

    The processes of individual adaptation to chronic pain are complex and occur across multiple domains. We examined the social, cognitive, and affective context of daily pain adaptation in individuals with fibromyalgia and osteoarthritis. By using a sample of 260 women with fibromyalgia or osteoarthritis, we examined the contributions of pain catastrophizing, negative interpersonal events, and positive interpersonal events to daily negative and positive affect across 30days of daily diary data. Individual differences and daily fluctuations in predictor variables were estimated simultaneously by utilizing multilevel structural equation modeling techniques. The relationships between pain and negative and positive affect were mediated by stable and day-to-day levels of pain catastrophizing as well as day-to-day positive interpersonal events, but not negative interpersonal events. There were significant and independent contributions of pain catastrophizing and positive interpersonal events to adaptation to pain and pain-related affective dysregulation. These effects occur both between persons and within a person's everyday life.

  14. HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology.

    Science.gov (United States)

    Favier, F B; Britto, F A; Freyssenet, D G; Bigard, X A; Benoit, H

    2015-12-01

    Skeletal muscle is a metabolically active tissue and the major body protein reservoir. Drop in ambient oxygen pressure likely results in a decrease in muscle cells oxygenation, reactive oxygen species (ROS) overproduction and stabilization of the oxygen-sensitive hypoxia-inducible factor (HIF)-1α. However, skeletal muscle seems to be quite resistant to hypoxia compared to other organs, probably because it is accustomed to hypoxic episodes during physical exercise. Few studies have observed HIF-1α accumulation in skeletal muscle during ambient hypoxia probably because of its transient stabilization. Nevertheless, skeletal muscle presents adaptations to hypoxia that fit with HIF-1 activation, although the exact contribution of HIF-2, I kappa B kinase and activating transcription factors, all potentially activated by hypoxia, needs to be determined. Metabolic alterations result in the inhibition of fatty acid oxidation, while activation of anaerobic glycolysis is less evident. Hypoxia causes mitochondrial remodeling and enhanced mitophagy that ultimately lead to a decrease in ROS production, and this acclimatization in turn contributes to HIF-1α destabilization. Likewise, hypoxia has structural consequences with muscle fiber atrophy due to mTOR-dependent inhibition of protein synthesis and transient activation of proteolysis. The decrease in muscle fiber area improves oxygen diffusion into muscle cells, while inhibition of protein synthesis, an ATP-consuming process, and reduction in muscle mass decreases energy demand. Amino acids released from muscle cells may also have protective and metabolic effects. Collectively, these results demonstrate that skeletal muscle copes with the energetic challenge imposed by O2 rarefaction via metabolic optimization. PMID:26298291

  15. Genome rearrangement affects RNA virus adaptability on prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Kendra ePesko

    2015-04-01

    Full Text Available Gene order is often highly conserved within taxonomic groups, such that organisms with rearranged genomes tend to be less fit than wildtype gene orders, and suggesting natural selection favors genome architectures that maximize fitness. But it is unclear whether rearranged genomes hinder adaptability: capacity to evolutionarily improve in a new environment. Negative-sense nonsegmented RNA viruses (order Mononegavirales have specific genome architecture: 3′ UTR – core protein genes – envelope protein genes – RNA-dependent RNA-polymerase gene – 5′ UTR. To test how genome architecture affects RNA virus evolution, we examined vesicular stomatitis virus (VSV variants with the nucleocapsid (N gene moved sequentially downstream in the genome. Because RNA polymerase stuttering in VSV replication causes greater mRNA production in upstream genes, N-gene translocation towards the 5’ end leads to stepwise decreases in N transcription, viral replication and progeny production, and also impacts the activation of type 1 interferon mediated antiviral responses. We evolved VSV gene-order variants in two prostate cancer cell lines: LNCap cells deficient in innate immune response to viral infection, and PC3 cells that mount an IFN stimulated anti-viral response to infection. We observed that gene order affects phenotypic adaptability (reproductive growth; viral suppression of immune function, especially on PC3 cells that strongly select against virus infection. Overall, populations derived from the least-fit ancestor (most-altered N position architecture adapted fastest, consistent with theory predicting populations with low initial fitness should improve faster in evolutionary time. Also, we observed correlated responses to selection, where viruses improved across both hosts, rather than suffer fitness trade-offs on unselected hosts. Whole genomics revealed multiple mutations in evolved variants, some of which were conserved across selective

  16. Juvenile fibromyalgia in an adolescent patient with sickle cell disease presenting with chronic pain.

    Science.gov (United States)

    Ramprakash, Stalin; Fishman, Daniel

    2015-10-01

    Juvenile fibromyalgia in children with sickle cell disease has not been reported in the literature. We report an adolescent patient with sickle cell whose pain symptoms progressed from having recurrent acute sickle cell pain crisis episodes to a chronic pain syndrome over several years. He was eventually diagnosed with juvenile fibromyalgia based on the clinical history and myofascial tender points and his pain symptoms responded better to multidisciplinary strategies for chronic fibromyalgia pain. Chronic pain in sickle cell disease is an area of poor research, and in addition there is inconsistency in the definition of chronic pain in sickle cell disease. Central sensitisation to pain is shown to occur after recurrent painful stimuli in a genetically vulnerable individual. In a chronic pain condition such as fibromyalgia central sensitisation is thought to play a key role. Fibromyalgia should be considered as one of the main differential diagnosis in any sickle cell patient with chronic pain.

  17. Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Michele Tanturli

    Full Text Available We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML cells and selects stem cells where BCR/Abl(protein is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby refractory to Imatinib-mesylate. The main target of this study was to address the effects of the proteasome inhibitor Bortezomib (BZ on the maintenance of stem or progenitor cells in hypoxic primary cultures (LC1, by determining the capacity of LC1 cells to repopulate normoxic secondary cultures (LC2 and the kinetics of this repopulation. Unselected K562 cells from day-2 hypoxic LC1 repopulated LC2 with rapid, progenitor-type kinetics; this repopulation was suppressed by BZ addition to LC1 at time 0, but completely resistant to day-1 BZ, indicating that progenitors require some time to adapt to stand hypoxia. K562 cells selected in hypoxic day-7 LC1 repopulated LC2 with stem-type kinetics, which was largely resistant to BZ added at either time 0 or day 1, indicating that hypoxia-selectable stem cells are BZ-resistant per se, i.e. before their selection. Furthermore, these cells were completely resistant to day-6 BZ, i.e. after selection. On the other hand, hypoxia-selected stem cells from CD34-positive cells of blast-crisis CML patients appeared completely resistant to either time-0 or day-1 BZ. To exploit in vitro the capacity of CML cells to adapt to hypoxia enabled to detect a subset of BZ-resistant leukemia stem cells, a finding of particular relevance in light of the fact that our experimental system mimics the physiologically hypoxic environment of bone marrow niches where leukemia stem cells most likely home and sustain minimal residual disease in vivo. This suggests the use of BZ as an enhanced strategy to control CML. in particular to prevent relapse of disease, to be considered with caution and to need further deepening.

  18. Myeloid-derived suppressor cells in Chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Cesarina eGiallongo

    2015-05-01

    Full Text Available The suppression of the immune system create a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells (MDSCs, immature myeloid cells able to induce immune-escape, angiogenesis and tumor progression. Two different subpopulations have been identified and studied: granulocytic and monocytic MDSCs, with a different immunophenotype and immunosuppressive properties. Recently, an accumulation of both Gr-MDSCs and Mo-MDSCs cells has been found in the peripheral blood of chronic myeloid leukemia (CML patients. They are part of the tumor clone showing BCR/ABL expression. Imatinib therapy decreases both MDSCs and arginase 1 levels to normal ones. This review will focus on actual knowledge for human MDSCs and their immunosuppressive activity in CML patients with a critical attention to comparison of Gr-MDSCs and polymorphonuclear cells (PMNs. We will then suggest the monitoring of MDSCs in patients who have discontinued tyrosine kinase inhibitors (TKIs therapy to evaluate if their increase could correlate with disease relapse.

  19. Combined action of cadmium(II) and lead(II) and chronic γ-radiation on radiosensitivity of rat bone marrow cells

    International Nuclear Information System (INIS)

    Heavy metals are the most widespread and harmful contaminants of environment. Cadmium and lead compounds have a particularly high genotoxic action. In addition, long-term, low-dose chronic irradiation occurs most frequently in nature. Thus, the goal of the present work was to study the effect of salts of heavy metals, lead and cadmium, on the cytogenetic damage in bone marrow cells of rats exposed to chronic and acute gamma irradiation, as well as on the magnitude of the adaptive response induced by chronic irradiation. Adult male rats were exposed to chronic gamma irradiation at low dose rate from 137Cs in a gamma-chamber (dose rate of 0.0013 Gy/h). Cumulative doses of chronic irradiation were 3, 9, 21 and 40 cGy at 1, 3, 7 and 14 days of exposition, respectively. Solutions of heavy metals Pb(CH3COO)2 . 3H2O and CdCl2 . 2.5H2O (50 mg/l) were given per os throughout the period of chronic irradiation. Rats subjected to chronic irradiation with an appropriate dose were immediately subjected to single acute dose 4 or 6 Gy (dose rate 47 cGy/min). Chromosome preparations of bone marrow cells were carried out by standard procedures. Percent of cells with aberrations and all types of chromosome aberrations were recorded. Five animals were used in each experiment. From each animal 100-200 cells were scored. The results of this study indicate that the administration of heavy metal salts to the diet of rats 1) enhances the cytogenetic damage in unirradiated animals; 2) increases the genotoxic effect of chronic and acute irradiation; 3) slightly decreases the value of the adaptive response induced by chronic irradiation. (author)

  20. Optimism and adaptation to chronic disease: the role of optimism in relation to self-care options of type I diabetes mellitus, rheumatoid arthritis and multiple sclerosis.

    NARCIS (Netherlands)

    Fournier, M.; Ridder, D. de; Bensing, J.

    2002-01-01

    OBJECTIVES: To determine the role of optimistic beliefs in adaptation processes of three chronic diseases different in controllability by self-care. It was expected that optimism towards the future would relate to adaptation independently of the controllability of disease. Optimism regarding one's c

  1. A model of human nasal epithelial cells adapted for direct and repeated exposure to airborne pollutants.

    Science.gov (United States)

    Bardet, Gaëlle; Achard, Sophie; Loret, Thomas; Desauziers, Valérie; Momas, Isabelle; Seta, Nathalie

    2014-08-17

    Airway epithelium lining the nasal cavity plays a pivotal role in respiratory tract defense and protection mechanisms. Air pollution induces alterations linked to airway diseases such as asthma. Only very few in vitro studies to date have succeeded in reproducing physiological conditions relevant to cellular type and chronic atmospheric pollution exposure. We therefore, set up an in vitro model of human Airway Epithelial Cells of Nasal origin (hAECN) close to real human cell functionality, specifically adapted to study the biological effects of exposure to indoor gaseous pollution at the environmental level. hAECN were exposed under air-liquid interface, one, two, or three-times at 24 h intervals for 1 h, to air or formaldehyde (200 μg/m(3)), an indoor air gaseous pollutant. All experiments were ended at day 4, when both cellular viability and cytokine production were assessed. Optimal adherence and confluence of cells were obtained 96 h after cell seeding onto collagen IV-precoated insert. Direct and repeated exposure to formaldehyde did not produce any cellular damage or IL-6 production change, although weak lower IL-8 production was observed only after the third exposure. Our model is significantly better than previous ones due to cell type and the repeated exposure protocol.

  2. Temporal perspective and other psychological factors making it difficult to adapt to requirements of treatment in chronic dialysis patients

    Directory of Open Access Journals (Sweden)

    Zawadzka, Barbara

    2014-10-01

    Full Text Available Aim. The study analyzed the relationship between temporal perspective, selected personal resources, and unhealthy behavior, manifesting in problems with adherence to fluid intake restrictions, in chronic hemodialyzis patients. The authors tried to answer the question whether there is temporal perspective and other psychological factors increasing the risk of non-adaptive behaviors. Methods. Sixty-one patients, aged 23–81 years (M = 59; SD = 13,9 on chronic hemodialysis at the Department of Nephrology University Hospital were qualified to the study. The study group consisted of 30 patients with poorer fluid regimen adherence and 31 controls, who maintained fluid regimen. The patients were qualified on the bases of the average interdialysis weight gains measured nine times during three weeks. The following research tools were used: P. Zimbardo and J. Boyd ZTPI test; P.T. Costa and R.R. McCrae NEO-FFI Inventory; J. Strelau Temperament Inventory, R. Schwarzer GSES; M. F. Scheier; C. S. Carver and M. W. Bridges LOT-R; M. Watson and S. Greer CECS; BJ. Felton, TA. Revenson, GA. Hinrichsen AIS. Results. Difficulties in adapting to the fluid intake restrictions are significantly associated with temporal orientation towards negative aspects of the present and the past. Non-adaptive health behaviors are typical for patients with temperamental lack of balance between agitation and inhibition processes and are characterized by high agreeableness and low conscientiousness. The association between excessive anger control and the risk of non-adherence medical recommendations. Conclusions. Time perception and other personality factors form mechanisms regulating health behaviors in chronically treatment patients.

  3. Chronic phase CML patients possess T cells capable of recognising autologous tumour cells.

    Science.gov (United States)

    Müller, Ludmila; Pawelec, Graham

    2002-05-01

    Much circumstantial evidence points to the immunogenicity of chronic myloid leukemia (CML) cells, most impressively the well-established T cell-dependent GvL effect seen in bone marrow transplantation. However, only a small number of shared antigens expressed by CML cells have been identified as potential targets for T cell-mediated immune responses which might be exploited for immunotherapy. It may be that unique antigens expressed by individual tumours are more potent rejection antigens if the patient's own T cells could be encouraged to react against them. Work is reviewed here which documents that in vitro mixed cultures between autologous T cells and dendritic cells of chronic-phase CML patients can give rise to sensitised T cells capable of recognising the patient's tumour cells. Additionally, mixed autologous tumour cell/lymphocyte cultures, modified by the addition of cytokine cocktails, may also result in the generation of similarly sensitised T cells. These results could be exploited for adoptive immunotherapy, and possibly, after identification of the antigens recognised, also for active immunotherapy, i.e. including therapeutic vaccination. PMID:12148904

  4. Adaptations to pain rehabilitation programmes for non-native patients with chronic pain

    NARCIS (Netherlands)

    Sloots, Maurits; Dekker, Jos H. M.; Bartels, Edien A. C.; Geertzen, Jan Henricus; Dekker, Joost

    2011-01-01

    Purpose. (i) To determine whether adaptations for non-native patients have been implemented in pain rehabilitation programmes; (ii) to determine whether characteristics of the rehabilitation institute are related to having adaptations for non-native patients in place. Subjects. Rehabilitation instit

  5. [The diagnostics of adaptive reactions of blood on application the stress-modulating therapy in patients with brain chronic ischemia].

    Science.gov (United States)

    Krylov, V N; Deriugina, A V; Antipenko, E A; Zakharova, O A

    2012-12-01

    The article deals with the results of analysis of electrophoretic mobility of erythrocytes and leukogram in patients with dyscirculatory encephalopathy on different stages of disease on application therapy with inclusion of stress-modulating pharmaceuticals into course of treatment. It is established that the electrophoretic mobiliy of erythrocytes makes it possible to evaluate the adaptive indicators blood in patients with dyscirculatory encephalopathy. The consideration of these indicators makes feasible the substantiation of inclusion of stress-modulating therapy into complex treatment of patients with chronic cerebrovascular inefficiency. PMID:23479969

  6. Oral manifestations of chronic disseminated langerhans cell histiocytosis: a case report

    OpenAIRE

    Namdar Pekiner, Filiz; BORAHAN, M.Oğuz; ÖZBAYRAK, Semih; Alatlı, Canan; Kızılyel, Gizem

    2012-01-01

    The term histiocytosis X was introduced as a collective designation for a spectrum of clinopathologic disorders characterized by proliferation of histiocyte-like cells. The distinctive histiocytic cells present in this lesion have been identified as Langerhans cells, and the condition is now designated as Langerhans cell histiocytosis. Chronic disseminated langerhans cell histiocytosis is a disease involving bone, skin, and viscera (Hand-Schüller-Christian disease). The often-cited Chronic di...

  7. Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus.

    Science.gov (United States)

    Wolf, Susanne A; Steiner, Barbara; Wengner, Antje; Lipp, Martin; Kammertoens, Thomas; Kempermann, Gerd

    2009-09-01

    To understand the link between peripheral immune activation and neuronal precursor biology, we investigated the effect of T-cell activation on adult hippocampal neurogenesis in female C57Bl/6 mice. A peripheral adaptive immune response triggered by adjuvant-induced rheumatoid arthritis (2 microg/microl methylated BSA) or staphylococcus enterotoxin B (EC(50) of 0.25 microg/ml per 20 g body weight) was associated with a transient increase in hippocampal precursor cell proliferation and neurogenesis as assessed by immunohistochemistry and confocal microscopy. Both treatments were paralleled by an increase in corticosterone levels in the hippocampus 1- to 2-fold over the physiological amount measured by quantitative radioimmunoassay. In contrast, intraperitoneal administration of the innate immune response activator lipopolysaccaride (EC(50) of 0.5 microg/ml per 20 g body weight) led to a chronic 5-fold increase of hippocampal glucocorticoid levels and a decrease of adult neurogenesis. In vitro exposure of murine neuronal progenitor cells to corticosterone triggered either cell death at high (1.5 nM) or proliferation at low (0.25 nM) concentrations. This effect could be blocked using a viral vector system expressing a transdomain of the glucocorticoid receptor. We suggest an evolutionary relevant communication route for the brain to respond to environmental stressors like inflammation mediated by glucocorticoid levels in the hippocampus.

  8. Circulating subsets and CD4(+)CD25(+) regulatory T cell function in chronic inflammatory demyelinating polyradiculoneuropathy.

    Science.gov (United States)

    Sanvito, Lara; Makowska, Anna; Gregson, Norman; Nemni, Raffaello; Hughes, Richard A C

    2009-01-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory disease of the peripheral nervous system that is probably autoimmune in origin. Different components of the adaptive and innate immunity may be responsible for the aberrant response towards nerve antigens. To investigate this, we examined lymphocyte subsets and regulatory T cell (Treg) function in the blood of CIDP patients, healthy controls (HC) and subjects with non-immune mediated neuropathies (other neuropathies, ON). We used flow cytometry to determine the frequency of monocytes, B cells, natural killer (NK) and NK-T cells, total and activated CD4(+) and CD8(+) T cells, effector memory and central memory CD4(+) and CD8(+) T cells, and CD4(+)CD25(high)Foxp3(+) Tregs. Treg function was studied after polyclonal stimulation and antigen specific stimulation with myelin protein peptides in CIDP and HC. There was an increased frequency of monocytes (p = 0.02) and decreased frequency of NK cells (p = 0.02) in CIDP compared with HC but not ON. There were no significant differences in other populations. Treg function was impaired in CIDP compared to HC (p = 0.02), whilst T cell proliferation to myelin protein peptides before and after depletion of Tregs was not different between patients and controls. This study shows increased circulating monocytes and reduced NK cells in CIDP. Although Treg frequency was not altered, we confirm that Tregs display a defect of suppressive function. Myelin protein peptides were not the target of the altered peripheral regulation of the immune response. The mechanisms of peripheral immune tolerance in CIDP and their relevance to the pathogenesis deserve further exploration.

  9. Children with chronic renal failure have reduced numbers of memory B cells.

    NARCIS (Netherlands)

    Bouts, A.H.M.; Davin, J.C.; Krediet, R.T.; Monnens, L.A.H.; Nauta, J.; Schröder, C.H.; Lier, R.A.W. van; Out, T.A.

    2004-01-01

    Reduced serum IgG and subclass levels have been demonstrated in children with chronic renal failure. To study possible causes of this reduction, we analysed B cell subset composition, T helper cell frequencies and immunoglobulin (Ig) production capacity in vitro in children with chronic renal failur

  10. Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

    Directory of Open Access Journals (Sweden)

    Philipp Koehler

    2012-01-01

    Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

  11. Effects of asymptomatic hyperuricemia on vascular endothelial cells and vascularsmoothmuscle cells in patients with primary chronic glomerulonephritis

    Institute of Scientific and Technical Information of China (English)

    连希艳

    2012-01-01

    Objective To explore the effects of asymptomatic hyperuricemia on the function of glomerular endothelial cells and vascular smooth muscle cell proliferation in patients with primary chronic glomerulonephritis and to determine if asymptomatic hyperuricemia could lead to kidney

  12. Predomination of IL-17-producing tryptase-positive/chymase-positive mast cells in azoospermic chronic testicular inflammation.

    Science.gov (United States)

    Chen, S-J; Duan, Y-G; Haidl, G; Allam, J-P

    2016-08-01

    Chronic testicular inflammation and infection have been regarded as important factors in the pathogenesis of azoospermia. As key effector cells in innate and adaptive immune system, mast cells (MCs) were observed in inflammation and autoimmune disease. Furthermore, increased expression of tryptase-positive MCs has been reported in testicular disorders associated with male infertility/subfertility. However, little is known about the potential relationship between MCs and chronic testicular inflammation in azoospermic patients. Moreover, the preferential expression of MCs' subtypes in testis of these patients is still far from being understood. Thus, this study aimed to investigate characteristics of testicular MCs as well as their subtypes in azoospermic men with chronic testicular inflammation (AZI, n = 5) by immunohistochemical techniques. Our results showed significant increase of MCs in AZI, and more importantly, considerable numbers of tryptase-positive/chymase-positive MCs could also be demonstrated in AZI, when compared to control groups representing azoospermia without chronic testicular inflammation (AZW, n = 5) and normal spermatogenesis (NT, n = 5) respectively. Most interestingly, immunofluorescence staining revealed autoimmune-associated interleukin (IL)-17-producing MCs in AZI, whereas co-expression of MC markers with tumour necrosis factor (TNF)-α, IL-10 and IL-1β could not be detected. In conclusion, AZI is associated with significant increase of tryptase-positive/chymase-positive MCs expressing IL-17, and these MCs might contribute to the pathogenesis of AZI. PMID:26420243

  13. Dissimilary in patients' and spouses' representations of chronic illness: exploration of relations to patient adaptation.

    NARCIS (Netherlands)

    Heijmans, M.; Ridder, D. de; Bensing, J.

    1999-01-01

    In this cross-sectional study, the illness representations of patients suffering from Chronic Fatigue Syndrome (n=49) and Addison's Disease (n=52) and those of their spouses were compared. Couples generally held similar views with regard to the dimensions of illness identity and cause but disagreed

  14. Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial)

    DEFF Research Database (Denmark)

    Qayyum, Abbas Ali; Haack-Sørensen, Mandana; Mathiasen, Anders Bruun;

    2012-01-01

    for regenerative therapy to replace injured tissue by creating new blood vessels and cardiomyocytes in patients with chronic ischemic heart disease. The aim of this special report is to review the present preclinical data leading to clinical stem cell therapy using ADSCs in patients with ischemic heart disease....... In addition, we give an introduction to the first-in-man clinical trial, MyStromalCell Trial, which is a prospective, randomized, double-blind, placebo-controlled study using culture-expanded ADSCs obtained from adipose-derived cells from abdominal adipose tissue and stimulated with VEGF-A(165) the week...

  15. Adapt

    Science.gov (United States)

    Bargatze, L. F.

    2015-12-01

    Active Data Archive Product Tracking (ADAPT) is a collection of software routines that permits one to generate XML metadata files to describe and register data products in support of the NASA Heliophysics Virtual Observatory VxO effort. ADAPT is also a philosophy. The ADAPT concept is to use any and all available metadata associated with scientific data to produce XML metadata descriptions in a consistent, uniform, and organized fashion to provide blanket access to the full complement of data stored on a targeted data server. In this poster, we present an application of ADAPT to describe all of the data products that are stored by using the Common Data File (CDF) format served out by the CDAWEB and SPDF data servers hosted at the NASA Goddard Space Flight Center. These data servers are the primary repositories for NASA Heliophysics data. For this purpose, the ADAPT routines have been used to generate data resource descriptions by using an XML schema named Space Physics Archive, Search, and Extract (SPASE). SPASE is the designated standard for documenting Heliophysics data products, as adopted by the Heliophysics Data and Model Consortium. The set of SPASE XML resource descriptions produced by ADAPT includes high-level descriptions of numerical data products, display data products, or catalogs and also includes low-level "Granule" descriptions. A SPASE Granule is effectively a universal access metadata resource; a Granule associates an individual data file (e.g. a CDF file) with a "parent" high-level data resource description, assigns a resource identifier to the file, and lists the corresponding assess URL(s). The CDAWEB and SPDF file systems were queried to provide the input required by the ADAPT software to create an initial set of SPASE metadata resource descriptions. Then, the CDAWEB and SPDF data repositories were queried subsequently on a nightly basis and the CDF file lists were checked for any changes such as the occurrence of new, modified, or deleted

  16. A differential role for neuropeptides in acute and chronic adaptive responses to alcohol: behavioural and genetic analysis in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Philippa Mitchell

    Full Text Available Prolonged alcohol consumption in humans followed by abstinence precipitates a withdrawal syndrome consisting of anxiety, agitation and in severe cases, seizures. Withdrawal is relieved by a low dose of alcohol, a negative reinforcement that contributes to alcohol dependency. This phenomenon of 'withdrawal relief' provides evidence of an ethanol-induced adaptation which resets the balance of signalling in neural circuits. We have used this as a criterion to distinguish between direct and indirect ethanol-induced adaptive behavioural responses in C. elegans with the goal of investigating the genetic basis of ethanol-induced neural plasticity. The paradigm employs a 'food race assay' which tests sensorimotor performance of animals acutely and chronically treated with ethanol. We describe a multifaceted C. elegans 'withdrawal syndrome'. One feature, decrease reversal frequency is not relieved by a low dose of ethanol and most likely results from an indirect adaptation to ethanol caused by inhibition of feeding and a food-deprived behavioural state. However another aspect, an aberrant behaviour consisting of spontaneous deep body bends, did show withdrawal relief and therefore we suggest this is the expression of ethanol-induced plasticity. The potassium channel, slo-1, which is a candidate ethanol effector in C. elegans, is not required for the responses described here. However a mutant deficient in neuropeptides, egl-3, is resistant to withdrawal (although it still exhibits acute responses to ethanol. This dependence on neuropeptides does not involve the NPY-like receptor npr-1, previously implicated in C. elegans ethanol withdrawal. Therefore other neuropeptide pathways mediate this effect. These data resonate with mammalian studies which report involvement of a number of neuropeptides in chronic responses to alcohol including corticotrophin-releasing-factor (CRF, opioids, tachykinins as well as NPY. This suggests an evolutionarily conserved role

  17. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy

    OpenAIRE

    Butler, A. E.; Cao-Minh, L.; Galasso, R; Rizza, R. A.; Corradin, A.; Cobelli, C; Butler, P C

    2010-01-01

    Aims/hypothesis We sought to establish the extent and basis for adaptive changes in beta cell numbers in human pregnancy. Methods Pancreas was obtained at autopsy from women who had died while pregnant (n = 18), post-partum (n = 6) or were not pregnant at or shortly before death (controls; n = 20). Pancreases were evaluated for fractional pancreatic beta cell area, islet size and islet fraction of beta cells, beta cell replication (Ki67) and apoptosis (TUNEL), and indirect markers of beta cel...

  18. RBC deformability and amino acid concentrations after hypo-osmotic challenge may reflect chronic cell hydration status in healthy young men.

    Science.gov (United States)

    Stookey, Jodi D; Klein, Alexis; Hamer, Janice; Chi, Christine; Higa, Annie; Ng, Vivian; Arieff, Allen; Kuypers, Frans A; Larkin, Sandra; Perrier, Erica; Lang, Florian

    2013-10-01

    Biomarkers of chronic cell hydration status are needed to determine whether chronic hyperosmotic stress increases chronic disease risk in population-representative samples. In vitro, cells adapt to chronic hyperosmotic stress by upregulating protein breakdown to counter the osmotic gradient with higher intracellular amino acid concentrations. If cells are subsequently exposed to hypo-osmotic conditions, the adaptation results in excess cell swelling and/or efflux of free amino acids. This study explored whether increased red blood cell (RBC) swelling and/or plasma or urine amino acid concentrations after hypo-osmotic challenge might be informative about relative chronic hyperosmotic stress in free-living men. Five healthy men (20-25 years) with baseline total water intake below 2 L/day participated in an 8-week clinical study: four 2-week periods in a U-shaped A-B-C-A design. Intake of drinking water was increased by +0.8 ± 0.3 L/day in period 2, and +1.5 ± 0.3 L/day in period 3, and returned to baseline intake (0.4 ± 0.2 L/day) in period 4. Each week, fasting blood and urine were collected after a 750 mL bolus of drinking water, following overnight water restriction. The periods of higher water intake were associated with significant decreases in RBC deformability (index of cell swelling), plasma histidine, urine arginine, and urine glutamic acid. After 4 weeks of higher water intake, four out of five participants had ½ maximal RBC deformability below 400 mmol/kg; plasma histidine below 100 μmol/L; and/or undetectable urine arginine and urine glutamic acid concentrations. Work is warranted to pursue RBC deformability and amino acid concentrations after hypo-osmotic challenge as possible biomarkers of chronic cell hydration. PMID:24303184

  19. Turkish version of the chronic urticaria quality of life questionnaire: cultural adaptation, assessment of reliability and validity.

    Science.gov (United States)

    Kocatürk, Emek; Weller, Karsten; Martus, Peter; Aktas, Selin; Kavala, Mukaddes; Sarigul, Sükran; Baiardini, Ilaria; Canonica, Giorgio W; Brzoza, Zenon; Kalogeromitros, Dimitrios; Maurer, Marcus

    2012-07-01

    Chronic spontaneous urticaria has a substantial impact on patients' quality of life. The first disease-specific tool to assess quality of life impairment in this condition, the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), was developed recently. The aim of this study was to adapt the original Italian version to the Turkish language and to evaluate its reliability, validity, and sensitivity to change. The Turkish version was developed by performing forward- and back-translation. It was then applied to 140 consecutive patients with chronic spontaneous urticaria, along with the Dermatology Life Quality Index and the Skindex-29. Disease activity was assessed using the Urticaria Activity Score. Sensitivity to change was measured in 101 patients, who completed the instruments twice at intervals of 4 weeks. Confirmatory factor analysis demonstrated that the six-scale structure of the original Italian version ("pruritus", "swelling", "impact on life activities", "sleep problems", "limits", "looks") can be retained in the Turkish instrument. Analysis regarding convergent validity showed good correlations of the Turkish CU-Q2oL with the other instruments. In addition, it was found to discriminate well between patients with different levels of urticaria activity, and to be sensitive to change. In conclusion, the Turkish version of CU-Q2oL is a reliable, valid, and sensitive instrument, which will help to characterize better the clinical impact of chronic spontaneous urticaria and treatment outcomes in Turkish patients. Its identical scale structure to that of other CU-Q2oL instruments makes it ideal for cross-cultural comparisons and for its application in future national and multinational studies. PMID:21918791

  20. Chronic stress and brain plasticity: Mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders.

    Science.gov (United States)

    Radley, Jason; Morilak, David; Viau, Victor; Campeau, Serge

    2015-11-01

    Stress responses entail neuroendocrine, autonomic, and behavioral changes to promote effective coping with real or perceived threats to one's safety. While these responses are critical for the survival of the individual, adverse effects of repeated exposure to stress are widely known to have deleterious effects on health. Thus, a considerable effort in the search for treatments to stress-related CNS disorders necessitates unraveling the brain mechanisms responsible for adaptation under acute conditions and their perturbations following chronic stress exposure. This paper is based upon a symposium from the 2014 International Behavioral Neuroscience Meeting, summarizing some recent advances in understanding the effects of stress on adaptive and maladaptive responses subserved by limbic forebrain networks. An important theme highlighted in this review is that the same networks mediating neuroendocrine, autonomic, and behavioral processes during adaptive coping also comprise targets of the effects of repeated stress exposure in the development of maladaptive states. Where possible, reference is made to the similarity of neurobiological substrates and effects observed following repeated exposure to stress in laboratory animals and the clinical features of stress-related disorders in humans. PMID:26116544

  1. Adaptation of children to a chronically ill or mentally handicapped sibling.

    OpenAIRE

    Seligman, M

    1987-01-01

    The presence of a chronically ill or mentally handicapped child in a family can be a stress for the child's siblings, who often are ill informed about the nature and prognosis of the illness, may be uncertain what is expected of them in the caregiving role, may feel their own identities threatened, and may experience ostracism by their friends and misunderstanding at school. Although individual reactions vary widely, feelings of anger, guilt, resentment and shame are commonly reported. Excess...

  2. Adapting HIV patient and program monitoring tools for chronic non-communicable diseases in Ethiopia

    OpenAIRE

    Letebo, Mekitew; Shiferaw, Fassil

    2016-01-01

    Background Chronic non-communicable diseases (NCDs) have become a huge public health concern in developing countries. Many resource-poor countries facing this growing epidemic, however, lack systems for an organized and comprehensive response to NCDs. Lack of NCD national policy, strategies, treatment guidelines and surveillance and monitoring systems are features of health systems in many developing countries. Successfully responding to the problem requires a number of actions by the countri...

  3. Hidden talents of natural killers: NK cells in innate and adaptive immunity

    OpenAIRE

    Cooper, Megan A.; Colonna, Marco; Yokoyama, Wayne M.

    2009-01-01

    Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells and producing immunoregulatory cytokines. Herein, we discuss recent studies that indicate that NK cells span the conventional boundaries between innate and adaptive immunity. For example, it was recently discovered that NK cells have the capacity for memory-like responses, a property that was previously thought to be limited to adaptive immunity. NK cells have also been identified in multiple tissues, and ...

  4. Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells.

    Science.gov (United States)

    Tobar, Jaime A; Carreño, Leandro J; Bueno, Susan M; González, Pablo A; Mora, Jorge E; Quezada, Sergio A; Kalergis, Alexis M

    2006-11-01

    Dendritic cells (DCs) constitute the link between innate and adaptive immunity by directly recognizing pathogen-associated molecular patterns (PAMPs) in bacteria and by presenting bacterial antigens to T cells. Recognition of PAMPs renders DCs as professional antigen-presenting cells able to prime naïve T cells and initiate adaptive immunity against bacteria. Therefore, interfering with DC function would promote bacterial survival and dissemination. Understanding the molecular mechanisms that have evolved in virulent bacteria to evade activation of adaptive immunity requires the characterization of virulence factors that interfere with DC function. Salmonella enterica serovar Typhimurium, the causative agent of typhoid-like disease in the mouse, can prevent antigen presentation to T cells by avoiding lysosomal degradation in DCs. Here, we show that this feature of virulent Salmonella applies in vivo to prevent activation of adaptive immunity. In addition, this attribute of virulent Salmonella requires functional expression of a type three secretion system (TTSS) and effector proteins encoded within the Salmonella pathogenicity island 2 (SPI-2). In contrast to wild-type virulent Salmonella, mutant strains carrying specific deletions of SPI-2 genes encoding TTSS components or effectors proteins are targeted to lysosomes and are no longer able to prevent DCs from activating T cells in vitro or in vivo. SPI-2 mutant strains are attenuated in vivo, showing reduced tissue colonization and enhanced T-cell activation, which confers protection against a challenge with wild-type virulent Salmonella. Our data suggest that impairment of DC function by the activity of SPI-2 gene products is crucial for Salmonella pathogenesis.

  5. Adaptation to Colombia and Venezuela of the economic model Dasatinib first-line treatment of chronic myeloid leukemia, developed by the York Health Economics Consortium

    OpenAIRE

    Juan E. Valencia; Orozco, John J

    2012-01-01

    Objective: To adapt an economic model of frontline dasatinib treatment for chronic myeloid leukemia developed by the York Consortium to the health care settings in Colombia and Venezuela. Methods: The original model considered treatment of naïve patients with CML and a Markov's model with probabilities of change between chronic, accelerated phases and death, over a patient’s lifetime. The applied discount rate is 3.5% for both costs and benefits. Direct medical and treatment costs, and mortal...

  6. Inherited adaptation of genome-rewired cells in response to a challenging environment

    Science.gov (United States)

    David, Lior; Stolovicki, Elad; Haziz, Efrat; Braun, Erez

    2010-01-01

    Despite their evolutionary significance, little is known about the adaptation dynamics of genomically rewired cells in evolution. We have confronted yeast cells carrying a rewired regulatory circuit with a severe and unforeseen challenge. The essential HIS3 gene from the histidine biosynthesis pathway was placed under the exclusive regulation of the galactose utilization system. Glucose containing medium strongly represses the GAL genes including HIS3 and these rewired cells are required to operate this essential gene. We show here that although there were no adapted cells prior to the encounter with glucose, a large fraction of cells adapted to grow in this medium and this adaptation was stably inherited. The adaptation relied on individual cells that switched into an adapted state and, thus, the adaptation was due to a response of many individual cells to the change in environment and not due to selection of rare advantageous phenotypes. The adaptation of numerous individual cells by heritable phenotypic switching in response to a challenge extends the common evolutionary framework and attests to the adaptive potential of regulatory circuits. PMID:20811567

  7. Inhibitory effects of rapamycin on proliferation of chronic myelogenous leukemia cells and its mechanism

    Institute of Scientific and Technical Information of China (English)

    李杰

    2012-01-01

    Objective To explore the inhibitory effects of rapamycin on proliferation of chronic myelogenous leukemia (CML) cells and its possible mechanism. Methods The effects of rapamycin at various concentrations on cell proliferation of CML cell line K562 cells were analyzed by MTT. The expressions

  8. Qualitative assessment of red blood cell parameters for signs of anemia in patients with chronic periodontitis

    OpenAIRE

    Khan, Nubesh S.; Luke, Roji; Soman, Rino Roopak; Krishna, Praveen M.; Safar, Iqbal P.; Swaminathan, Senthil Kumar

    2015-01-01

    Aim: Anemia of chronic disease is defined as anemia occurring in chronic infections and inflammatory conditions that is not caused by marrow deficiencies or other diseases and in the presence of adequate iron stores and vitamins. The present case control study was aimed to assess the red blood cell parameters for signs of anemia in patients with mild, moderate, and severe chronic periodontitis. Materials and Methods: A simple random sampling method was used to select 80 healthy male patients,...

  9. Intestinal Adaptations in Chronic Kidney Disease and the Influence of Gastric Bypass Surgery

    OpenAIRE

    Hatch, Marguerite

    2014-01-01

    Studies have shown that compensatory adaptations in gastrointestinal oxalate transport can impact the amount of oxalate excreted by the kidney. Hyperoxaluria is a major risk factor in the formation of kidney stones and oxalate is derived from both the diet as well as from liver metabolism of glyoxylate. Although the intestine generally absorbs oxalate from dietary sources, and can contribute as much as 50% of urinary oxalate, enteric oxalate elimination plays a significant role when renal fun...

  10. T Cell Adaptive Immunity Proceeds through Environment-Induced Adaptation from the Exposure of Cryptic Genetic Variation

    Science.gov (United States)

    Whitacre, James M.; Lin, Joseph; Harding, Angus

    2011-01-01

    Evolution is often characterized as a process involving incremental genetic changes that are slowly discovered and fixed in a population through genetic drift and selection. However, a growing body of evidence is finding that changes in the environment frequently induce adaptations that are much too rapid to occur by an incremental genetic search process. Rapid evolution is hypothesized to be facilitated by mutations present within the population that are silent or “cryptic” within the first environment but are co-opted or “exapted” to the new environment, providing a selective advantage once revealed. Although cryptic mutations have recently been shown to facilitate evolution in RNA enzymes, their role in the evolution of complex phenotypes has not been proven. In support of this wider role, this paper describes an unambiguous relationship between cryptic genetic variation and complex phenotypic responses within the immune system. By reviewing the biology of the adaptive immune system through the lens of evolution, we show that T cell adaptive immunity constitutes an exemplary model system where cryptic alleles drive rapid adaptation of complex traits. In naive T cells, normally cryptic differences in T cell receptor reveal diversity in activation responses when the cellular population is presented with a novel environment during infection. We summarize how the adaptive immune response presents a well studied and appropriate experimental system that can be used to confirm and expand upon theoretical evolutionary models describing how seemingly small and innocuous mutations can drive rapid cellular evolution. PMID:22363338

  11. Pattern of hemodynamic adaptation to exercises in patients with chronic coronary heart diseases during trainings

    International Nuclear Information System (INIS)

    The character of hemodynamic supply of organism of patients with chronic ischemia, participating in physicoel training in cardiological hospitals was studied. It is shown that efficiency of physical training in patients with stenokardia are considerably connected with initial functional state of patients, blood viscosity, contractibility, myocardium electric activity, state of liver blood flow. During brief training of 6-8 weeks half of patients achieves training threshold which symptoms are absence of blood volume increase in the lungs, increase of liver blood flow, maximal frequency of cardiac contractions

  12. Downregulation of aquaporin-1 in alveolar microvessels in lungs adapted to chronic heart failure

    DEFF Research Database (Denmark)

    Müllertz, Katrine M; Strøm, Claes; Trautner, Simon;

    2011-01-01

    The threshold pressure for lung edema formation is increased in severe chronic heart failure (CHF) due to reduced microvascular permeability. The water channel aquaporin-1 (AQP1) is present in the pulmonary microvascular endothelium, and a number of studies suggest the importance of AQP1...... as a molecular determinant of pulmonary microvascular water transport. The present study examined the abundance and localization of AQP1 in lungs from rats with CHF. We used two different models of CHF: ligation of the left anterior descending coronary artery (LAD ligation) and aorta-banding (AB). Sham...

  13. Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    Sk Md Fazle Akbar; Norio Horiike; Morikazu Onji

    2006-01-01

    Hepatitis B virus (HBV) infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects.Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection: (1) These influence acquisition of chronic HBV carrier state, (2) They are important in the context of liver damages, (3) Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses.However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult.During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach (vaccine therapy). The present regimen of vaccine therapy is safe and cheap, but not so effective.A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV-specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection.

  14. MicroRNA expression profiling identifies activated B cell status in chronic lymphocytic leukemia cells.

    Directory of Open Access Journals (Sweden)

    Shuqiang Li

    Full Text Available Chronic lymphocytic leukemia (CLL is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70(+ and IgV(H unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL.

  15. Nociceptors as chronic drivers of pain and hyperreflexia after spinal cord injury: an adaptive-maladaptive hyperfunctional state hypothesis

    Directory of Open Access Journals (Sweden)

    Edgar T Walters

    2012-08-01

    Full Text Available Spinal cord injury (SCI causes chronic peripheral sensitization of nociceptors and persistent generation of spontaneous action potentials (SA in peripheral branches and the somata of hyperexcitable nociceptors within dorsal root ganglia (DRG. Here it is proposed that SCI triggers in numerous nociceptors a persistent hyperfunctional state (peripheral, synaptic, and somal that originally evolved as an adaptive response to compensate for loss of sensory terminals after severe but survivable peripheral injury. In this hypothesis, nociceptor somata monitor the status of their own receptive field and the rest of the body by integrating signals received by their peripheral and central branches and the soma itself. A nociceptor switches into a potentially permanent hyperfunctional state when central neural, glial, and inflammatory signal combinations are detected that indicate extensive peripheral injury. Similar signal combinations are produced by SCI and disseminated widely to uninjured as well as injured nociceptors. This paper focuses on the uninjured nociceptors that are altered by SCI. Enhanced activity generated in below-level nociceptors promotes below-level central sensitization, somatic and autonomic hyperreflexia, and visceral dysfunction. If sufficient ascending fibers survive, enhanced activity in below-level nociceptors contributes to below-level pain. Nociceptor activity generated above the injury level contributes to at- and above-level sensitization and pain (evoked and spontaneous. Thus, SCI triggers a potent nociceptor state that may have been adaptive (from an evolutionary perspective after severe peripheral injury but is maladaptive after SCI. Evidence that hyperfunctional nociceptors make large contributions to behavioral hypersensitivity after SCI suggests that nociceptor-specific ion channels required for nociceptor SA and hypersensitivity offer promising targets for treating chronic pain and hyperreflexia after SCI.

  16. Chronic alcohol consumption enhances iNKT cell maturation and activation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Hui, E-mail: hzhang@wsu.edu; Zhang, Faya; Zhu, Zhaohui; Luong, Dung; Meadows, Gary G.

    2015-01-15

    Alcohol consumption exhibits diverse effects on different types of immune cells. NKT cells are a unique T cell population and play important immunoregulatory roles in different types of immune responses. The effects of chronic alcohol consumption on NKT cells remain to be elucidated. Using a mouse model of chronic alcohol consumption, we found that alcohol increases the percentage of NKT cells, especially iNKT cells in the thymus and liver, but not in the spleen or blood. Alcohol consumption decreases the percentage of NK1.1{sup −} iNKT cells in the total iNKT cell population in all of the tissues and organs examined. In the thymus, alcohol consumption increases the number of NK1.1{sup +}CD44{sup hi} mature iNKT cells but does not alter the number of NK1.1{sup −} immature iNKT cells. A BrdU incorporation assay shows that alcohol consumption increases the proliferation of thymic NK1.1{sup −} iNKT cells, especially the NK1.1{sup −}CD44{sup lo} Stage I iNKT cells. The percentage of NKG2A{sup +} iNKT cells increases in all of the tissues and organs examined; whereas CXCR3{sup +} iNKT cells only increases in the thymus of alcohol-consuming mice. Chronic alcohol consumption increases the percentage of IFN-γ-producing iNKT cells and increases the blood concentration of IFN-γ and IL-12 after in vivo α-galactosylceramide (αGalCer) stimulation. Consistent with the increased cytokine production, the in vivo activation of iNKT cells also enhances the activation of dendritic cells (DC) and NK, B, and T cells in the alcohol-consuming mice. Taken together the data indicate that chronic alcohol consumption enhances iNKT cell maturation and activation, which favors the Th1 immune response. - Highlights: • Chronic alcohol consumption increases iNKT cells in the thymus and liver • Chronic alcohol consumption enhances thymic Stage I iNKT cell proliferation • Chronic alcohol consumption enhances iNKT cell maturation in thymus and periphery • Chronic alcohol

  17. Downregulation of aquaporin-1 in alveolar microvessels in lungs adapted to chronic heart failure

    DEFF Research Database (Denmark)

    Müllertz, Katrine M; Strøm, Claes; Trautner, Simon;

    2011-01-01

    The threshold pressure for lung edema formation is increased in severe chronic heart failure (CHF) due to reduced microvascular permeability. The water channel aquaporin-1 (AQP1) is present in the pulmonary microvascular endothelium, and a number of studies suggest the importance of AQP1 as a mol......The threshold pressure for lung edema formation is increased in severe chronic heart failure (CHF) due to reduced microvascular permeability. The water channel aquaporin-1 (AQP1) is present in the pulmonary microvascular endothelium, and a number of studies suggest the importance of AQP1...... as a molecular determinant of pulmonary microvascular water transport. The present study examined the abundance and localization of AQP1 in lungs from rats with CHF. We used two different models of CHF: ligation of the left anterior descending coronary artery (LAD ligation) and aorta-banding (AB). Sham......-operated rats served as controls. Echocardiographic verification of left ventricular dysfunction, enhanced left ventricular end-diastolic pressure, and right ventricular hypertrophy confirmed the presence of CHF. Western blotting of whole-lung homogenates revealed significant downregulation of AQP1 in LAD...

  18. Elevated glutathione level does not protect against chronic alcohol mediated apoptosis in recombinant human hepatoma cell line VL-17A over-expressing alcohol metabolizing enzymes--alcohol dehydrogenase and Cytochrome P450 2E1.

    Science.gov (United States)

    Chandrasekaran, Karthikeyan; Swaminathan, Kavitha; Kumar, S Mathan; Chatterjee, Suvro; Clemens, Dahn L; Dey, Aparajita

    2011-06-01

    Chronic consumption of alcohol leads to liver injury. Ethanol-inducible Cytochrome P450 2E1 (CYP2E1) plays a critical role in alcohol mediated oxidative stress due to its ability to metabolize ethanol. In the present study, using the recombinant human hepatoma cell line VL-17A that over-expresses the alcohol metabolizing enzymes-alcohol dehydrogenase (ADH) and CYP2E1; and control HepG2 cells, the mechanism and mode of cell death due to chronic ethanol exposure were studied. Untreated VL-17A cells exhibited apoptosis and oxidative stress when compared with untreated HepG2 cells. Chronic alcohol exposure, i.e., 100 mM ethanol treatment for 72 h caused a significant decrease in viability (47%) in VL-17A cells but not in HepG2 cells. Chronic ethanol mediated cell death in VL-17A cells was predominantly apoptotic, with increased oxidative stress as the underlying mechanism. Chronic ethanol exposure of VL-17A cells resulted in 1.1- to 2.5-fold increased levels of ADH and CYP2E1. Interestingly, the level of the antioxidant GSH was found to be 3-fold upregulated in VL-17A cells treated with ethanol, which may be a metabolic adaptation to the persistent and overwhelming oxidative stress. In conclusion, the increased GSH level may not be sufficient enough to protect VL-17A cells from chronic alcohol mediated oxidative stress and resultant apoptosis. PMID:21414402

  19. Plasmacytoid Dendritic Cells Act as the Most Competent Cell Type in Linking Antiviral Innate and Adaptive Immune Responses

    Institute of Scientific and Technical Information of China (English)

    Zheng Zhang; Fu-Sheng Wang

    2005-01-01

    Appropriate in vivo control of plasmacytoid dendritic cell (pDC) recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies,pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exanining the functional and antiviral properties of in vivo pDC plasticity.

  20. Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis

    OpenAIRE

    Taverna, S; Flugy Papè, AM; SAIEVA, L; Kohn, EC; A. Santoro; Meraviglia, S; De Leo, G; ALESSANDRO, R

    2011-01-01

    The present study is designed to assess if exosomes released from Chronic Myelogenous Leukemia (CML) cells may modulate angiogenesis. We have isolated and characterized the exosomes generated from LAMA84 CML cells and demonstrated that addition of exosomes to human vascular endothelial cells (HUVEC) induces an increase of both ICAM-1 and VCAM-1 cell adhesion molecules and interleukin-8 expression. The stimulation of cell-cell adhesion molecules was paralleled by a dose-dependent increase of a...

  1. Cardiac Response to Chronic Intermittent Hypoxia with a Transition from Adaptation to Maladaptation: The Role of Hydrogen Peroxide

    Directory of Open Access Journals (Sweden)

    Xia Yin

    2012-01-01

    Full Text Available Obstructive sleep apnea (OSA is a highly prevalent respiratory disorder of sleep, and associated with chronic intermittent hypoxia (CIH. Experimental evidence indicates that CIH is a unique physiological state with potentially “adaptive” and “maladaptive” consequences for cardio-respiratory homeostasis. CIH is also a critical element accounting for most of cardiovascular complications of OSA. Cardiac response to CIH is time-dependent, showing a transition from cardiac compensative (such as hypertrophy to decompensating changes (such as failure. CIH-provoked mild and transient oxidative stress can induce adaptation, but severe and persistent oxidative stress may provoke maladaptation. Hydrogen peroxide as one of major reactive oxygen species plays an important role in the transition of adaptive to maladaptive response to OSA-associated CIH. This may account for the fact that although oxidative stress has been recognized as a driver of cardiac disease progression, clinical interventions with antioxidants have had little or no impact on heart disease and progression. Here we focus on the role of hydrogen peroxide in CIH and OSA, trying to outline the potential of antioxidative therapy in preventing CIH-induced cardiac damage.

  2. MR findings of squamous cell carcinoma arising from chronic osteomyelitis of the tibia: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Han, Dong Hwa; Lee, Ji Hae; Cho, Woo Ho; Kim, Jae Hyung; Jeong, Myeong Ja; Kim, Soung Hee; Kim, Ji Young; Kim, Soo Hyun; Kang, Mi Jin; Bae, Kyung Eun [Dept. of Radiology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul (Korea, Republic of)

    2016-05-15

    Malignant transformation is a rare and late complication of untreated chronic osteomyelitis. Known radiographic findings of the malignant transformation of chronic osteomyelitis are osteolytic or mixed sclerotic and osteolytic lesions with or without soft tissue mass. But its magnetic resonance (MR) imaging findings are rarely described in the literature. We experienced a case of an 82-year-old man diagnosed with squamous cell carcinoma arising from long standing chronic osteomyelitis of the tibia. Our case indicates that radiologists should consider the possibility of malignant transformation in patients with untreated chronic osteomyelitis, with enhancing soft tissue mass invading and extending through underlying bone cortex and medulla on MR imaging.

  3. Influence of omega-3 fatty acid status on the way rats adapt to chronic restraint stress.

    Directory of Open Access Journals (Sweden)

    Marie Hennebelle

    Full Text Available Omega-3 fatty acids are important for several neuronal and cognitive functions. Altered omega-3 fatty acid status has been implicated in reduced resistance to stress and mood disorders. We therefore evaluated the effects of repeated restraint stress (6 h/day for 21 days on adult rats fed omega-3 deficient, control or omega-3 enriched diets from conception. We measured body weight, plasma corticosterone and hippocampus glucocorticoid receptors and correlated these data with emotional and depression-like behaviour assessed by their open-field (OF activity, anxiety in the elevated-plus maze (EPM, the sucrose preference test and the startle response. We also determined their plasma and brain membrane lipid profiles by gas chromatography. Repeated restraint stress caused rats fed a control diet to lose weight. Their plasma corticosterone increased and they showed moderate behavioural changes, with increases only in grooming (OF test and entries into the open arms (EPM. Rats fed the omega-3 enriched diet had a lower stress-induced weight loss and plasma corticosterone peak, and reduced grooming. Rats chronically lacking omega-3 fatty acid exhibited an increased startle response, a stress-induced decrease in locomotor activity and exaggerated grooming. The brain omega-3 fatty acids increased as the dietary omega-3 fatty acids increased; diets containing preformed long-chain omega-3 fatty acid were better than diets containing the precursor alpha-linolenic acid. However, the restraint stress reduced the amounts of omega-3 incorporated. These data showed that the response to chronic restraint stress was modulated by the omega-3 fatty acid supply, a dietary deficiency was deleterious while enrichment protecting against stress.

  4. Correlation between myeloid-derived suppressor cells and gastric cancer begin with chronic gastritis

    Institute of Scientific and Technical Information of China (English)

    朱立宁

    2012-01-01

    Objective To investigate the correlation between the ratio change of circulating myeloid-derived suppressor cells(MDSCs) and cellular immune function in healthy volunteers,chronic gastritis patients,gastric intraepithelial neoplasia patients and gastric cancer patients

  5. Allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia:a report of 12 patients

    Institute of Scientific and Technical Information of China (English)

    孙于谦

    2013-01-01

    Objective To retrospectively review the efficacy of allogeneic hematopoietic stem cell transplantation(allo-HSCT)for chronic myelomonocytic leukemia(CMML).Methods The engraftment,graft versus host disease(GVHD)

  6. Specific cytotoxic T-cell immune responses against autoantigens recognized by chronic lymphocytic leukaemia cells.

    Science.gov (United States)

    Zaleska, Joanna; Skorka, Katarzyna; Zajac, Malgorzata; Karczmarczyk, Agnieszka; Karp, Marta; Tomczak, Waldemar; Hus, Marek; Wlasiuk, Paulina; Giannopoulos, Krzysztof

    2016-08-01

    Mounting evidence suggests that autoreactivity and inflammatory processes are involved in the pathogenesis of chronic lymphocytic leukaemia (CLL). Cytoskeletal proteins, including non-muscle myosin heavy chain IIA (MYHIIA), vimentin (VIM) and cofilin-1 (CFL1), exposed on the surface of apoptotic cells have been identified as autoantigens that are recognized by the specific B-cell receptors of the CLL cells. In 212 CLL patients analysed with quantitative reverse transcriptase-polymerase chain reaction we found CFL1 overexpression and low expression of MYH9 in comparison with healthy volunteers. We detected specific cytotoxic immune responses for peptides derived from MYHIIA in 66·7%, VIM in 87·5% and CFL1 in 62·5% CLL patients in an Enzyme-Linked ImmunoSpot assay. Low frequencies of autoreactive peptide-specific T cells were detected against MYHIIA, VIM and CFL1 in CLL patients ex vivo; most of the detected cells had an effector-memory phenotype. Our findings support the existence of cytotoxic immune responses against three autoantigens that have been identified as targets of CLL clonotypic B-cell receptors. The presence of autoreactive CD8(+) T cells against MYHIIA, VIM and CFL1 in CLL patients indicates the involvement of antigen-specific autoreactive T cells in the pathogenesis of CLL.

  7. Ex vivo transcriptional profiling reveals a common set of genes important for the adaptation of Pseudomonas aeruginosa to chronically infected host sites

    NARCIS (Netherlands)

    Bielecki, P.; Komor, U.; Bielecka, A.; Müsken, M.; Puchalka, J.; Pletz, M.W.; Ballmann, M.; Martins Dos Santos, V.A.P.; Weiss, S.; Häussler, S.

    2013-01-01

    The opportunistic bacterium Pseudomonas aeruginosa is a major nosocomial pathogen causing both devastating acute and chronic persistent infections. During the course of an infection, P.¿ aeruginosa rapidly adapts to the specific conditions within the host. In the present study, we aimed at the ident

  8. Intermittent and continuous high-intensity exercise training induce similar acute but different chronic muscle adaptations.

    Science.gov (United States)

    Cochran, Andrew J R; Percival, Michael E; Tricarico, Steven; Little, Jonathan P; Cermak, Naomi; Gillen, Jenna B; Tarnopolsky, Mark A; Gibala, Martin J

    2014-05-01

    High-intensity interval training (HIIT) performed in an 'all-out' manner (e.g. repeated Wingate tests) is a time-efficient strategy to induce skeletal muscle remodelling towards a more oxidative phenotype. A fundamental question that remains unclear, however, is whether the intermittent or 'pulsed' nature of the stimulus is critical to the adaptive response. In study 1, we examined whether the activation of signalling cascades linked to mitochondrial biogenesis was dependent on the manner in which an acute high-intensity exercise stimulus was applied. Subjects performed either four 30 s Wingate tests interspersed with 4 min of rest (INT) or a bout of continuous exercise (CONT) that was matched for total work (67 ± 7 kJ) and which required ∼4 min to complete as fast as possible. Both protocols elicited similar increases in markers of adenosine monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase activation, as well as Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA expression (main effects for time, P ≤ 0.05). In study 2, we determined whether 6 weeks of the CONT protocol (3 days per week) would increase skeletal muscle mitochondrial content to a similar extent to what we have previously reported after 6 weeks of INT. Despite similar acute signalling responses to the CONT and INT protocols, training with CONT did not increase the maximal activity or protein content of a range of mitochondrial markers. However, peak oxygen uptake was higher after CONT training (from 45.7 ± 5.4 to 48.3 ± 6.5 ml kg(-1) min(-1); P muscle adaptations to low-volume, all-out HIIT. Despite the lack of skeletal muscle mitochondrial adaptations, our data show that a training programme based on a brief bout of high-intensity exercise, which lasted <10 min per session including warm-up, and performed three times per week for 6 weeks, improved peak oxygen uptake in young healthy subjects.

  9. Two cases of basal cell carcinoma arising from chronic radiation dermatitis

    Energy Technology Data Exchange (ETDEWEB)

    Wakamori, Takeshi; Takenaka, Hideya; Ueda, Eiichiro; Katoh, Norito; Kishimoto, Saburo [Kyoto Prefectural Univ. of Medicine (Japan)

    2003-04-01

    A 48-year-old female and a 51-year-old male with basal cell carcinoma (BCC) arising from chronic radiation dermatitis are reviewed. They are treated with radiotherapy for hemangioma on their right cheek in their childhood. Review in the literature showed high incidence of the histological diagnosis of malignant skin tumors arising from chronic radiation dermatitis are follows: squamous cell carcinoma (SCC), BCC, sarcoma, and Bowen's disease. (author)

  10. Genome and low-iron response of an oceanic diatom adapted to chronic iron limitation

    Science.gov (United States)

    2012-01-01

    Background Biogeochemical elemental cycling is driven by primary production of biomass via phototrophic phytoplankton growth, with 40% of marine productivity being assigned to diatoms. Phytoplankton growth is widely limited by the availability of iron, an essential component of the photosynthetic apparatus. The oceanic diatom Thalassiosira oceanica shows a remarkable tolerance to low-iron conditions and was chosen as a model for deciphering the cellular response upon shortage of this essential micronutrient. Results The combined efforts in genomics, transcriptomics and proteomics reveal an unexpected metabolic flexibility in response to iron availability for T. oceanica CCMP1005. The complex response comprises cellular retrenchment as well as remodeling of bioenergetic pathways, where the abundance of iron-rich photosynthetic proteins is lowered, whereas iron-rich mitochondrial proteins are preserved. As a consequence of iron deprivation, the photosynthetic machinery undergoes a remodeling to adjust the light energy utilization with the overall decrease in photosynthetic electron transfer complexes. Conclusions Beneficial adaptations to low-iron environments include strategies to lower the cellular iron requirements and to enhance iron uptake. A novel contribution enhancing iron economy of phototrophic growth is observed with the iron-regulated substitution of three metal-containing fructose-bisphosphate aldolases involved in metabolic conversion of carbohydrates for enzymes that do not contain metals. Further, our data identify candidate components of a high-affinity iron-uptake system, with several of the involved genes and domains originating from duplication events. A high genomic plasticity, as seen from the fraction of genes acquired through horizontal gene transfer, provides the platform for these complex adaptations to a low-iron world. PMID:22835381

  11. Subcellular adaptation of the human diaphragm in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Orozco-Levi, M; Gea, J; Lloreta, J L; Félez, M; Minguella, J; Serrano, S; Broquetas, J M

    1999-02-01

    Pulmonary hyperinflation impairs the function of the diaphragm in patients with chronic obstructive pulmonary disease (COPD). However, it has been recently demonstrated that the muscle can counterbalance this deleterious effect, remodelling its structure (i.e. changing the proportion of different types of fibres). The aim of this study was to investigate whether the functional impairment present in COPD patients can be associated with structural subcellular changes of the diaphragm. Twenty individuals (60+/-9 yrs, 11 COPD patients and 9 subjects with normal spirometry) undergoing thoracotomy were included. Nutritional status and respiratory function were evaluated prior to surgery. Then, small samples of the costal diaphragm were obtained and processed for electron microscopy analysis. COPD patients showed a mean forced expiratory volume in one second (FEV1) of 60+/-9% predicted, a higher concentration of mitochondria (n(mit)) in their diaphragm than controls (0.62+/-0.16 versus 0.46+/-0.16 mitochondrial transections (mt) x microm(-2), p37%) disclosed not only a higher n(mit) (0.63+/-0.17 versus 0.43+/-0.07 mt x microm(-2), p<0.05) but shorter sarcomeres (L(sar)) than subjects without this functional abnormality (2.08+/-0.16 to 2.27+/-0.15 microm, p<0.05). Glycogen stores were similar in COPD and controls. The severity of airways obstruction (i.e. FEV1) was associated with n(mit) (r=-0.555, p=0.01), while the amount of air trapping (i.e. RV/TLC) was found to correlate with both n(mit) (r=0.631, p=0.005) and L(sar) (r=-0.526, p<0.05). Finally, maximal inspiratory pressure (PI,max) inversely correlated with n(mit) (r=-0.547, p=0.01). In conclusion, impairment in lung function occurring in patients with chronic obstructive pulmonary disease is associated with subcellular changes in their diaphragm, namely a shortening in the length of sarcomeres and an increase in the concentration of mitochondria. These changes form a part of muscle remodelling, probably contributing

  12. Giant cell arteritis associated with chronic active Epstein-Barr virus infection

    Directory of Open Access Journals (Sweden)

    A. Giardina

    2013-03-01

    Full Text Available Giant cell arteritis is an inflammatory vasculopathy that preferentially affects medium-sized and large arteries. A viral cause has been suspected but not confirmed in polymyalgia rheumatica and giant-cell arteritis. We report the case of a 81-year-old female who suffered from chronic active Epstein-Barr virus infection and developed giant cell temporal arteritis.

  13. Effect of Chronic Exposure to Acidic Environment on Radiosensitivity of Gliosarcoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sora; Kim, Eunhee [Seoul National Univ., Seoul (Korea, Republic of)

    2014-05-15

    In this study, the chronic exposure of cells to acid culture medium, prior or posterior to irradiation, has been investigated for its effect on clonogenic cell survival. Unconventional high-dose radiation therapy, such as SRS, SBRT and MRT, may cause severe vascular damage in tumors, thereby a number of tumor cells facing chronic hypoxia and thus acidosis. According to our observation, gliosarcoma cells become more vulnerable to radiation damage by chronic exposure to acidic condition before irradiation. The longer the preirradiation exposure is, the more vulnerable to radiation damage the cells become. However, the repair of PLD by post-irradiation exposure to acid medium is efficient enough to eliminate the difference in number of the cells carrying PLDs due to different durations of preirradiation exposure to acidic condition.

  14. Metabolic programming in chronically stimulated T cells: Lessons from cancer and viral infections.

    Science.gov (United States)

    Bettonville, Marie; D'Aria, Stefania; Braun, Michel Y

    2016-07-01

    T-cell metabolism is central to the shaping of a successful immune response. However, there are pathological situations where T cells are rendered dysfunctional and incapable of eliminating infected or transformed cells. Here, we review the current knowledge on T-cell metabolism and how persistent antigenic stimulation, in the form of cancer and chronic viral infection, modifies both metabolic and functional pathways in T cells. PMID:27271222

  15. Hematopoietic Stem and Immune Cells in Chronic HIV Infection

    OpenAIRE

    Jielin Zhang; Clyde Crumpacker

    2015-01-01

    Hematopoietic stem cell (HSC) belongs to multipotent adult somatic stem cells. A single HSC can reconstitute the entire blood system via self-renewal, differentiation into all lineages of blood cells, and replenishment of cells lost due to attrition or disease in a person's lifetime. Although all blood and immune cells derive from HSC, immune cells, specifically immune memory cells, have the properties of HSC on self-renewal and differentiation into lineage effector cells responding to the in...

  16. The importance of trabecular hypertrophy in right ventricular adaptation to chronic pressure overload.

    Science.gov (United States)

    van de Veerdonk, Mariëlle C; Dusoswa, Sophie A; Marcus, J Tim; Bogaard, Harm-Jan; Spruijt, Onno; Kind, Taco; Westerhof, Nico; Vonk-Noordegraaf, Anton

    2014-02-01

    To assess the contribution of right ventricular (RV) trabeculae and papillary muscles (TPM) to RV mass and volumes in controls and patients with pulmonary arterial hypertension (PAH). Furthermore, to evaluate whether TPM shows a similar response as the RV free wall (RVFW) to changes in pulmonary artery pressure (PAP) during follow-up. 50 patients underwent cardiac magnetic resonance (CMR) and right heart catheterization at baseline and after one-year follow-up. Furthermore 20 controls underwent CMR. RV masses were assessed with and without TPM. TPM constituted a larger proportion of total RV mass and RV end-diastolic volume (RVEDV) in PAH than in controls (Mass: 35 ± 7 vs. 25 ± 5 %; p TPM mass was related to the RVFW mass in patients (baseline: R = 0.65; p TPM from the assessment resulted in altered RV mass, volumes and function than when included (all p TPM mass (β = 0.44; p = 0.004) but not the changes in RVFW mass (p = 0.095) were independently related to changes in PAP during follow-up. RV TPM showed a larger contribution to total RV mass in PAH (~35 %) compared to controls (~25 %). Inclusion of TPM in the analyses significantly influenced the magnitude of the RV volumes and mass. Furthermore, TPM mass was stronger related to changes in PAP than RVFW mass. Our results implicate that TPM are important contributors to RV adaptation during pressure overload and cannot be neglected from the RV assessment.

  17. Host culling as an adaptive management tool for chronic wasting disease in white-tailed deer: a modelling study.

    Science.gov (United States)

    Wasserberg, Gideon; Osnas, Erik E; Rolley, Robert E; Samuel, Michael D

    2009-04-01

    Emerging wildlife diseases pose a significant threat to natural and human systems. Because of real or perceived risks of delayed actions, disease management strategies such as culling are often implemented before thorough scientific knowledge of disease dynamics is available. Adaptive management is a valuable approach in addressing the uncertainty and complexity associated with wildlife disease problems and can be facilitated by using a formal model.We developed a multi-state computer simulation model using age, sex, infection-stage, and seasonality as a tool for scientific learning and managing chronic wasting disease (CWD) in white-tailed deer Odocoileus virginianus. Our matrix model used disease transmission parameters based on data collected through disease management activities. We used this model to evaluate management issues on density- (DD) and frequency-dependent (FD) transmission, time since disease introduction, and deer culling on the demographics, epizootiology, and management of CWD.Both DD and FD models fit the Wisconsin data for a harvested white-tailed deer population, but FD was slightly better. Time since disease introduction was estimated as 36 (95% CI, 24-50) and 188 (41->200) years for DD and FD transmission, respectively. Deer harvest using intermediate to high non-selective rates can be used to reduce uncertainty between DD and FD transmission and improve our prediction of long-term epidemic patterns and host population impacts. A higher harvest rate allows earlier detection of these differences, but substantially reduces deer abundance.Results showed that CWD has spread slowly within Wisconsin deer populations, and therefore, epidemics and disease management are expected to last for decades. Non-hunted deer populations can develop and sustain a high level of infection, generating a substantial risk of disease spread. In contrast, CWD prevalence remains lower in hunted deer populations, but at a higher prevalence the disease competes with

  18. An aggressive merkel cell carcinoma in a patient with chronic renal failure

    Directory of Open Access Journals (Sweden)

    Sevda Gizlenti

    2014-12-01

    Full Text Available Merkel cell carcinoma (MCC is a rare cutaneous tumor arising from neuroendocrine cells and Merkel cells. Early diagnosis and treatment is important because of its aggressive course. We here report a 61 years old man with chronic renal failure, 3x5 cm mass on his right leg and inguinal-paraaortic lymph node metastases and resulting in death. MCC in the literature of the AIDS disease, organ transplantation, immunosuppressive therapy areas, and additional malignancies (multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and melanoma have been reported in patients with increased incidence. Up to date a patient with renal transplantation and Merkel cell carcinoma have been reported in the literature, Merkel cell carcinoma with chronic renal failure have not been reported.

  19. Mechanisms of β-cell functional adaptation to changes in workload.

    Science.gov (United States)

    Wortham, M; Sander, M

    2016-09-01

    Insulin secretion must be tightly coupled to nutritional state to maintain blood glucose homeostasis. To this end, pancreatic β-cells sense and respond to changes in metabolic conditions, thereby anticipating insulin demands for a given physiological context. This is achieved in part through adjustments of nutrient metabolism, which is controlled at several levels including allosteric regulation, post-translational modifications, and altered expression of metabolic enzymes. In this review, we discuss mechanisms of β-cell metabolic and functional adaptation in the context of two physiological states that alter glucose-stimulated insulin secretion: fasting and insulin resistance. We review current knowledge of metabolic changes that occur in the β-cell during adaptation and specifically discuss transcriptional mechanisms that underlie β-cell adaptation. A more comprehensive understanding of how β-cells adapt to changes in nutrient state could identify mechanisms to be co-opted for therapeutically modulating insulin secretion in metabolic disease. PMID:27615135

  20. Effects of Arachidonic Acid Supplementation on Acute Anabolic Signaling and Chronic Functional Performance and Body Composition Adaptations.

    Directory of Open Access Journals (Sweden)

    Eduardo O De Souza

    Full Text Available The primary purpose of this investigation was to examine the effects of arachidonic acid (ARA supplementation on functional performance and body composition in trained males. In addition, we performed a secondary study looking at molecular responses of ARA supplementation following an acute exercise bout in rodents.Thirty strength-trained males (age: 20.4 ± 2.1 yrs were randomly divided into two groups: ARA or placebo (i.e. CTL. Then, both groups underwent an 8-week, 3-day per week, non-periodized training protocol. Quadriceps muscle thickness, whole-body composition scan (DEXA, muscle strength, and power were assessed at baseline and post-test. In the rodent model, male Wistar rats (~250 g, ~8 weeks old were pre-fed with either ARA or water (CTL for 8 days and were fed the final dose of ARA prior to being acutely strength trained via electrical stimulation on unilateral plantar flexions. A mixed muscle sample was removed from the exercised and non-exercised leg 3 hours post-exercise.Lean body mass (2.9%, p<0.0005, upper-body strength (8.7%, p<0.0001, and peak power (12.7%, p<0.0001 increased only in the ARA group. For the animal trial, GSK-β (Ser9 phosphorylation (p<0.001 independent of exercise and AMPK phosphorylation after exercise (p-AMPK less in ARA, p = 0.041 were different in ARA-fed versus CTL rats.Our findings suggest that ARA supplementation can positively augment strength-training induced adaptations in resistance-trained males. However, chronic studies at the molecular level are required to further elucidate how ARA combined with strength training affect muscle adaptation.

  1. Stochastic adaptation and fold-change detection: from single-cell to population behavior

    Directory of Open Access Journals (Sweden)

    Leier André

    2011-02-01

    Full Text Available Abstract Background In cell signaling terminology, adaptation refers to a system's capability of returning to its equilibrium upon a transient response. To achieve this, a network has to be both sensitive and precise. Namely, the system must display a significant output response upon stimulation, and later on return to pre-stimulation levels. If the system settles at the exact same equilibrium, adaptation is said to be 'perfect'. Examples of adaptation mechanisms include temperature regulation, calcium regulation and bacterial chemotaxis. Results We present models of the simplest adaptation architecture, a two-state protein system, in a stochastic setting. Furthermore, we consider differences between individual and collective adaptive behavior, and show how our system displays fold-change detection properties. Our analysis and simulations highlight why adaptation needs to be understood in terms of probability, and not in strict numbers of molecules. Most importantly, selection of appropriate parameters in this simple linear setting may yield populations of cells displaying adaptation, while single cells do not. Conclusions Single cell behavior cannot be inferred from population measurements and, sometimes, collective behavior cannot be determined from the individuals. By consequence, adaptation can many times be considered a purely emergent property of the collective system. This is a clear example where biological ergodicity cannot be assumed, just as is also the case when cell replication rates are not homogeneous, or depend on the cell state. Our analysis shows, for the first time, how ergodicity cannot be taken for granted in simple linear examples either. The latter holds even when cells are considered isolated and devoid of replication capabilities (cell-cycle arrested. We also show how a simple linear adaptation scheme displays fold-change detection properties, and how rupture of ergodicity prevails in scenarios where transitions between

  2. Perturbed T cell IL7 receptor-signaling in chronic Chagas disease

    Science.gov (United States)

    Albareda, M. Cecilia; Perez-Mazliah, Damián; Natale, M. Ailén; Castro-Eiro, Melisa; Alvarez, María G.; Viotti, Rodolfo; Bertocchi, Graciela; Lococo, Bruno; Tarleton, Rick L; Laucella, Susana A.

    2015-01-01

    We have previously demonstrated that immune responses in subjects with chronic Trypanosoma cruzi infection display features common to other persistent infections with signs of T cell exhaustion. Alterations in cytokine receptor signal transduction have emerged as one of the cell-intrinsic mechanisms of T cell exhaustion. Herein, we performed an analysis of the expression of IL-7R components (CD127 and CD132) on CD4+ and CD8+ T cells, and evaluated IL-7-dependent signaling events in patients at different clinical stages of chronic chagasic heart disease. Subjects with no signs of cardiac disease showed a decrease in CD127+CD132+ cells and a reciprocal gain of CD127-CD132+ in CD8+ and CD4+ T cells compared to either patients exhibiting heart enlargement or uninfected controls. T. cruzi infection, in vitro, was able to stimulate the downregulation of CD127 and the upregulation of CD132 on T cells. IL-7-induced phosphorylation of STAT5 as well as Bcl-2 and CD25 expression were lower in T. cruzi-infected subjects compared with uninfected controls. The serum levels of IL-7 was also increased in chronic chagasic patients. The present study highlights perturbed IL-7/IL-7R T cell signaling through STAT5 as a potential mechanism of T cell exhaustion in chronic T. cruzi infection. PMID:25769928

  3. Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia

    OpenAIRE

    Hiroko Endo; Hiroaki Okuyama; Masayuki Ohue; Masahiro Inoue

    2014-01-01

    A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these c...

  4. Chronic morphine induces premature mitosis of proliferating cells in the adult mouse subgranular zone.

    Science.gov (United States)

    Mandyam, Chitra D; Norris, Rebekah D; Eisch, Amelia J

    2004-06-15

    The birth of cells with neurogenic potential in the adult brain is assessed commonly by detection of exogenous S phase markers, such as bromodeoxyuridine (BrdU). Analysis of other phases of the cell cycle, however, can provide insight into how external factors, such as opiates, influence the cycling of newly born cells. To this end, we examined the expression of two endogenous cell cycle markers in relation to BrdU: proliferating cell nuclear antigen (PCNA) and phosphorylated histone H3 (pHisH3). Two hours after one intraperitoneal BrdU injection, BrdU-, PCNA-, and pHisH3-immunoreactive (IR) cells exhibited similar distribution in the adult mouse subgranular zone (SGZ). Quantitative analysis within the SGZ revealed a relative abundance of cells labeled for PCNA > BrdU > pHisH3. Similar to our reports in rat SGZ, chronic morphine treatment decreased BrdU- and PCNA-IR cells in mouse SGZ by 28 and 38%, respectively. We also show that pHisH3-IR cells are influenced by chronic morphine to a greater extent (58% decrease) than are BrdU- or PCNA-IR cells. Cell cycle phase analysis of SGZ BrdU-IR cells using triple labeling for BrdU, PCNA, and pHisH3 revealed premature mitosis in chronic morphine-treated mice. These results suggest that morphine-treated mice have a shorter Gap2/mitosis (G(2)/M) phase when compared to sham-treated mice. These findings demonstrate the power of using a combination of exogenous and endogenous cell cycle markers and nuclear morphology to track proliferating cells through different phases of the cell cycle and to reveal the regulation of cell cycle phase by chronic morphine. PMID:15160390

  5. Activity of mesenchymal stem cells in therapies for chronic skin wound healing

    OpenAIRE

    Nuschke, Austin

    2013-01-01

    Chronic or non-healing skin wounds present an ongoing challenge in advanced wound care, particularly as the number of patients increases while technology aimed at stimulating wound healing in these cases remains inefficient. Mesenchymal stem cells (MSCs) have proved to be an attractive cell type for various cell therapies due to their ability to differentiate into various cell lineages, multiple donor tissue types, and relative resilience in ex-vivo expansion, as well as immunomodulatory effe...

  6. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival.

    Science.gov (United States)

    Utzschneider, Daniel T; Alfei, Francesca; Roelli, Patrick; Barras, David; Chennupati, Vijaykumar; Darbre, Stephanie; Delorenzi, Mauro; Pinschewer, Daniel D; Zehn, Dietmar

    2016-08-22

    Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment.

  7. Chronic rhinosinusitis pathogenesis.

    Science.gov (United States)

    Stevens, Whitney W; Lee, Robert J; Schleimer, Robert P; Cohen, Noam A

    2015-12-01

    There are a variety of medical conditions associated with chronic sinonasal inflammation, including chronic rhinosinusitis (CRS) and cystic fibrosis. In particular, CRS can be divided into 2 major subgroups based on whether nasal polyps are present or absent. Unfortunately, clinical treatment strategies for patients with chronic sinonasal inflammation are limited, in part because the underlying mechanisms contributing to disease pathology are heterogeneous and not entirely known. It is hypothesized that alterations in mucociliary clearance, abnormalities in the sinonasal epithelial cell barrier, and tissue remodeling all contribute to the chronic inflammatory and tissue-deforming processes characteristic of CRS. Additionally, the host innate and adaptive immune responses are also significantly activated and might be involved in pathogenesis. Recent advancements in the understanding of CRS pathogenesis are highlighted in this review, with special focus placed on the roles of epithelial cells and the host immune response in patients with cystic fibrosis, CRS without nasal polyps, or CRS with nasal polyps. PMID:26654193

  8. STUDY ON INFLAMMATORY CELLS IN BALF OF SMOKE-INDUCED CHRONIC BRONCHITIS RAT MODEL

    Institute of Scientific and Technical Information of China (English)

    李庆云; 黄绍光; 吴华成; 程齐俭; 项轶; 万欢英

    2004-01-01

    Objective To establish a smoke-induced chronic bronchitis rat model and evaluate the pathological change semi-quantitatively, and study the characteristics of the inflammatory cells in the bronchoalveolar lavage fluid (BALF) in various stages. Methods Chronic bronchitis sequential rat model was established by passively inhaling smoke mixture. Experiments were performed in 30 young male Sprague-Dawley rats, which comprised 5 groups in random, i.e.,4 chronic bronchitis model groups and I control group. After stained with hematoxylin and eosin, the specimens were studied by semi-quantitative method to evaluate the morphologic changes in various stages. Meanwhile, the inflammatory cells of the BALF and the activity of myeloperoxidase ( MPO ) of lung tissue were analysed. Results During the process of the chronic bronchitis, the pathologic score was increasing as time went on, and the typical morphologic changes of chronic bronchitis emerged in the group 7 weeks. The total number of inflammatory cells in BALF was increasing as time went on, correlated with the pathologic scores ( P < 0. 01 ).And the percentage of lymphocyte increased as well as positively correlated with pathologic scores ( P < 0. 05 ),whereas that of macrophage decreased and negatively correlated with pathologic scores (P <0. 05). The MPO lever of lung tissue was correlated with the pathologic scores ( P < 0. 01 ). But the percentage of the neutrophil in the BALF was just in a high level during the first week, then it maintained relatively lower. Conclusion Smoke-induced chronic bronchitis is a slowly progressive inflammation process. The model we established is convenient and simple for the longitudinal study on the inflammatory process of chronic bronchitis and the therapy in the early stage. The semi-quantitative evaluation for the pathological change is with much more value. During the inflammatory sequential process of early stage of chronic bronchitis, the cellular characteristics are

  9. Successful Outcome of Chronic Intrahepatic Cholestasis in an Adult Patient with Sickle Cell/β+ Thalassemia

    Directory of Open Access Journals (Sweden)

    Efthymia Vlachaki

    2014-01-01

    Full Text Available Sickle cell/β+ thalassemia (Hb S/β+thal is considered as a variant form of sickle cell disease. Acute episodes of vasoocclusive pain crisis are characteristic for sickle cell disorders and may be complicated by an acute or chronic life-threatening organ dysfunction. Chronic intrahepatic cholestasis is a rare and severe complication in sickle cell disease, characterized by marked hyperbilirubinemia and acute hepatic failure with an often fatal course. Despite the fact that patients with Hb S/β+thal usually have a mild type of disease, herein we describe an interesting case of chronic intrahepatic cholestasis with successful outcome in an adult patient with Hb S/β+thal.

  10. A Robot-Assisted Cell Manipulation System with an Adaptive Visual Servoing Method

    OpenAIRE

    Yu Xie; Feng Zeng; Wenming Xi; Yunlei Zhou; Houde Liu; Mingliang Chen

    2016-01-01

    Robot-assisted cell manipulation is gaining attention for its ability in providing high throughput and high precision cell manipulation for the biological industry. This paper presents a visual servo microrobotic system for cell microinjection. We investigated the automatic cell autofocus method that reduced the complexity of the system. Then, we produced an adaptive visual processing algorithm to detect the location of the cell and micropipette toward the uneven illumination problem. Fourtee...

  11. ADAPTIVE LAYERED CARTESIAN CUT CELL METHOD FOR THE UNSTRUCTURED HEXAHEDRAL GRIDS GENERATION

    Institute of Scientific and Technical Information of China (English)

    WU Peining; TAN Jianrong; LIU Zhenyu

    2007-01-01

    Adaptive layered Cartesian cut cell method is presented to solve the difficulty of the unstructured hexahedral anisotropic Cartesian grids generation from the complex CAD model. Vertex merging algorithm based on relaxed AVL tree is investigated to construct topological structure for stereo lithography (STL) files, and a topology-based self-adaptive layered slicing algorithm with special features control strategy is brought forward. With the help of convex hull, a new points-in-polygon method is employed to improve the Cartesian cut cell method. By integrating the self-adaptive layered slicing algorithm and the improved Cartesian cut cell method, the adaptive layered Cartesian cut cell method gains the volume data of the complex CAD model in STL file and generates the unstructured hexahedral anisotropic Cartesian grids.

  12. Immunohistochemical study of hepatic oval cells in human chronic viral hepatitis

    Institute of Scientific and Technical Information of China (English)

    Xiong Ma; De Kai Qiu; Yan Shen Peng

    2001-01-01

    AIM To detect immunohistochemically the presence of oval cells in chronic viral hepatitis with antibody against c-kit.METHODS We detected oval cells in paraffin-embedded liver sections of 3 normal controls and 26 liver samples from patients with chronic viral hepatitis, using immunohistochemistry with antibodies against c-kit, π-class glutathione Stransferase ( Tr-GST ) and cytokeratins 19(CK19).RESULTS Oval cells were not observed in normal livers. In chronic viral hepatitis, hepatic oval cells were located predominantly in the periportal . region and fibrosis septa,characterized by an ovoid nucleus, small size,and scant cytoplasm. Antibody against stem cell factor receptor, c-kit, had higher sensitivity and specificity than π-GST and CK19. About 50% -70% of c-kit positive oval cells were stained positively for either π-GST or CK19.CONCLUSION Oval cells are frequently detected in human livers with chronic viral hepatitis, suggesting that oval cell proliferation is associated with the liver regeneration in this condition.

  13. The effect of chronic calcium treatment on thyroid C cells in ovariectomized rats.

    Science.gov (United States)

    Filipović, B; Jurjević, B Sosić; Stojanoski, M Manojlović; Nestorović, N; Milosević, V; Sekulić, M

    2005-05-27

    The purpose of this study was to investigate the influence of chronic calcium treatment on the structure and function of thyroid C cells in ovariectomzed adult female rats. Eighteen 3-month-old, female Wistar rats were divided into three groups. The first group was used as the sham-operated control, and the other two were surgically ovariectomized (Ovx). One month after gonadectomy, one group of Ovx rats was injected with 28.55 mg Ca-glucoheptonate (Ca)/kg b.w., while the other two groups were chronically treated with vehicle alone (Ovx and sham control). Two months after surgery, the animals were killed. In the thyroid C cells, calcitonin (CT) was localized with the peroxidase-antiperoxidase method. Stereology was used to evaluate morphometric changes in the volume of C cells, their nuclei and relative volume density. The number of C cells per unit area was calculated. Serum CT content was determined by radioimmunoassay. After chronic Ca treatment C cells were numerous with darker cytoplasm than in C cells of sham-operated control animals, but more degranulated than the corresponding cells of Ovx rats. Their volume was significantly decreased by 14% (p Calcium treatment of Ovx rats led to a 32% increase of serum CT concentration in relation to untreated Ovx animals. These results suggest that chronic Ca treatment of Ovx female rats positively affected CT release from thyroid C cells, without any significant changes in morphometric parameters.

  14. Study on Tibetan Chicken embryonic adaptability to chronic hypoxia by revealing differential gene expression in heart tissue

    Institute of Scientific and Technical Information of China (English)

    LI Mei; ZHAO ChunJiang

    2009-01-01

    Oxygen concentration is essential for appropriate metabolism. Hypoxia can exert a significant impact on physiological alteration of the cell and organism. Tibetan Chicken (Gallus gallus) is a Chinese in-digenous breed inhabiting in Tibetan areas, which is also a chicken breed living at high altitude for the longest time in the world. It has developed an adaptive mechanism to hypoxia, which is demonstrated by that Tibetan Chicken has much higher hatchability than low-land chicken breeds in high-altitude areas of Tibet. In the present study, Tibetan Chicken fertilized full sib eggs were incubated up to Ham-burger-Hamilton stage 43 under 13% and 21% oxygen concentration, respectively. Shouguang Chicken and Dwarf Recessive White Chicken were used as control groups. The hearts in all of the 3 chicken breeds under hypoxic and normoxic conditions were isolated and hybridized to GeneChip Chicken Genome Array to study molecular mechanisms underlying the adaptation to high altitude of Tibetan Chicken. As a result, 50 transcripts highly expressed in hypoxia are screened out. Among up-regulated genes, some are involved in the gone ontology (GO) such as cell growth, cell difference, muscle con-traction and signal transduction. However, the expression levels of 21 transcripts are lower in hypoxia than those in normoxia. Some down-regulated genes take part in cell communication, ion transport, protein amino acid phosphorylation and signal transduction. Interestingly, gene enrichment analyses of these differential gone expressions are mainly associated with immune system response and ion channel activity in response to stimulus. Moreover, the transcriptional expression profiles analyzed by hierarchical clustering and CPP-SOM software in all of the 3 different chicken breeds revealed that TI-betan Chicken is much closely related to Shouguang Chicken rather than Dwarf Recessive White Chicken. In addition, 12 transcripts of Tibetan Chicken breed-specific expressed genes were

  15. Study on Tibetan Chicken embryonic adaptability to chronic hypoxia by revealing differential gene expression in heart tissue

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Oxygen concentration is essential for appropriate metabolism.Hypoxia can exert a significant impact on physiological alteration of the cell and organism.Tibetan Chicken(Gallus gallus) is a Chinese indigenous breed inhabiting in Tibetan areas,which is also a chicken breed living at high altitude for the longest time in the world.It has developed an adaptive mechanism to hypoxia,which is demonstrated by that Tibetan Chicken has much higher hatchability than low-land chicken breeds in high-altitude areas of Tibet.In the present study,Tibetan Chicken fertilized full sib eggs were incubated up to Hamburger-Hamilton stage 43 under 13% and 21% oxygen concentration,respectively.Shouguang Chicken and Dwarf Recessive White Chicken were used as control groups.The hearts in all of the 3 chicken breeds under hypoxic and normoxic conditions were isolated and hybridized to Genechip Chicken Genome Array to study molecular mechanisms underlying the adaptation to high altitude of Tibetan Chicken.As a result,50 transcripts highly expressed in hypoxia are screened out.Among up-regulated genes,some are involved in the gene ontology(GO) such as cell growth,cell difference,muscle contraction and signal transduction.However,the expression levels of 21 transcripts are lower in hypoxia than those in normoxia.Some down-regulated genes take part in cell communication,ion transport,protein amino acid phosphorylation and signal transduction.Interestingly,gene enrichment analyses of these differential gene expressions are mainly associated with immune system response and ion channel activity in response to stimulus.Moreover,the transcriptional expression profiles analyzed by hierarchical clustering and CPP-SOM software in all of the 3 different chicken breeds revealed that Tibetan Chicken is much closely related to Shouguang Chicken rather than Dwarf Recessive White Chicken.In addition,12 transcripts of Tibetan Chicken breed-specific expressed genes were identified,which seem to result in a

  16. Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: A surrogate marker for NK-cell clonality

    NARCIS (Netherlands)

    P. Bárcena (Paloma); M. Jara-Acevedo (M.); M.D. Tabernero; A. López (Antonio); M.-L. Sánchez (M.); A.C. García-Montero (Andrés); N. Muñoz-García (Noemí); M.B. Vidriales (M.); A. Paiva (Artur); Q. Lecrevisse (Quentin); M. Lima (Margarida); A.W. Langerak (Ton); S. Böttcher (Stephan); J.J.M. van Dongen (Jacques); A. Orfao (Alberto); J. Almeida (Julia)

    2015-01-01

    textabstractCurrently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for

  17. New method for selection of hydrogen peroxide adapted bifidobacteria cells using continuous culture and immobilized cell technology

    Directory of Open Access Journals (Sweden)

    Meile Leo

    2010-07-01

    Full Text Available Abstract Background Oxidative stress can severely compromise viability of bifidobacteria. Exposure of Bifidobacterium cells to oxygen causes accumulation of reactive oxygen species, mainly hydrogen peroxide, leading to cell death. In this study, we tested the suitability of continuous culture under increasing selective pressure combined with immobilized cell technology for the selection of hydrogen peroxide adapted Bifidobacterium cells. Cells of B. longum NCC2705 were immobilized in gellan-xanthan gum gel beads and used to continuously ferment MRS medium containing increasing concentration of H2O2 from 0 to 130 ppm. Results At the beginning of the culture, high cell density of 1013 CFU per litre of reactor was tested. The continuous culture gradually adapted to increasing H2O2 concentrations. However, after increasing the H2O2 concentration to 130 ppm the OD of the culture decreased to 0. Full wash out was prevented by the immobilization of the cells in gel matrix. Hence after stopping the stress, it was possible to re-grow the cells that survived the highest lethal dose of H2O2 and to select two adapted colonies (HPR1 and HPR2 after plating of the culture effluent. In contrast to HPR1, HPR2 showed stable characteristics over at least 70 generations and exhibited also higher tolerance to O2 than non adapted wild type cells. Preliminary characterization of HPR2 was carried out by global genome expression profile analysis. Two genes coding for a protein with unknown function and possessing trans-membrane domains and an ABC-type transporter protein were overexpressed in HPR2 cells compared to wild type cells. Conclusions Our study showed that continuous culture with cell immobilization is a valid approach for selecting cells adapted to hydrogen peroxide. Elucidation of H2O2 adaptation mechanisms in HPR2 could be helpful to develop oxygen resistant bifidobacteria.

  18. Transplanted Bone Marrow Cells Repair Heart Tissue and Reduce Myocarditis in Chronic Chagasic Mice

    OpenAIRE

    MILENA B. P. SOARES; Lima, Ricardo S.; Rocha, Leonardo L.; Takyia, Christina M; Pontes-de-Carvalho, Lain; Campos de Carvalho, Antonio C.; Ribeiro-dos-Santos, Ricardo

    2004-01-01

    A progressive destruction of the myocardium occurs in ∼30% of Trypanosoma cruzi-infected individuals, causing chronic chagasic cardiomyopathy, a disease so far without effective treatment. Syngeneic bone marrow cell transplantation has been shown to cause repair and improvement of heart function in a number of studies in patients and animal models of ischemic cardiopathy. The effects of bone marrow transplant in a mouse model of chronic chagasic cardiomyopathy, in the presence of the disease ...

  19. Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

    OpenAIRE

    Tackenberg, Björn; Jelčić, Ilijas; Baerenwaldt, Anne; Wolfgang H Oertel; Sommer, Norbert; Nimmerjahn, Falk; Lünemann, Jan D.

    2009-01-01

    The inhibitory Fc-γ receptor FcγRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcγRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is wide...

  20. Anti-androgen resistance in prostate cancer cells chronically induced by interleukin-1β

    OpenAIRE

    Staverosky, Julia A.; Zhu, Xin-Hua; Ha, Susan; Logan, Susan K.

    2013-01-01

    Chronic inflammation has been linked to cancer initiation and progression in a variety of tissues, yet the impact of acute and chronic inflammatory signaling on androgen receptor function has not been widely studied. In this report, we examine the impact of the inflammation-linked cytokine, interleukin-1β on androgen receptor function in prostate cancer cells. We demonstrate that acute interleukin-1β treatment inhibits the transcription of the androgen receptor gene itself, resulting in the r...

  1. Renal Cell Protection of Erythropoietin beyond Correcting The Anemia in Chronic Kidney Disease Patients

    OpenAIRE

    Hamid Nasri

    2013-01-01

    Currently many patients with chronic renal failure have profited from the use of erythropoietin to correct anemia (1,2). In chronic kidney disease, anemia is believed to be a surrogate index for tissue hypoxia that continues preexisting renal tissue injury (1-3). Erythropoietin is an essential glycoprotein that accelerates red blood cell maturation from erythroid progenitors and facilitates erythropoiesis. It is a 30.4 kD glycoprotein and class I cytokine containing 165 amino acids (3,4). App...

  2. Glial cell line-derived neurotrophic factor gene therapy ameliorates chronic hyperprolactinemia in senile rats

    OpenAIRE

    Morel, Gustavo R.; Sosa, Yolanda E.; Bellini, Maria J.; Carri, Nestor G.; Rodriguez, Silvia S.; Bohn, Martha C.; Goya, Rodolfo G.

    2010-01-01

    Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (1010 pfu) of either an adenovir...

  3. High-Pass Filtering at Vestibular Frequencies by Transducer Adaptation in Mammalian Saccular Hair Cells

    Science.gov (United States)

    Songer, Jocelyn E.; Eatock, Ruth Anne

    2011-11-01

    The mammalian saccule detects head tilt and low-frequency head accelerations as well as higher-frequency bone vibrations and sounds. It has two different hair cell types, I and II, dispersed throughout two morphologically distinct regions, the striola and extrastriola. Afferents from the two zones have distinct response dynamics which may arise partly from zonal differences in hair cell properties. We find that type II hair cells in the rat saccular epithelium adapt with a time course appropriate for influencing afferent responses to head motions. Moreover, striolar type II hair cells adapted by a greater extent than extrastriolar type II hair cells and had greater phase leads in the mid-frequency range (5-50 Hz). These differences suggest that hair cell transduction may contribute to zonal differences in the adaptation of vestibular afferents to head motions.

  4. Chronic oxidative stress causes estrogen-independent aggressive phenotype, and epigenetic inactivation of estrogen receptor alpha in MCF-7 breast cancer cells.

    Science.gov (United States)

    Mahalingaiah, Prathap Kumar S; Ponnusamy, Logeswari; Singh, Kamaleshwar P

    2015-08-01

    The role of chronic oxidative stress in the development and aggressive growth of estrogen receptor (ER)-positive breast cancer is well known; however, the mechanistic understanding is not clear. Estrogen-independent growth is one of the features of aggressive subtype of breast cancer. Therefore, the objective of this study was to evaluate the effect of oxidative stress on estrogen sensitivity and expression of nuclear estrogen receptors in ER-positive breast cancer cells. MCF-7 cells chronically exposed to hydrogen peroxide were used as a cell model in this study, and their growth in response to 17-β estradiol was evaluated by cell viability, cell cycle, and cell migration analysis. Results were further confirmed at molecular level by analysis of gene expressions at transcript and protein levels. Histone H3 modifications, expression of epigenetic regulatory genes, and the effect of DNA demethylation were also analyzed. Loss of growth in response to estrogen with a decrease in ERα expression was observed in MCF-7 cells adapted to chronic oxidative stress. Increases in mtTFA and NRF1 in these cells further suggested the role of mitochondria-dependent redox-sensitive growth signaling as an alternative pathway to estrogen-dependent growth. Changes in expression of epigenetic regulatory genes, levels of histone H3 modifications as well as significant restorations of both ERα expression and estrogen response by 5-Aza-2'-deoxycytidine further confirmed the epigenetic basis for estrogen-independent growth in these cells. In conclusion, results of this study suggest that chronic oxidative stress can convert estrogen-dependent nonaggressive breast cancer cells into estrogen-independent aggressive form potentially by epigenetic mechanism.

  5. Impact of host cell line adaptation on quasispecies composition and glycosylation of influenza A virus hemagglutinin.

    Directory of Open Access Journals (Sweden)

    Jana Verena Roedig

    Full Text Available The genome of influenza A viruses is constantly changing (genetic drift resulting in small, gradual changes in viral proteins. Alterations within antibody recognition sites of the viral membrane glycoproteins hemagglutinin (HA and neuraminidase (NA result in an antigenetic drift, which requires the seasonal update of human influenza virus vaccines. Generally, virus adaptation is necessary to obtain sufficiently high virus yields in cell culture-derived vaccine manufacturing. In this study detailed HA N-glycosylation pattern analysis was combined with in-depth pyrosequencing analysis of the virus genomic RNA. Forward and backward adaptation from Madin-Darby Canine Kidney (MDCK cells to African green monkey kidney (Vero cells was investigated for two closely related influenza A virus PR/8/34 (H1N1 strains: from the National Institute for Biological Standards and Control (NIBSC or the Robert Koch Institute (RKI. Furthermore, stability of HA N-glycosylation patterns over ten consecutive passages and different harvest time points is demonstrated. Adaptation to Vero cells finally allowed efficient influenza A virus replication in Vero cells. In contrast, during back-adaptation the virus replicated well from the very beginning. HA N-glycosylation patterns were cell line dependent and stabilized fast within one (NIBSC-derived virus or two (RKI-derived virus successive passages during adaptation processes. However, during adaptation new virus variants were detected. These variants carried "rescue" mutations on the genomic level within the HA stem region, which result in amino acid substitutions. These substitutions finally allowed sufficient virus replication in the new host system. According to adaptation pressure the composition of the virus populations varied. In Vero cells a selection for "rescue" variants was characteristic. After back-adaptation to MDCK cells some variants persisted at indifferent frequencies, others slowly diminished and even

  6. Characterization of adaptation motors in saccular hair cells by fluctuation analysis.

    OpenAIRE

    Frank, Jonathan E.; Markin, Vladislav; Jaramillo, Fernán

    2002-01-01

    The mechanical sensitivity of hair cells, the sensory receptors of the vestibular and auditory systems, is maintained by adaptation, which resets the transducer to cancel the effects of static stimuli. Adaptation motors in hair cells can be experimentally activated by externally applying a transduction channel blocker to the hair bundle, causing the hair bundle to move in the negative direction. We studied the variance in the position of the hair bundle during these displacements and found th...

  7. Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia.

    Science.gov (United States)

    Kikushige, Yoshikane; Miyamoto, Toshihiro

    2015-11-01

    Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.

  8. The influence of chronic stress on T cell immunity

    OpenAIRE

    Sommershof, Annette

    2010-01-01

    Chronic environmental and psychological stress has long been suspected to increase the susceptibility and outcome of numerous infectious and inflammatory diseases. The release of neurotransmitters (catecholamines) and adrenal hormones (glucocorticoids) has been well documented as the basis for a connection between the central nervous system and peripheral components of the immune system. Glucocorticoids, the end products of stress-induced neuroendocrine pathways and the hypothalamic-pituitary...

  9. Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Hiroko Endo

    Full Text Available A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

  10. Atherosclerosis: a chronic inflammatory disease mediated by mast cells.

    Science.gov (United States)

    Conti, Pio; Shaik-Dasthagirisaeb, Yazdami

    2015-01-01

    Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endothelial cells which respond to modified lipoproteins and lead to Th1 cell subset activation and generation of inflammatory cytokines and chemoattractant chemokines. Other immune cells, such as CD4+ T inflammatory cells, which play a critical role in the development and progression of atherosclerosis, and regulatory T cells [Treg], which have a protective effect on the development of atherosclerosis are involved. Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation. Here we discuss the relationship between atherosclerosis, inflammation and mast cells. PMID:26648785

  11. Implications for the offspring of circulating factors involved in beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Ringholm, Lene; Søstrup, Birgitte;

    2014-01-01

    there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors. SAMPLES: Serum samples from nonpregnant and pregnant women. METHODS: The effect of serum from pregnant women...... is able to stimulate proliferation of rat beta cells. We have identified several circulating factors that may contribute to beta cell adaptation to pregnancy. Further studies are needed to elucidate their possible role in glucose homeostasis in the mother and her offspring....

  12. Can engineered "designer" T cells outsmart chronic hepatitis B?

    Science.gov (United States)

    Protzer, U; Abken, H

    2010-01-01

    More than 350 million people worldwide are persistently infected with human heptatitis B virus (HBV) and at risk to develop liver cirrhosis and hepatocellular carcinoma making long-term treatment necessary. While a vaccine is available and new antiviral drugs are being developed, elimination of persistently infected cells is still a major issue. Recent efforts in adoptive cell therapy are experimentally exploring immunotherapeutic elimination of HBV-infected cells by means of a biological attack with genetically engineered "designer" T cells. PMID:21188203

  13. Atherosclerosis: a chronic inflammatory disease mediated by mast cells

    OpenAIRE

    Conti, Pio; Shaik-Dasthagirisaeb, Yazdami

    2015-01-01

    Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endotheli...

  14. Impact of Ambient Air Pollution on the Differential White Blood Cell Count in Patients with Chronic Pulmonary Disease

    OpenAIRE

    Brüske, Irene; Hampel, Regina; Socher, Martin M.; Rückerl, Regina; Schneider, Alexandra; Heinrich, Joachim; Oberdörster, Günter; Wichmann, H.-Erich; Peters, Annette

    2010-01-01

    Epidemiologic studies report associations between particulate air pollution and increased mortality from pulmonary diseases.To examine whether the exposure to ambient gaseous and particulate air pollution leads to an alteration of the differential white blood cell count in patients with chronic pulmonary diseases like chronic bronchitis, chronic obstructive pulmonary disease, and asthma.

  15. Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Schock, Sarah C. [Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Edrissi, Hamidreza [University of Ottawa, Neuroscience Graduate Program, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Burger, Dylan [Ottawa Hospital Research Institute, Kidney Centre, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Cadonic, Robert; Hakim, Antoine [Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Thompson, Charlie, E-mail: charliet@uottawa.ca [Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada)

    2014-07-18

    Highlights: • Microparticles are elevated in the plasma in a rodent model of chronic cerebral ischemia. • These microparticles initiate apoptosis in cultured cells. • Microparticles contain caspase 3 and they activate receptors for TNF-α and TRAIL. - Abstract: Circulating microparticles (MPs) are involved in many physiological processes and numbers are increased in a variety of cardiovascular disorders. The present aims were to characterize levels of MPs in a rodent model of chronic cerebral hypoperfusion (CCH) and to determine their signaling properties. MPs were isolated from the plasma of rats exposed to CCH and quantified by flow cytometry. When MPs were added to cultured endothelial cells or normal rat kidney cells they induced cell death in a time and dose dependent manner. Analysis of pellets by electron microscopy indicates that cell death signals are carried by particles in the range of 400 nm in diameter or less. Cell death involved the activation of caspase 3 and was not a consequence of oxidative stress. Inhibition of the Fas/FasL signaling pathway also did not improve cell survival. MPs were found to contain caspase 3 and treating the MPs with a caspase 3 inhibitor significantly reduced cell death. A TNF-α receptor blocker and a TRAIL neutralizing antibody also significantly reduced cell death. Levels of circulating MPs are elevated in a rodent model of chronic cerebral ischemia. MPs with a diameter of 400 nm or less activate the TNF-α and TRAIL signaling pathways and may deliver caspase 3 to cultured cells.

  16. Biological Analysis of Human CML Stem Cells; Xenograft Model of Chronic Phase Human Chronic Myeloid Leukemia.

    Science.gov (United States)

    Abraham, Sheela A

    2016-01-01

    Xenograft mouse models have been instrumental in expanding our knowledge of hematopoiesis and can provide a functional description of stem cells that possess engrafting potential. Here we describe methodology outlining one way of analyzing human malignant cells that are able to engraft immune compromised mice. Using models such as these will allow researchers to gain valuable insight into the primitive leukemic subtypes that evade current therapy regimes and are critical to understand, in order to eradicate malignancy. PMID:27581148

  17. p53-Dependent Adaptive Responses in Human Cells Exposed to Space Radiations

    International Nuclear Information System (INIS)

    Purpose: It has been reported that priming irradiation or conditioning irradiation with a low dose of X-rays in the range of 0.02-0.1 Gy induces a p53-dependent adaptive response in mammalian cells. The aim of the present study was to clarify the effect of space radiations on the adaptive response. Methods and Materials: Two human lymphoblastoid cell lines were used; one cell line bears a wild-type p53 (wtp53) gene, and another cell line bears a mutated p53 (mp53) gene. The cells were frozen during transportation on the space shuttle and while in orbit in the International Space Station freezer for 133 days between November 15, 2008 and March 29, 2009. After the frozen samples were returned to Earth, the cells were cultured for 6 h and then exposed to a challenging X-ray-irradiation (2 Gy). Cellular sensitivity, apoptosis, and chromosome aberrations were scored using dye-exclusion assays, Hoechst33342 staining assays, and chromosomal banding techniques, respectively. Results: In cells exposed to space radiations, adaptive responses such as the induction of radioresistance and the depression of radiation-induced apoptosis and chromosome aberrations were observed in wtp53 cells but not in mp53 cells. Conclusion: These results have confirmed the hypothesis that p53-dependent adaptive responses are apparently induced by space radiations within a specific range of low doses. The cells exhibited this effect owing to space radiations exposure, even though the doses in space were very low.

  18. Innate lymphoid cell function in the context of adaptive immunity.

    Science.gov (United States)

    Bando, Jennifer K; Colonna, Marco

    2016-06-21

    Innate lymphoid cells (ILCs) are a family of innate immune cells that have diverse functions during homeostasis and disease. Subsets of ILCs have phenotypes that mirror those of polarized helper T cell subsets in their expression of core transcription factors and effector cytokines. Given the similarities between these two classes of lymphocytes, it is important to understand which functions of ILCs are specialized and which are redundant with those of T cells. Here we discuss genetic mouse models that have been used to delineate the contributions of ILCs versus those of T cells and review the current understanding of the specialized in vivo functions of ILCs. PMID:27328008

  19. Larger adaptive response of 5-HT1A autoreceptors to chronic fluoxetine in a mouse model of depression than in healthy mice

    Institute of Scientific and Technical Information of China (English)

    N.FROGER; E.PALAZZO; T.RENOIR; M.MELFORT; N.BARDEN; M.HAMON; L.LANFUMEY

    2004-01-01

    Vulnerability to major depressive disorders, in particular depression, is often associated with both hypoactivity of the central serotoninergic (5-HT) system and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Extensive studies in normal healthy rodents showed that chronic treatment with SSRI antidepressants produced a marked functional desensitization of somatodendritic 5-HT1A autoreceptors, and this adaptive change has been claimed to play a key role in the therapeutic action of

  20. A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells

    Science.gov (United States)

    Yigit, Burcu; Halibozek, Peter J.; Chen, Shih-Shih; O'Keeffe, Michael S.; Arnason, Jon; Avigan, David; Gattei, Valter; Bhan, Atul; Cen, Osman; Longnecker, Richard; Chiorazzi, Nicholas; Wang, Ninghai; Engel, Pablo; Terhorst, Cox

    2016-01-01

    The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo, we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors. PMID:27029059

  1. A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih; O'Keeffe, Michael S; Arnason, Jon; Avigan, David; Gattei, Valter; Bhan, Atul; Cen, Osman; Longnecker, Richard; Chiorazzi, Nicholas; Wang, Ninghai; Engel, Pablo; Terhorst, Cox

    2016-05-01

    The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo, we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors. PMID:27029059

  2. CXCR4 is dispensable for T cell egress from chronically inflamed skin via the afferent lymph.

    Directory of Open Access Journals (Sweden)

    Skye A Geherin

    Full Text Available T cell recirculation through extralymphoid tissues is essential to immune surveillance, host defense and inflammation. In this process, T cells enter the tissue from the blood and subsequently leave via the afferent lymph. In the absence of inflammation, T cells require CCR7 expression to egress from the skin or lung, which is consistent with the constitutive expression of the CCR7 ligand CCL21 on lymphatic endothelium. However, during chronic inflammation alternative chemoattractants come into play, allowing Ccr7-deficient (Ccr7-/- T cells to egress efficiently from affected skin. As T cell egress from inflamed sites is a potential control point of the inflammatory response, we aimed to determine alternative T cell exit receptors using a mouse and a sheep model. We show that CCR7+ and CCR7- T cells exiting from the chronically inflamed skin were highly responsive to the CXCR4 ligand CXCL12, which was induced in the lymphatics in the inflamed site. Based on these findings, we hypothesized that CXCR4 mediates T cell egress from inflamed skin. However, pharmacological inhibition of CXCR4 did not affect the tissue egress of wildtype or Ccr7-/- CD4 and CD8 T cells after adoptive transfer into chronically inflamed skin. Similarly, adoptively transferred Cxcr4-/- Ccr7-/- and Ccr7-/- T cells egressed from the inflamed skin equally well. Based on these data, we conclude that, while CXCR4 might play an essential role for other cell types that enter the afferent lymphatics, it is dispensable for T cell egress from the chronically inflamed skin.

  3. Neural Stem Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy

    OpenAIRE

    Hattiangady, Bharathi; Shetty, Ashok K.

    2011-01-01

    Neural stem cell (NSC) transplantation into the hippocampus could offer an alternative therapy to hippocampal resection in patients with drug-resistant chronic epilepsy, which afflicts ~30% of mesial temporal lobe epilepsy (TLE) cases. Multipotent, self-renewing NSCs could be expanded from multiple regions of the developing and adult brain, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs). However, to provide a comprehensive methodology involved in testing the effica...

  4. Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection

    OpenAIRE

    Dimitra Peppa; Lorenzo Micco; Alia Javaid; Kennedy, Patrick T.F.; Anna Schurich; Claire Dunn; Celeste Pallant; Gidon Ellis; Pooja Khanna; Geoffrey Dusheiko; Gilson, Richard J.; Mala K Maini

    2010-01-01

    NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to...

  5. In vitro effects of piracetam on the radiosensitivity of hypoxic cells (adaptation of MTT assay to hypoxic conditions)

    International Nuclear Information System (INIS)

    This paper describes the adaptation of the MTT assay to hypoxic conditions in order to test the in vitro effect of piracetam on hypoxic cells and particularly on the radiosensitivity of hypoxic cells since this drug has shown clinical effect on acute and chronic hypoxia. The V79 cell line was selected by reference to preliminary hypoxic experiments using clonogenic assay and euoxic experiments using clonogenic and MTT assays. Cell growth and survival in our hypoxic conditions were assessed using MTT assay with an enclosure and special 48-well plates both made of glass. Growth curves on glass plates after 1-hour exposure to nitrogen versus air were comparable, so there is no bias effect due to gas composition. Survival curves using MTT versus reference clonogenic assay were comparable after radiation exposure in eu- and hypoxic conditions, and confirm the validity of our original technique for creating hypoxia. The Oxygen Enhancement Ratio was of about 3 for 1-hour hypoxic exposure. Piracetam gave no cytotoxic effect up to 10 mM of piracetam. Growth curves after continuous drug exposure and 1-hour euoxic versus hypoxic exposure gave no cytotoxic effect up to 10 mM of piracetam. Survival curves after continuous drug exposure to 10 mM of piracetam gave no significant effect on the radiosensitivity of hypoxic V79 cells using MTT or clonogenic assay. (author). 32 refs., 6 figs

  6. Sensorineural Hearing Affection In Sickle Cell Disease Patients With Chronic Renal Failure Under Dialysis

    Directory of Open Access Journals (Sweden)

    Saeed Abdelwhab Saeed MD*, Magdy M El Sharkawy

    2002-09-01

    Full Text Available Objective: to study the problem of hearing loss in patients of chronic renal failure on regular haemodialysis and The factors which affect it. And to study the effect of sickle cell disease on hearing loss. we studied hearing loss in dialysis patients, sickle cell disease patients and patients of sickle cell disease with chronic renal failure under dialysis compared to normal control subjects. Design: !"",include sickle cell disease patients with chronic renal fa"# $%& ' ", i ,nclude ( # #"# $%&'", , ,( #&'", i 9nclude the normal *+&*+' All groups are subjected to full history, thorough clinical examination including neurological and ENT examination, investigations includes Hb, s. creatinine, s.albumen, s.calcium and calculation of kt/v for dialysis patients. Full audiological assessment, using #,-GSI audiometer was done for all groups with special concentration at frequency of - .Results: hearing loss was found in patients with chronic renal failure more than normal control. Patient with sickle cell disease have hearing disorders significantly higher than $/%- .% 0( # #cell disease have significantly. Marked degree of SNHL than those with SCD only. Hearing loss in patients with 12( # * 3 &4 !4! '#"#"patients with chronic renal failure with or without SCD correlate with duration of dialysis , presence of peripheral neuropathy, s. calcium level, efficiency of dialysis marked by kt/v. Conclusion and recommendation: hearing disorder is common in patients with chronic renal failure under regular haemodialysis and it increase with duration of dialysis it should be suspected if there is Peripheral neuropathy. It can be reduced with efficient dialysis, correction of anemia, adjustment of calcium level. Patients with SCD suffer also some degree of hearing loss especially at higher frequency and this degree of hearing loss

  7. Autologous Bone Marrow Stem Cell Infusion (AMBI therapy for Chronic Liver Diseases

    Directory of Open Access Journals (Sweden)

    Rajkumar JS

    2007-01-01

    Full Text Available Liver Cirrhosis is the end stage of chronic liver disease which may happen due to alcoholism, viral infections due to Hepatitis B, Hepatitis C viruses and is difficult to treat. Liver transplantation is the only available definitive treatment which is marred by lack of donors, post operative complications such as rejection and high cost. Autologous bone marrow stem cells have shown a lot of promise in earlier reported animal studies and clinical trials. We have in this study administered in 22 patients with chronic liver disease, autologous bone marrow stem cell whose results are presented herewith.

  8. Stress-induced adaptive islet cell identity changes.

    Science.gov (United States)

    Cigliola, V; Thorel, F; Chera, S; Herrera, P L

    2016-09-01

    The different forms of diabetes mellitus differ in their pathogenesis but, ultimately, they are all characterized by progressive islet β-cell loss. Restoring the β-cell mass is therefore a major goal for future therapeutic approaches. The number of β-cells found at birth is determined by proliferation and differentiation of pancreatic progenitor cells, and it has been considered to remain mostly unchanged throughout adult life. Recent studies in mice have revealed an unexpected plasticity in islet endocrine cells in response to stress; under certain conditions, islet non-β-cells have the potential to reprogram into insulin producers, thus contributing to restore the β-cell mass. Here, we discuss the latest findings on pancreas and islet cell plasticity upon physiological, pathological and experimental conditions of stress. Understanding the mechanisms involved in cell reprogramming in these models will allow the development of new strategies for the treatment of diabetes, by exploiting the intrinsic regeneration capacity of the pancreas. PMID:27615136

  9. Chaetoglobosin A preferentially induces apoptosis in chronic lymphocytic leukemia cells by targeting the cytoskeleton

    DEFF Research Database (Denmark)

    Knudsen, Peter Boldsen; Hanna, B.; Ohl, S.;

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B cells. One of the major challenges in treatment of CLL is the achievement of a complete remission to prevent relapse of disease originating from cells within lymphoid tissues and subsequent chemoresistance. In search...... for novel drugs that target CLL cells also in protective microenvironments, we performed a fungal extract screen using cocultures of primary CLL cells with bone marrow-derived stromal cells. A metabolite produced by Penicillium aquamarinium was identified as Chaetoglobosin A, a member of the cytochalasan...

  10. Chronic stress induces ageing-associated degeneration in rat Leydig cells

    Institute of Scientific and Technical Information of China (English)

    Fei-Fei Wang; Qian Wang; Yong Chen; Qiang Lin; Hui-Bao Gao; Ping Zhang

    2012-01-01

    Several studies have suggested that stress and ageing exert inhibitory effects on rat Leydig cells.In a pattern similar to the normal process of Leydig cell ageing,stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression that then results in decreased testosterone secretion.We hypothesized that chronic stress accelerates the degenerative changes associated with ageing in Leydig cells.To test this hypothesis,we established a model of chronic stress to evaluate stress-induced morphological and functional alterations in Brown Norway rat Leydig cells; additionally,intracellular lipofuscin levels,reactive oxygen species (ROS)levels and DNA damage were assessed.The results showed that chronic stress accelerated ageing-related changes:ultrastructural alterations associated with ageing,cellular lipofuscin accumulation,increased ROS levels and more extensive DNA damage were observed.Additionally,testosterone levels were decreased.This study sheds new light on the idea that chronic stress contributes to the degenerative changes associated with ageing in rat Leydig cells in vivo.

  11. A Distributed Taxation Based Rank Adaptation Scheme for 5G Small Cells

    DEFF Research Database (Denmark)

    Catania, Davide; Cattoni, Andrea Fabio; Mahmood, Nurul Huda;

    2015-01-01

    The further densification of small cells impose high and undesirable levels of inter-cell interference. Multiple Input Multiple Output (MIMO) systems along with advanced receiver techniques provide us with extra degrees of freedom to combat such a problem. With such tools, rank adaptation algorit...

  12. Constant Power Control of a Proton Exchange Membrane Fuel Cell through Adaptive Fuzzy Sliding Mode

    Directory of Open Access Journals (Sweden)

    Minxiu Yan

    2013-05-01

    Full Text Available Fuel cell is a device that converts the chemical energy from a fuel into electricity through a chemical reaction with oxygen or another oxidizing agent. The paper describes a mathematical model of proton exchange membrane fuel cells by analyzing the working mechanism of the proton exchange membrane fuel cell. Furthermore, an adaptive fuzzy sliding mode controller is designed for the constant power output of PEMFC system. Simulation results prove that adaptive fuzzy sliding mode control has better control effect than conventional fuzzy sliding mode control.

  13. Functional adaptation of the human β-cells after frequent exposure to noradrenaline

    DEFF Research Database (Denmark)

    Dela, Flemming

    2015-01-01

    noradrenaline is most likely the stimulus that introduces a memory in the insulin-producing cells. ABSTRACT: Physical training decreases glucose- and arginine-stimulated insulin secretion. The mechanism by which the pancreatic β-cells adapt to the training status of the individual is not known. We hypothesized......KEY POINTS: Trained people produce less insulin than untrained; there is an adaptation of the insulin-producing cells to the trained state. The mechanism behind this adaptation is not known, but some sort of memory must be introduced into the insulin-producing cells. Here it is shown that this...... memory is introduced by 10 daily intravenous infusions of noradrenaline, mimicking the increases that occur during a 10 day training programme. Thus, after the infusion period, the subjects produced less insulin in response to the same stimulus. It is concluded that exercise-induced increases in...

  14. Incretin hormones and beta cell function in chronic pancreatitis

    DEFF Research Database (Denmark)

    Knop, Filip Krag

    2010-01-01

    . It is unknown whether the incretin defect is a primary event leading to T2DM or arises as a consequence of the diabetic state. To investigate this we studied patients with chronic pancreatitis (CP). Over time, CP leads to secondary diabetes mellitus (DM). If patients with CP and secondary DM exhibit...... independently of the endocrine status of patients with CP, the incretin defect could represent a primary pathogenetic defect. Three protocols have been employed to investigate this. In a study investigating postprandial incretin responses in 8 patients with CP and exocrine pancreatic insufficiency......, with and without pancreatic enzyme supplementation (PES), we observed preserved incretin responses as compared to matched healthy subjects; and, further, that PES increased postprandial incretin responses in these patients. This suggests not only that the secretion of incretin hormones is regulated by the mere...

  15. A Robot-Assisted Cell Manipulation System with an Adaptive Visual Servoing Method

    Directory of Open Access Journals (Sweden)

    Yu Xie

    2016-06-01

    Full Text Available Robot-assisted cell manipulation is gaining attention for its ability in providing high throughput and high precision cell manipulation for the biological industry. This paper presents a visual servo microrobotic system for cell microinjection. We investigated the automatic cell autofocus method that reduced the complexity of the system. Then, we produced an adaptive visual processing algorithm to detect the location of the cell and micropipette toward the uneven illumination problem. Fourteen microinjection experiments were conducted with zebrafish embryos. A 100% success rate was achieved either in autofocus or embryo detection, which verified the robustness of the proposed automatic cell manipulation system.

  16. Pancreatic hormone secretion in chronic pancreatitis without residual beta-cell function

    DEFF Research Database (Denmark)

    Larsen, S; Hilsted, J; Tronier, B;

    1988-01-01

    Hormonal responses (glucagon, pancreatic polypeptide and somatostatin) to iv glucagon, iv arginine, and ingestion of a mixed meal were investigated in 6 patients with insulin-dependent diabetes secondary to chronic pancreatitis without beta-cell function, in 8 Type I (insulin-dependent) diabetics...... without beta-cell function, and 8 healthy subjects. No significant differences were found between the two diabetic groups regarding glucagon responses to arginine and meal ingestion. In the patients with diabetes secondary to chronic pancreatitis compared with Type I diabetics and normal controls......, the pancreatic polypeptide concentrations were significantly lower and somatostatin concentrations were significantly higher after glucagon, arginine and a mixed meal. Thus, pancreatic glucagon secretion was preserved in patients with insulin-dependent diabetes secondary to chronic pancreatitis, having...

  17. Squamous cell carcinoma of the penis and scrotum in a patient with chronic scrotal and penile lymphedema

    OpenAIRE

    Abhyankar Suhas; Kulkarni Ananta; Kulkarni Madhuri; Agarwal Naveen

    2010-01-01

    Squamous cell carcinoma arising from tissue affected by chronic lymphedema is rare, though it is recognized that a variety of malignant tumors can arise in chronic congenital or acquired lymphedema. We describe, a case of scrotal and penile squamous cell carcinoma arising in a patient with a history of chronic scrotal and penile lymphedema of filarial origin. We here discuss the management and possible etiology of this unusual case.

  18. Squamous cell carcinoma of the penis and scrotum in a patient with chronic scrotal and penile lymphedema

    Directory of Open Access Journals (Sweden)

    Abhyankar Suhas

    2010-01-01

    Full Text Available Squamous cell carcinoma arising from tissue affected by chronic lymphedema is rare, though it is recognized that a variety of malignant tumors can arise in chronic congenital or acquired lymphedema. We describe, a case of scrotal and penile squamous cell carcinoma arising in a patient with a history of chronic scrotal and penile lymphedema of filarial origin. We here discuss the management and possible etiology of this unusual case.

  19. Squamous cell carcinoma of the penis and scrotum in a patient with chronic scrotal and penile lymphedema.

    Science.gov (United States)

    Abhyankar, Suhas V; Kulkarni, Ananta; Kulkarni, Madhuri; Agarwal, Naveen Kumar

    2010-10-01

    Squamous cell carcinoma arising from tissue affected by chronic lymphedema is rare, though it is recognized that a variety of malignant tumors can arise in chronic congenital or acquired lymphedema. We describe, a case of scrotal and penile squamous cell carcinoma arising in a patient with a history of chronic scrotal and penile lymphedema of filarial origin. We here discuss the management and possible etiology of this unusual case. PMID:21430898

  20. The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation.

    Science.gov (United States)

    Grabiec, Aleksander M; Hussell, Tracy

    2016-07-01

    Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. PMID:26957481

  1. Adaptation of HIV-1 Depends on the Host-Cell Environment

    Science.gov (United States)

    van Opijnen, Tim; de Ronde, Anthony; Boerlijst, Maarten C.; Berkhout, Ben

    2007-01-01

    Many viruses have the ability to rapidly develop resistance against antiviral drugs and escape from the host immune system. To which extent the host environment affects this adaptive potential of viruses is largely unknown. Here we show that for HIV-1, the host-cell environment is key to the adaptive potential of the virus. We performed a large-scale selection experiment with two HIV-1 strains in two different T-cell lines (MT4 and C8166). Over 110 days of culture, both virus strains adapted rapidly to the MT4 T-cell line. In contrast, when cultured on the C8166 T-cell line, the same strains did not show any increase in fitness. By sequence analyses and infections with viruses expressing either yellow or cyan fluorescent protein, we were able to show that the absence of adaptation was linked to a lower recombination rate in the C8166 T-cell line. Our findings suggest that if we can manipulate the host-cellular factors that mediate viral evolution, we may be able to significantly retard viral adaptability. PMID:17342205

  2. Effects of Chronic Low-Dose Radiation on Human Neural Progenitor Cells

    Science.gov (United States)

    Katsura, Mari; Cyou-Nakamine, Hiromasa; Zen, Qin; Zen, Yang; Nansai, Hiroko; Amagasa, Shota; Kanki, Yasuharu; Inoue, Tsuyoshi; Kaneki, Kiyomi; Taguchi, Akashi; Kobayashi, Mika; Kaji, Toshiyuki; Kodama, Tatsuhiko; Miyagawa, Kiyoshi; Wada, Youichiro; Akimitsu, Nobuyoshi; Sone, Hideko

    2016-01-01

    The effects of chronic low-dose radiation on human health have not been well established. Recent studies have revealed that neural progenitor cells are present not only in the fetal brain but also in the adult brain. Since immature cells are generally more radiosensitive, here we investigated the effects of chronic low-dose radiation on cultured human neural progenitor cells (hNPCs) derived from embryonic stem cells. Radiation at low doses of 31, 124 and 496 mGy per 72 h was administered to hNPCs. The effects were estimated by gene expression profiling with microarray analysis as well as morphological analysis. Gene expression was dose-dependently changed by radiation. By thirty-one mGy of radiation, inflammatory pathways involving interferon signaling and cell junctions were altered. DNA repair and cell adhesion molecules were affected by 124 mGy of radiation while DNA synthesis, apoptosis, metabolism, and neural differentiation were all affected by 496 mGy of radiation. These in vitro results suggest that 496 mGy radiation affects the development of neuronal progenitor cells while altered gene expression was observed at a radiation dose lower than 100 mGy. This study would contribute to the elucidation of the clinical and subclinical phenotypes of impaired neuronal development induced by chronic low-dose radiation. PMID:26795421

  3. Effects of Chronic Low-Dose Radiation on Human Neural Progenitor Cells

    Science.gov (United States)

    Katsura, Mari; Cyou-Nakamine, Hiromasa; Zen, Qin; Zen, Yang; Nansai, Hiroko; Amagasa, Shota; Kanki, Yasuharu; Inoue, Tsuyoshi; Kaneki, Kiyomi; Taguchi, Akashi; Kobayashi, Mika; Kaji, Toshiyuki; Kodama, Tatsuhiko; Miyagawa, Kiyoshi; Wada, Youichiro; Akimitsu, Nobuyoshi; Sone, Hideko

    2016-01-01

    The effects of chronic low-dose radiation on human health have not been well established. Recent studies have revealed that neural progenitor cells are present not only in the fetal brain but also in the adult brain. Since immature cells are generally more radiosensitive, here we investigated the effects of chronic low-dose radiation on cultured human neural progenitor cells (hNPCs) derived from embryonic stem cells. Radiation at low doses of 31, 124 and 496 mGy per 72 h was administered to hNPCs. The effects were estimated by gene expression profiling with microarray analysis as well as morphological analysis. Gene expression was dose-dependently changed by radiation. By thirty-one mGy of radiation, inflammatory pathways involving interferon signaling and cell junctions were altered. DNA repair and cell adhesion molecules were affected by 124 mGy of radiation while DNA synthesis, apoptosis, metabolism, and neural differentiation were all affected by 496 mGy of radiation. These in vitro results suggest that 496 mGy radiation affects the development of neuronal progenitor cells while altered gene expression was observed at a radiation dose lower than 100 mGy. This study would contribute to the elucidation of the clinical and subclinical phenotypes of impaired neuronal development induced by chronic low-dose radiation.

  4. Autonomous Image Segmentation using Density-Adaptive Dendritic Cell Algorithm

    Directory of Open Access Journals (Sweden)

    Vishwambhar Pathak

    2013-08-01

    Full Text Available Contemporary image processing based applications like medical diagnosis automation and analysis of satellite imagery include autonomous image segmentation as inevitable facility. The research done shows the efficiency of an adaptive evolutionary algorithm based on immune system dynamics for the task of autonomous image segmentation. The recognition dynamics of immune-kernels modeled with infinite Gaussian mixture models exhibit the capability to automatically determine appropriate number of segments in presence of noise. In addition, the model using representative density-kernel-parameters processes the information with much reduced space requirements. Experiments conducted with synthetic images as well as real images recorded assured convergence and optimal autonomous model estimation. The segmentation results tested in terms of PBM-index values have been found comparable to those of the Fuzzy C-Means (FCM for the same number of segments as generated by our algorithm.

  5. Renal T-cell lymphoma with cerebral metastasis in a dog with chronic canine ehrlichiosis

    Directory of Open Access Journals (Sweden)

    E.P. Lane

    2002-07-01

    Full Text Available A renal T-cell lymphoma with exclusive cerebral metastasis was diagnosed in a 5-year-old Staffordshire bull terrier bitch euthanased for aggression. This is the first recorded case of primary renal lymphoma in a dog. Immune suppression, due to chronic canine monocytic ehrlichiosis, mayaccount for the unusual primary site and metastatic patternof the tumour.

  6. The expression of PML in chronic myeloid leukemia and effect on cell proliferation

    Institute of Scientific and Technical Information of China (English)

    吴洁

    2013-01-01

    Objective To investigate whether PML is expressed differently in chronic myeloid leukemia (CML) patients and healthy controls,then explore the effect of PML on proliferation in leukemia cell lines K562.Methods Realtime PCR was used to detect the PML expression in

  7. Vascular endothelial cell function and cardiovascular risk factors in patients with chronic renal failure

    DEFF Research Database (Denmark)

    Haaber, A B; Eidemak, I; Jensen, T;

    1995-01-01

    Cardiovascular risk factors and markers of endothelial cell function were studied in nondiabetic patients with mild to moderate chronic renal failure. The transcapillary escape rate of albumin and the plasma concentrations of von Willebrand factor, fibrinogen, and plasma lipids were measured in 29...

  8. Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas

    NARCIS (Netherlands)

    R.J. Bende; F. van Maldegem; C.J.M. van Noesel

    2009-01-01

    Chronic autoimmune or pathogen-induced immune reactions resulting in lymphoid neogenesis are associated with development of malignant lymphomas, mostly extranodal marginal zone B-cell lymphomas (MZBCLs). In this review we address (i) chemokines and adhesion molecules involved in lymphoid neogenesis;

  9. B-Cell Receptor Epitope Recognition Correlates With the Clinical Course of Chronic Lymphocytic Leukemia

    NARCIS (Netherlands)

    Binder, Mascha; Mueller, Fabian; Jackst, Antje; Lechenne, Barbara; Pantic, Milena; Bacher, Ulrike; Eulenburg, Christine Zu; Veelken, Hendrik; Mertelsmann, Roland; Pasqualini, Renata; Arap, Wadih; Trepel, Martin

    2011-01-01

    BACKGROUND: B-cell receptors (BCRs) and their recognition of specific epitopes may play a pivotal role in the development and progression of chronic lymphocytic leukemia (CLL). In this study, the authors set up a model system to explore epitope reactivity and its clinical relevance in CLL. METHODS:

  10. Weaver mutant mouse cerebellar granule cells respond normally to chronic depolarization

    DEFF Research Database (Denmark)

    Bjerregaard, Annette; Mogensen, Helle Smidt; Hack, N;

    1997-01-01

    We studied the effects of chronic K(+)-induced membrane depolarization and treatment with N-methyl-D-aspartate (NMDA) on cerebellar granule cells (CGCs) from weaver mutant mice and non-weaver litter-mates. The weaver mutation is a Gly-to-Ser substitution in a conserved region of the Girk2 G prote...

  11. Clinical Applications of Mesenchymal Stem Cells in Chronic Diseases

    Directory of Open Access Journals (Sweden)

    Andrea Farini

    2014-01-01

    Full Text Available Extraordinary progress in understanding several key features of stem cells has been made in the last ten years, including definition of the niche, and identification of signals regulating mobilization and homing as well as partial understanding of the mechanisms controlling self-renewal, commitment, and differentiation. This progress produced invaluable tools for the development of rational cell therapy protocols that have yielded positive results in preclinical models of genetic and acquired diseases and, in several cases, have entered clinical experimentation with positive outcome. Adult mesenchymal stem cells (MSCs are nonhematopoietic cells with multilineage potential to differentiate into various tissues of mesodermal origin. They can be isolated from bone marrow and other tissues and have the capacity to extensively proliferate in vitro. Moreover, MSCs have also been shown to produce anti-inflammatory molecules which can modulate humoral and cellular immune responses. Considering their regenerative potential and immunoregulatory effect, MSC therapy is a promising tool in the treatment of degenerative, inflammatory, and autoimmune diseases. It is obvious that much work remains to be done to increase our knowledge of the mechanisms regulating development, homeostasis, and tissue repair and thus to provide new tools to implement the efficacy of cell therapy trials.

  12. Merkel cell carcinoma, Bowen's disease and chronic occupational arsenic poisoning.

    Science.gov (United States)

    Tsuruta, D; Hamada, T; Mochida, K; Nakagawa, K; Kobayashi, H; Ishii, M

    1998-08-01

    We diagnosed a unique case of Merkel cell carcinoma (MCC) coexisting with Bowen's disease on the sole of the foot of a 72-year-old man who had worked for about 4 years in a factory handling inorganic arsenic. He had a past history of arsenical keratosis and multiple Bowen's disease. The tumour first appeared as a reddish macule and then showed marked growth over the next month. The tumour was excised and the specimen was examined histopathologically. The tumour consisted of two components: a group of atypical cells representing Bowen's disease in the epidermis and another group of atypical cells with a trabecular pattern characteristic of MCC in the dermis. Neither group of cells showed transitional findings, and the tumour elements were divided by a clear basement membrane. The tumour cells in the dermis were positive for neurone-specific enolase, and on electron microscopy had dense core granules in the cytoplasm. Inorganic arsenic can cause various cutaneous neoplasms, but to our knowledge, this is the first report of a case of MCC associated with Bowen's disease.

  13. Reversible Adaptive Plasticity: A Mechanism for Neuroblastoma Cell Heterogeneity and Chemo-Resistance

    OpenAIRE

    AnthonyDSandler

    2012-01-01

    We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD) or sphere forming, anchorage independent (AI) growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nest...

  14. Mesenchymal stem cells and chronic renal artery stenosis.

    Science.gov (United States)

    Oliveira-Sales, Elizabeth B; Boim, Mirian A

    2016-01-01

    Renal artery stenosis is the main cause of renovascular hypertension and results in ischemic nephropathy characterized by inflammation, oxidative stress, microvascular loss, and fibrosis with consequent functional failure. Considering the limited number of strategies that effectively control renovascular hypertension and restore renal function, we propose that cell therapy may be a promising option based on the regenerative and immunosuppressive properties of stem cells. This review addresses the effects of mesenchymal stem cells (MSC) in an experimental animal model of renovascular hypertension known as 2 kidney-1 clip (2K-1C). Significant benefits of MSC treatment have been observed on blood pressure and renal structure of the stenotic kidney. The mechanisms involved are discussed.

  15. Multiple metastatic basal cell carcinoma with concurrent metastatic pleomorphic sarcoma in chronic lymphedema area - Case report *

    OpenAIRE

    Giuliano da Paz Oliveira; Régio José Santiago Girão; Cléverson Teixeira Soares; Edgard Jose Franco Mello Junior

    2012-01-01

    Chronic lymphedema presents as interstitial fluid retention due to a failure in the lymphatic system drainage. The affected region becomes more vulnerable immunologically and predisposed to the onset of neoplasms. Basal Cell Carcinoma is the most common sort of neoplasm, nevertheless it rarely metastisizes. Sarcomas are malignant mesenchymal neoplasms, locally aggressive, which can spread. Here is reported an infrequent case of multiple basal cell carcinoma, synchronous to a poorly differenti...

  16. Embryonic Stem Cells-loaded Gelatin Microcryogels Slow Progression of Chronic Kidney Disease

    OpenAIRE

    Xiao-Dong Geng; Wei Zheng; Cong-Mei Wu; Shu-Qiang Wang; Quan Hong; Guang-Yan Cai; Xiang-Mei Chen; Di Wu

    2016-01-01

    Background: Chronic kidney disease (CKD) has become a public health problem. New interventions to slow or prevent disease progression are urgently needed. In this setting, cell therapies associated with regenerative effects are attracting increasing interest. We evaluated the effect of embryonic stem cells (ESCs) on the progression of CKD. Methods: Adult male Sprague–Dawley rats were subjected to 5/6 nephrectomy. We used pedicled greater omentum flaps packing ESC-loaded gelatin microcryoge...

  17. Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander?

    Science.gov (United States)

    D’Arena, Giovanni; Simeon, Vittorio; D’Auria, Fiorella; Statuto, Teodora; Sanzo, Paola Di; Martino, Laura De; Marandino, Aurelio; Sangiorgio, Michele; Musto, Pellegrino; Feo, Vincenzo De

    2013-01-01

    Regulatory T (Treg) cells are now under extensive investigation in chronic lymphocytic leukemia (CLL). This small subset of T-cells has been, in fact, considered to be involved in the pathogenesis and progression of CLL. However, whether Treg dysregulation in CLL plays a key role or it rather represents a simple epiphenomenon is still matter of debate. In the former case, Treg cells could be appealing for targeting therapies. Finally, Treg cells have also been proposed as a prognostic indicator of the disease clinical course. PMID:23358515

  18. Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking Filamin A

    OpenAIRE

    Onoprishvili, Irma; Simon, Eric J.

    2007-01-01

    We investigated the effects of morphine and other agonists on the human mu opioid receptor (MOP) expressed in M2 melanoma cells, lacking the actin cytoskeleton protein filamin A and in A7, a sub clone of the M2 melanoma cells, stably transfected with filamin A cDNA. The results of binding experiments showed, that after chronic morphine treatment (24 hr) of A7 cells, MOP binding sites were down-regulated to 63% of control, whereas, unexpectedly, in M2 cells, MOP binding was up-regulated to 188...

  19. Measurement of streptococcal cell wall in tissues of rats resistant or susceptible to cell wall-induced chronic erosive arthritis.

    OpenAIRE

    Anderle, S K; Allen, J B; Wilder, R L; Eisenberg, R A; Cromartie, W J; Schwab, J. H.

    1985-01-01

    The quantity of streptococcal cell wall localized in the joints of rats of strains which are either susceptible (Sprague-Dawley, LEW/N, M520/N) or resistant (Buffalo, WKY/N, F344/N) to cell wall-induced chronic erosive arthritis was measured after intraperitoneal injection of group A streptococcal cell wall fragments. Susceptibility or resistance was not associated with a difference in the amount of cell wall localized in limbs or other tissues. It is concluded that although localization of c...

  20. Child and parental adaptation to pediatric stem cell transplantation

    NARCIS (Netherlands)

    C.M.J. Vrijmoet-Wiersma; A.M. Kolk; M.A. Grootenhuis; E.M. Spek; J.M.M. van Klink; R.M. Egeler; R.G.M. Bredius; H.M. Koopman

    2009-01-01

    Goals of work: Allogeneic pediatric stem cell transplantation (SCT) is a very intensive treatment with a high mortality and morbidity. The objectives of this study were to assess the (1) self- and proxy-reported health-related quality of life (HRQoL) compared to a norm group, (2) levels of parenting

  1. Molecular diagnosis and adaptation of highly virulent infectious bursal disease virus on chicken embryo fibroblast cell

    Directory of Open Access Journals (Sweden)

    Yogender Singh

    2014-05-01

    Full Text Available Aim: To collect Infectious bursal disease virus (IBDV infected bursae based on postmortem findings of clinical samples followed by molecular confirmation and adaptation on chicken embryo fibroblast cell. Material and Methods: Enlarged bursae were processed to make 10% suspension in phosphate buffer saline and were used for viral RNA isolation to carryout VP2 gene fragment amplification using RT-PCR technique. Suspension was also used for adaptation of IBDV on chicken embryo fibroblast cells prepared from 11 day old chicken embryos. Infective titer of virus was calculated using Reed and Muench method. Results: Fifteen dead birds suspected of IBD infection were collected from different local poultry farms of Jabalpur (Madhya Pradesh. After post-mortem, twelve enlarged bursae sample were used for total RNA isolation which was used for amplification of VP2 gene. Out of twelve, eleven were found positive for VP2 gene amplification. Virological characterization of PCR positive sample was done on chicken embryo fibroblast cell culture and various cytopathic effects like rounding of cells, cellular detachment and vacuolation were shown by five IBD field isolates after 48 hours on 4th passage. TCID50 per ml of the adapted virus on 4th passage at 48 hours after infection was 1.46 x 107 . Conclusion: VP2 gene amplification using RT-PCR technique is a specific target for IBDV detection. Passaging of highly virulent IBDV field isolates in cell culture leads to attenuation of virus which can be exploited as a cell culture adapted vaccine candidate.

  2. Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-feng LI; Hong-xia CHEN; Ying LIU; You-zhi ZHANG; Yan-qin LIU; Jin LI

    2006-01-01

    Aim:To explore the mechanism of agmatine's antidepressant action.Methods: Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period.The open-field behaviors of the mice were displayed and recorded using a Videomex-V image analytic system automatically.For bromodeoxyuridine (BrdU;thymidine analog as a marker for dividing cells) labeling,the mice were injected with BrdU (100 mg/kg,ip,twice per d for 2 d),and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry.The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and 3H-thymidine incorporation assay.Results:After the onset of chronic stress,the locomotor activity of the mice in the open field significantly decreased,while coadministration of agmatine 10 mg/kg (po) blocked it.Furthermore,the number of BrdU-labeled cells in the hippocampal dentate gyrus significantly decreased in chronically stressed mice, which was also blocked by chronic coadministration with agmatine 10 mg/kg (po). Four weeks after the BrdU injection, some of the new born cells matured and became neurons, as determined by double labeling for BrdU and neuron specific enolase (NSE), a marker for mature neurons.In vitro treatment with agmatine 0.1-10 μmo1/L for 3 d significantly increased the proliferation of the cultured hippocampal progenitor cells in a dose-dependent manner.Conclusion:We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice.This may be one of the important mechanisms involved in agmatine's antidepressant action.

  3. YKL-40 expression in CD14+ liver cells in acute and chronic injury

    Institute of Scientific and Technical Information of China (English)

    Oscar Pizano-Martínez; Vidal Delgado-Rizo; Irinea Ya(n)ez-Sánchez; Pilar Alatorre-Carranza; Alejandra Miranda-Díaz; Pablo C Ortiz-Lazareno; Trinidad García-Iglesias; Adrian Daneri-Navarro; Mónica Vázquez-Del Mercado; Mary Fafutis-Morris

    2011-01-01

    AIM: To demonstrate that CD14+ cells are an important source of the growth factor YKL-40 in acute and chronic liver damage.METHODS: Rats were inoculated with one dose of CCl4 to induce acute damage. Liver biopsies were obtained at 0, 6, 12, 24, 48 and 72 h. For chronic damage, CCl4 was administered three days per week for 6 or 8 wk. Tissue samples were collected, and cellular populations were isolated by liver digestion and purified by cell sorting. YKL-40 mRNA and protein expression were evaluated by real-time polymerase chain reaction and western blot. RESULTS: Acute liver damage induced a rapid increase of YKL-40 mRNA beginning at 12 h. Expression peaked at 24 h, with a 26-fold increase over basal levels. By 72 h however, YKL-40 expression levels had nearly returned to control levels. On the other hand, chronic damage induced a sustained increase in YKL-40 expression, with 7- and 9-fold higher levels at 6 and 8 wk, respectively. The pattern of YKL-40 expression in different subpopulations showed that CD14+ cells, which include Kupffer cells, are a source of YKL-40 after acute damage at 72 h [0.09 relative expression units (REU)] as well as after chronic injury at 6 wk (0.11 REU). Hepatocytes, in turn, accounted for 0.06 and 0.01 REU after 72 h (acute) or 6 wk (chronic), respectively. The rest of the CD14- cells (including T lymphocytes, B lymphocytes, natural killer and natural killer T cells) yielded 0.07 and 0.15 REU at 72 h and 6 wk, respectively. YKL-40 protein expression in liver was detected at 72 h as well as 6 and 8 wk, with the highest expression relative to controls (11-fold; P ≤ 0.05) seen at 6 wk. Macrophages were stimulated by lipopolysaccharide. We demonstrate that under these conditions, these cells showed maximum expression of YKL-40 at 12 h, with P < 0.05 compared with controls.CONCLUSION: Hepatic CD14+ cells are an YKL-40 mRNA and protein source in acute and chronic liver injury, with expression patterns similar to growth factors implicated

  4. Characterization of Adapter Protein NRBP as a Negative Regulator of T Cell Activation

    Institute of Scientific and Technical Information of China (English)

    WANG Hui; LIN Zhi-xin; WU Jun

    2008-01-01

    Adapter proteins can regulate the gene transcriptions in disparate signaling pathway by interacting with multiple signaling molecules, including T cell activation signaling. Nuclear receptor binding protein (NRBP), a novel adapter protein, represents a small family of evolutionarily conserved proteins with homologs in Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D.melanogaster), mouse and human. Here, we demonstrated that overexpression of NRBP in Jurkat TAg cells specifically impairs T cell receptor (TCR) or phorbol myristate acetate (PMA)/ionomycin-mediated signaling leading to nuclear factor of activated T cells (NFAT) promoter activation. Furthermore, the N-terminal of NRBP is necessary for its regulation of NFAT activation. Finally, we showed that NRBP has minimal effect on both TCR- and PMA-induced CD69 up-regulation in Jurkat TAg cells, which suggests that NRBP may function downstream of protein kinase C (PKC)/Ras pathway.

  5. Regulatory Allospecific T Cell Clones Abrogate Chronic Allograft Rejection

    OpenAIRE

    Waaga-Gasser, Ana Maria; Grimm, Martin R.; Lutz, Jens; Lange, Volkmar; Lenhard, Susanne M.; Aviles, Beatriz; Kist-van Holthe, Joana E; Lebedeva, Tatiana; Samsonov, Dimitry; Meyer, Detlef; Hancock, Wayne W.; Heemann, Uwe; Gasser, Martin; Chandraker, Anil

    2009-01-01

    True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar...

  6. Adaptation of CD8 T cell responses to changing HIV-1 sequences in a cohort of HIV-1 infected individuals not selected for a certain HLA allele.

    Directory of Open Access Journals (Sweden)

    Julia Roider

    Full Text Available HIV evades CD8 T cell mediated pressure by viral escape mutations in targeted CD8 T cell epitopes. A viral escape mutation can lead to a decline of the respective CD8 T cell response. Our question was what happened after the decline of a CD8 T cell response and - in the case of viral escape - if a new CD8 T cell response towards the mutated antigen could be generated in a population not selected for certain HLA alleles. We studied 19 antiretroviral-naïve HIV-1 infected individuals with different disease courses longitudinally. A median number of 12 (range 2-24 CD8 T cell responses towards Gag and Nef were detected per study subject. A total of 30 declining CD8 T cell responses were studied in detail and viral sequence analyses showed amino acid changes in 25 (83% of these. Peptide titration assays and definition of optimal CD8 T cell epitopes revealed 12 viral escape mutations with one de-novo response (8%. The de-novo response, however, showed less effector functions than the original CD8 T cell response. In addition we identified 4 shifts in immunodominance. For one further shift in immunodominance, the mutations occurred outside the optimal epitope and might represent processing changes. Interestingly, four adaptations to the virus (the de-novo response and 3 shifts in immunodominance occurred in the group of chronically infected progressors. None of the subjects with adaptation to the changing virus carried the HLA alleles B57, B*58:01 or B27. Our results show that CD8 T cell responses adapt to the mutations of HIV. However it was limited to only 20% (5 out of 25 of the epitopes with viral sequence changes in a cohort not expressing protective HLA alleles.

  7. Adaptation of CD8 T cell responses to changing HIV-1 sequences in a cohort of HIV-1 infected individuals not selected for a certain HLA allele.

    Science.gov (United States)

    Roider, Julia; Kalteis, Anna-Lena; Vollbrecht, Thomas; Gloning, Lisa; Stirner, Renate; Henrich, Nadja; Bogner, Johannes R; Draenert, Rika

    2013-01-01

    HIV evades CD8 T cell mediated pressure by viral escape mutations in targeted CD8 T cell epitopes. A viral escape mutation can lead to a decline of the respective CD8 T cell response. Our question was what happened after the decline of a CD8 T cell response and - in the case of viral escape - if a new CD8 T cell response towards the mutated antigen could be generated in a population not selected for certain HLA alleles. We studied 19 antiretroviral-naïve HIV-1 infected individuals with different disease courses longitudinally. A median number of 12 (range 2-24) CD8 T cell responses towards Gag and Nef were detected per study subject. A total of 30 declining CD8 T cell responses were studied in detail and viral sequence analyses showed amino acid changes in 25 (83%) of these. Peptide titration assays and definition of optimal CD8 T cell epitopes revealed 12 viral escape mutations with one de-novo response (8%). The de-novo response, however, showed less effector functions than the original CD8 T cell response. In addition we identified 4 shifts in immunodominance. For one further shift in immunodominance, the mutations occurred outside the optimal epitope and might represent processing changes. Interestingly, four adaptations to the virus (the de-novo response and 3 shifts in immunodominance) occurred in the group of chronically infected progressors. None of the subjects with adaptation to the changing virus carried the HLA alleles B57, B*58:01 or B27. Our results show that CD8 T cell responses adapt to the mutations of HIV. However it was limited to only 20% (5 out of 25) of the epitopes with viral sequence changes in a cohort not expressing protective HLA alleles.

  8. Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality.

    Science.gov (United States)

    Bárcena, Paloma; Jara-Acevedo, María; Tabernero, María Dolores; López, Antonio; Sánchez, María Luz; García-Montero, Andrés C; Muñoz-García, Noemí; Vidriales, María Belén; Paiva, Artur; Lecrevisse, Quentin; Lima, Margarida; Langerak, Anton W; Böttcher, Sebastian; van Dongen, Jacques J M; Orfao, Alberto; Almeida, Julia

    2015-12-15

    Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56(low) NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56(low) NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94(hi)/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality.

  9. Therapy with bone marrow cells reduces liver alterations in mice chronically infected by Schistosoma mansoni

    Institute of Scientific and Technical Information of China (English)

    Sheilla Andrade Oliveira; Bruno Solano Freitas Souza; Cada Adriana Guimar(a)es-Ferreira; Elton Sá Barreto; Siane Campos Souza; Luiz Antonio Rodrigues Freitas; Ricardo Ribeiro-dos-Santos; Milena Botelho Pereira Soares

    2008-01-01

    AIM: To investigate the potential of bone marrow mononuclear cells (BM-MCs) in the regeneration of hepatic lesions induced by Schistosoma mansoni (S.mansoni) chronic infection.METHODS: Female mice chronically infected with S.mansoni were treated with BM-MCs obtained from male green fluorescent protein (GFP) transgenic mice by intravenous or intralobular injections. Control mice received injections of saline in similar conditions. Enzyme-linked immunosorbent assay (ELISA) assay for transforming growth factor-beta (TGF-β), polymerase chain reaction (PCR) for GFP DNA, immunofluorescence and morphometric studies were performed.RESULTS: Transplanted GFP+ cells migrated to granuloma areas and reduced the percentage of liver fibrosis. The presence of donor-derived cells was confirmed by Fluorescence in situ hybridization (FISH) analysis for detection of cells bearing Y chromosome and by PCR analysis for detection of GFP DNA. The levels of TGF-β, a cytokine associated with fibrosis deposition, in liver fragments of mice submitted to therapy were reduced. The number of oval cells in liver sections of S.rnansoni-infected mice increased 3-4 fold after transplantation. A partial recovery in albumin expression, which is decreased upon infection with S.mansoni, was found in livers of infected mice after cellular therapy.CONCLUSION: In conclusion, transplanted BMCs migrate to and reduce the damage of chronic fibrotic liver lesions caused by S.mansoni.

  10. Langerhans cells in human chronic gingivitis and phenytoin-induced gingival hyperplasia.

    Science.gov (United States)

    Kinane, D F; Drummond, J R; Chisholm, D M

    1990-01-01

    Langerhans cell numbers in oral epithelium increase as dental plaque accumulates. The anti-convulsant drug phenytoin predisposes to gingival hyperplasia in certain patients who take this medication for epilepsy and who also have poor oral hygiene. In this study 7 patients with phenytoin-induced gingival hyperplasia were compared with 5 subjects with chronic marginal gingivitis. On initial examination and on completion of the hygiene phase of periodontal therapy (a period ranging from 3.0 to 4.25 months), clinical indices of plaque and gingivitis were recorded and biopsies were taken from the lower anterior labial gingiva. Frozen sections were stained by an immunoperoxidase technique using the monoclonal antibody OKT6, and the number of Langerhans cells in a defined cross-sectional area was counted. In phenytoin-induced gingival hyperplasia there was a marked increase in Langerhans cells (13.8 +/- 0.45) when compared with chronic gingivitis (7.7 +/- 0.31; p less than 0.05). Both groups showed marked reductions in their plaque and gingival indices and numbers of Langerhans cells once treatment had been completed. However, levels of Langerhans cells in the drug-induced hyperplasia remained significantly higher (3.5 +/- 0.26) than in chronic gingivitis (1.5 +/- 0.22; p less than 0.05).

  11. Robust Cell Detection of Histopathological Brain Tumor Images Using Sparse Reconstruction and Adaptive Dictionary Selection.

    Science.gov (United States)

    Su, Hai; Xing, Fuyong; Yang, Lin

    2016-06-01

    Successful diagnostic and prognostic stratification, treatment outcome prediction, and therapy planning depend on reproducible and accurate pathology analysis. Computer aided diagnosis (CAD) is a useful tool to help doctors make better decisions in cancer diagnosis and treatment. Accurate cell detection is often an essential prerequisite for subsequent cellular analysis. The major challenge of robust brain tumor nuclei/cell detection is to handle significant variations in cell appearance and to split touching cells. In this paper, we present an automatic cell detection framework using sparse reconstruction and adaptive dictionary learning. The main contributions of our method are: 1) A sparse reconstruction based approach to split touching cells; 2) An adaptive dictionary learning method used to handle cell appearance variations. The proposed method has been extensively tested on a data set with more than 2000 cells extracted from 32 whole slide scanned images. The automatic cell detection results are compared with the manually annotated ground truth and other state-of-the-art cell detection algorithms. The proposed method achieves the best cell detection accuracy with a F1 score = 0.96.

  12. Microfluidic gradient device for studying mesothelial cell migration and the effect of chronic carbon nanotube exposure

    International Nuclear Information System (INIS)

    Cell migration is one of the crucial steps in many physiological and pathological processes, including cancer development. Our recent studies have shown that carbon nanotubes (CNTs), similarly to asbestos, can induce accelerated cell growth and invasiveness that contribute to their mesothelioma pathogenicity. Malignant mesothelioma is a very aggressive tumor that develops from cells of the mesothelium, and is most commonly caused by exposure to asbestos. CNTs have a similar structure and mode of exposure to asbestos. This has raised a concern regarding the potential carcinogenicity of CNTs, especially in the pleural area which is a key target for asbestos-related diseases. In this paper, a static microfluidic gradient device was applied to study the migration of human pleural mesothelial cells which had been through a long-term exposure (4 months) to subcytotoxic concentration (0.02 µg cm−2) of single-walled CNTs (SWCNTs). Multiple migration signatures of these cells were investigated using the microfluidic gradient device for the first time. During the migration study, we observed that cell morphologies changed from flattened shapes to spindle shapes prior to their migration after their sensing of the chemical gradient. The migration of chronically SWCNT-exposed mesothelial cells was evaluated under different fetal bovine serum (FBS) concentration gradients, and the migration speeds and number of migrating cells were extracted and compared. The results showed that chronically SWCNT-exposed mesothelial cells are more sensitive to the gradient compared to non-SWCNT-exposed cells. The method described here allows simultaneous detection of cell morphology and migration under chemical gradient conditions, and also allows for real-time monitoring of cell motility that resembles in vivo cell migration. This platform would be much needed for supporting the development of more physiologically relevant cell models for better assessment and characterization of the

  13. Microfluidic gradient device for studying mesothelial cell migration and the effect of chronic carbon nanotube exposure

    Science.gov (United States)

    Zhang, Hanyuan; Lohcharoenkal, Warangkana; Sun, Jianbo; Li, Xiang; Wang, Liying; Wu, Nianqiang; Rojanasakul, Yon; Liu, Yuxin

    2016-01-01

    Cell migration is one of the crucial steps in many physiological and pathological processes, including cancer development. Our recent studies have shown that carbon nanotubes (CNTs), similarly to asbestos, can induce accelerated cell growth and invasiveness that contribute to their mesothelioma pathogenicity. Malignant mesothelioma is a very aggressive tumor that develops from cells of the mesothelium, and is most commonly caused by exposure to asbestos. CNTs have a similar structure and mode of exposure to asbestos. This has raised a concern regarding the potential carcinogenicity of CNTs, especially in the pleural area which is a key target for asbestos-related diseases. In this paper, a static microfluidic gradient device was applied to study the migration of human pleural mesothelial cells which had been through a long-term exposure (4 months) to subcytotoxic concentration (0.02 μg cm−2) of single-walled CNTs (SWCNTs). Multiple migration signatures of these cells were investigated using the microfluidic gradient device for the first time. During the migration study, we observed that cell morphologies changed from flattened shapes to spindle shapes prior to their migration after their sensing of the chemical gradient. The migration of chronically SWCNT-exposed mesothelial cells was evaluated under different fetal bovine serum (FBS) concentration gradients, and the migration speeds and number of migrating cells were extracted and compared. The results showed that chronically SWCNT-exposed mesothelial cells are more sensitive to the gradient compared to non-SWCNT-exposed cells. The method described here allows simultaneous detection of cell morphology and migration under chemical gradient conditions, and also allows for real-time monitoring of cell motility that resembles in vivo cell migration. This platform would be much needed for supporting the development of more physiologically relevant cell models for better assessment and characterization of the

  14. Effects of pattern shape on adaptation of dLGN cell

    Institute of Scientific and Technical Information of China (English)

    JIN Jianzhong; XU Pengjing; LI Xiangrui; ZHOU Yifeng

    2003-01-01

    Pattern adaptation is one of the fundamental sensory processes in the visual system. In this study, we compared pattern adaptation induced by two types of sinusoidal drifting grating in dLGN cells of cat. The two types ofgrating have the same parameters (e.g. spatial frequency, temporal frequency and contrast) except their pattern shapes, one of which is normal grating and the other annular grating. The results suggested that the annular grating elicited stronger response and stronger pattern adaptation than the normal grating. This is consistent with the adaptation and aftereffect to the two types of drifting gratings seen in psychology and may reflect the subcortical neural mechanism underlying these psychological phenomena.

  15. Effects of Copper-phenanthroline on Pentschlorophenol-induced Adaptation and Cell Death of Escherichia coli

    Institute of Scientific and Technical Information of China (English)

    XUE-WEN ZHANG; RONG-GUI LI; XIN WANG; SHUAN-HU ZHOU

    2007-01-01

    Objective To evaluate the effects of copper-phenanthroline (CuOP) on pentachlorophenol (PCP)-induced adaptation and cell death of Escherichia coli. Methods Bacterial growth and adaptation to PCP were monitored spectrophotometrically at 600 nm. Inactivation of bacterial cells was determined from colony count on agar dishes. Cellular ATP content and accumulation of PCP were assessed by chemiluminescence and HPLC analysis respectively. The formation of PCP-Cu-OP complex was shown by UV-visible spectra. Results Escherichia coli (E. coli) could adapt to PCP, a wood preservative and insecticide used in agriculture. The adaptation of E. coli to PCP prevented its death to the synergistic cytotoxicity of CuOP plus PCP and declined cellular accumulation and uncoupling of oxidative phosphorylafion of PCP. Furthermore, CuOP and PCP neither produced reactive oxygen species (ROS) nor had a synergistic effect on uncoupling of oxidative phosphorylation in E.coli. The synergistic cytotoxicity of CuOP and PCP in E. coli might be due to the formation of lipophillc PCP-Cu-OP complex.Conclsion Our data suggested that adaptation of E. coli to PCP decreased the synergistic effects of CuOP and PCP on prokaryotic cell death due to the formation of lipophilic PCP-Cu-OP complex, but it had no effect on the uncoupling of oxidative phosphorylation and production of reactive oxygen species in E. coli.

  16. Optimality and adaptation of phenotypically switching cells in fluctuating environments.

    Science.gov (United States)

    Belete, Merzu Kebede; Balázsi, Gábor

    2015-12-01

    Stochastic switching between alternative phenotypic states is a common cellular survival strategy during unforeseen environmental fluctuations. Cells can switch between different subpopulations that proliferate at different rates in different environments. Optimal population growth is typically assumed to occur when phenotypic switching rates match environmental switching rates. However, it is not well understood how this optimum behaves as a function of the growth rates of phenotypically different cells. In this study, we use mathematical and computational models to test how the actual parameters associated with optimal population growth differ from those assumed to be optimal. We find that the predicted optimum is practically always valid if the environmental durations are long. However, the regime of validity narrows as environmental durations shorten, especially if subpopulation growth rate differences differ from each other (are asymmetric) in two environments. Furthermore, we study the fate of mutants with switching rates previously predicted to be optimal. We find that mutants which match their phenotypic switching rates with the environmental ones can only sweep the population if the assumed optimum is valid, but not otherwise.

  17. Optimality and adaptation of phenotypically switching cells in fluctuating environments

    Science.gov (United States)

    Belete, Merzu Kebede; Balázsi, Gábor

    2015-12-01

    Stochastic switching between alternative phenotypic states is a common cellular survival strategy during unforeseen environmental fluctuations. Cells can switch between different subpopulations that proliferate at different rates in different environments. Optimal population growth is typically assumed to occur when phenotypic switching rates match environmental switching rates. However, it is not well understood how this optimum behaves as a function of the growth rates of phenotypically different cells. In this study, we use mathematical and computational models to test how the actual parameters associated with optimal population growth differ from those assumed to be optimal. We find that the predicted optimum is practically always valid if the environmental durations are long. However, the regime of validity narrows as environmental durations shorten, especially if subpopulation growth rate differences differ from each other (are asymmetric) in two environments. Furthermore, we study the fate of mutants with switching rates previously predicted to be optimal. We find that mutants which match their phenotypic switching rates with the environmental ones can only sweep the population if the assumed optimum is valid, but not otherwise.

  18. Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis.

    Science.gov (United States)

    Hwang, SuJin; Cobb, Dustin A; Bhadra, Rajarshi; Youngblood, Ben; Khan, Imtiaz A

    2016-08-22

    CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)-susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell-intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches. PMID:27481131

  19. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress.

    Science.gov (United States)

    Makkinje, A; Quinn, D A; Chen, A; Cadilla, C L; Force, T; Bonventre, J V; Kyriakis, J M

    2000-06-01

    Chronic stresses, including the mechanical strain caused by hypertension or excess pulmonary ventilation pressure, lead to important clinical consequences, including hypertrophy and acute respiratory distress syndrome. Pathologic hypertrophy contributes to decreased organ function and, ultimately, organ failure; and cardiac and diabetic renal hypertrophy are major causes of morbidity and morality in the developed world. Likewise, acute respiratory distress syndrome is a serious potential side effect of mechanical pulmonary ventilation. Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-inducible gene-6, mig-6) is an immediate early gene that is transcriptionally induced by a divergent array of extracellular stimuli. The physiologic function of Gene 33 is unknown. Here we show that gene 33 mRNA levels increase sharply in response to a set of commonly occurring chronic stress stimuli: mechanical strain, vasoactive peptides, and diabetic nephropathy. Induction of gene 33 requires the stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases. This expression pattern suggests that gene 33 is a potential marker for diabetic nephropathy and other pathologic responses to persistent sublethal stress. The structure of Gene 33 indicates an adapter protein capable of binding monomeric GTPases of the Rho subfamily. Consistent with this, Gene 33 interacts in vivo and, in a GTP-dependent manner, in vitro with Cdc42Hs; and transient expression of Gene 33 results in the selective activation of the SAPKs. These results imply a reciprocal, positive feedback relationship between Gene 33 expression and SAPK activation. Expression of Gene 33 at sufficient levels may enable a compensatory reprogramming of cellular function in response to chronic stress, which may have pathophysiological consequences. PMID:10749885

  20. Adaptive sliding mode control of interleaved parallel boost converter for fuel cell energy generation system

    DEFF Research Database (Denmark)

    El Fadil, H.; Giri, F.; Guerrero, Josep M.

    2013-01-01

    This paper deals with the problem of controlling energy generation systems including fuel cells (FCs) and interleaved boost power converters. The proposed nonlinear adaptive controller is designed using sliding mode control (SMC) technique based on the system nonlinear model. The latter accounts...... for the boost converter large-signal dynamics as well as for the fuel-cell nonlinear characteristics. The adaptive nonlinear controller involves online estimation of the DC bus impedance ‘seen’ by the converter. The control objective is threefold: (i) asymptotic stability of the closed loop system......, (ii) output voltage regulation under bus impedance uncertainties and (iii) equal current sharing between modules. It is formally shown, using theoretical analysis and simulations, that the developed adaptive controller actually meets its control objectives....

  1. Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search.

    Directory of Open Access Journals (Sweden)

    G Matthew Fricke

    2016-03-01

    Full Text Available Effective search strategies have evolved in many biological systems, including the immune system. T cells are key effectors of the immune response, required for clearance of pathogenic infection. T cell activation requires that T cells encounter antigen-bearing dendritic cells within lymph nodes, thus, T cell search patterns within lymph nodes may be a crucial determinant of how quickly a T cell immune response can be initiated. Previous work suggests that T cell motion in the lymph node is similar to a Brownian random walk, however, no detailed analysis has definitively shown whether T cell movement is consistent with Brownian motion. Here, we provide a precise description of T cell motility in lymph nodes and a computational model that demonstrates how motility impacts T cell search efficiency. We find that both Brownian and Lévy walks fail to capture the complexity of T cell motion. Instead, T cell movement is better described as a correlated random walk with a heavy-tailed distribution of step lengths. Using computer simulations, we identify three distinct factors that contribute to increasing T cell search efficiency: 1 a lognormal distribution of step lengths, 2 motion that is directionally persistent over short time scales, and 3 heterogeneity in movement patterns. Furthermore, we show that T cells move differently in specific frequently visited locations that we call "hotspots" within lymph nodes, suggesting that T cells change their movement in response to the lymph node environment. Our results show that like foraging animals, T cells adapt to environmental cues, suggesting that adaption is a fundamental feature of biological search.

  2. Mesenchymal stromal cells and chronic inflammatory bowel disease.

    Science.gov (United States)

    Algeri, M; Conforti, A; Pitisci, A; Starc, N; Tomao, L; Bernardo, M E; Locatelli, F

    2015-12-01

    Recent experimental findings have shown the ability of mesenchymal stromal cells (MSCs) to home to damaged tissues and to produce paracrine factors with anti-inflammatory properties, potentially resulting in reduction of inflammation and functional recovery of the damaged tissues. Prompted by these intriguing properties and on the basis of encouraging preclinical data, MSCs are currently being studied in several immune-mediated disorders. Inflammatory bowel diseases (IBD) represent a setting in which MSCs-based therapy has been extensively investigated. Phase I and II studies have documented the safety and feasibility of MSCs. However, efficacy results have so far been conflicting. In this review, we will discuss the biologic rationale that makes MSCs a promising therapeutic tool for IBD, and analyze recent experimental and clinical findings, highlighting current limitations and future perspectives of MSCs-related immunotherapy for IBD. PMID:26170204

  3. Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction.

    OpenAIRE

    Vos, R.; Desmet, V

    1992-01-01

    Previous immunohistochemical studies on human liver biopsies with chronic ductular reaction revealed the presence of "small cells" with bile-duct type cytokeratin profile in the periportal area. This study identified similar cells by electron microscopy. The authors studied 13 human liver specimens with various liver diseases, but all characterized by chronic ductular reaction. In all specimens, variable numbers of "small cells" with common epithelial characteristics were identified in the pe...

  4. Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications

    Directory of Open Access Journals (Sweden)

    Zsuzsa eSzondy

    2014-08-01

    Full Text Available In healthy individuals billions of cells die by apoptosis every day. Removal of the dead cells by phagocytosis (a process called efferocytosis must be efficient to prevent secondary necrosis and the consequent release of proinflammatory cell contents that damages the tissue environment and provokes autoimmunity. In addition, detection and removal of apoptotic cells generally induces an anti-inflammatory response. As a consequence improper clearance of apoptotic cells, being the result of either genetic anomalies and /or a persistent disease state, contributes to the establishment and progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases, obesity, type 2 diabetes or atherosclerosis. During the past decade our knowledge about the mechanism of efferocytosis has significantly increased, providing therapeutic targets through which impaired phagocytosis of apoptotic cells and the consequent inflammation could be influenced in these diseases.

  5. Emerging roles of extracellular vesicles in the adaptive response of tumour cells to microenvironmental stress

    Directory of Open Access Journals (Sweden)

    Paulina Kucharzewska

    2013-03-01

    Full Text Available Cells are constantly subjected to various types of endogenous and exogenous stressful stimuli, which can cause serious and even permanent damage. The ability of a cell to sense and adapt to environmental alterations is thus vital to maintain tissue homeostasis during development and adult life. Here, we review some of the major phenotypic characteristics of the hostile tumour microenvironment and the emerging roles of extracellular vesicles in these events.

  6. Determining adaptive and adverse oxidative stress responses in human bronical epithelial cells exposed to zinc

    Science.gov (United States)

    Determining adaptive and adverse oxidative stress responses in human bronchial epithelial cells exposed to zincJenna M. Currier1,2, Wan-Yun Cheng1, Rory Conolly1, Brian N. Chorley1Zinc is a ubiquitous contaminant of ambient air that presents an oxidant challenge to the human lung...

  7. Comparison of adaptive response to γ-radiation and nickel sulfate treatment in human cells

    International Nuclear Information System (INIS)

    The comparison of the adaptive response to the impact of the γ-irradiation and nickel sulfate treatment in human cells, as the adaptive factors relative to these mutagens in the challenging doses by the cells survival criterium, is carried out. The pretreatment of human fibroblasts (the rhabdomyosarcoma line) with the low dose γ-radiation (10-14 cGy) formed increased viability of human cells to the nickel sulfate high concentrations (10-5-10-3 M). The adaptive response observed was similar to the radioadaptive response in human fibroblasts pretreated with low doses of γ-radiation with subsequent impact of high dose radiation. The pretreatment of human cells with the nickel sulfate low concentrations induced the DNA increased stability by impact of challenging doses of the γ-radiation and stimulated the DNA reparative synthesis by impact of both NiSO4 and 4-nitroquinoline-1-oxide. These data confirm the existence of the cross-sectional adaptive response in the experiments with the nickel sulfate

  8. Group-specific human granulocyte antigens on a chronic myelogenous leukemia cell line with a Philadelphia chromosome marker.

    Science.gov (United States)

    Drew, S I; Terasaki, P I; Billing, R J; Bergh, O J; Minowada, J; Klein, E

    1977-05-01

    Group-specific human granulocyte antigens are serologically detectable with granulocytotoxic-positive human alloantisera on a cell line, K562, of chronic myelogenous leukemia origin which bears a Philadelphia chromosomal marker. The same cell line lacks serologically detectable HLA, B2 microglobulin, and B-lymphocyte antigens. Granulocyte antigens are important cell markers for cell lines of suspected myeloid lineage.

  9. Bmi-1 confers adaptive radioresistance to KYSE-150R esophageal carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Guanyu [Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Liu, Luying [Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou (China); Sharma, Sherven [David Geffen School of Medicine at UCLA, and the Department of Veterans Affairs, Los Angeles, CA (United States); Liu, Hai; Yang, Weifang; Sun, Xiaonan [Department of Radiotherapy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Dong, Qinghua, E-mail: dongqinghua@zju.edu.cn [Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou (China)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Adaptive radioresistant KYSE-150R cells expressed high level of Bmi-1. Black-Right-Pointing-Pointer Bmi-1 depletion sensitized KYSE-150R cells to RT. Black-Right-Pointing-Pointer Bmi-1 depletion increased the generation of ROS in KYSE-150R cells exposed to radiation. Black-Right-Pointing-Pointer Bmi-1 depletion impaired DNA repair capacities in KYSE-150R cells exposed to radiation. -- Abstract: Radiotherapy (RT) is a major modality of cancer treatment. However, tumors often acquire radioresistance, which causes RT to fail. The exact mechanisms by which tumor cells subjected to fractionated irradiation (FIR) develop an adaptive radioresistance are largely unknown. Using the radioresistant KYSE-150R esophageal squamous cell carcinoma (ESCC) model, which was derived from KYSE-150 parental cells using FIR, the role of Bmi-1 in mediating the radioadaptive response of ESCC cells to RT was investigated. The results showed that the level of Bmi-1 expression was significantly higher in KYSE-150R cells than in the KYSE-150 parental cells. Bmi-1 depletion sensitized the KYSE-150R cells to RT mainly through the induction of apoptosis, partly through the induction of senescence. A clonogenic cell survival assay showed that Bmi-1 depletion significantly decreased the radiation survival fraction in KYSE-150R cells. Furthermore, Bmi-1 depletion increased the generation of reactive oxygen species (ROS) and the expression of oxidase genes (Lpo, Noxo1 and Alox15) in KYSE-150R cells exposed to irradiation. DNA repair capacities assessed by {gamma}-H2AX foci formation were also impaired in the Bmi-1 down-regulated KYSE-150R cells. These results suggest that Bmi-1 plays an important role in tumor radioadaptive resistance under FIR and may be a potent molecular target for enhancing the efficacy of fractionated RT.

  10. Distribution specificity of polarized populations of T helper cells in patients with chronic hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    JIANG Rong-long; FENG Xiao-rong; LU Qiao-sheng; LUO Kang-xian; FU Ning

    2001-01-01

    Objective: To investigate the roles of the polarized populations of T helper cells isolated from the peripheral blood mononuclear cells (PBMCs) of individuals with chronic hepatitis B virus (HBV) infection. Methods: PBMCs from patients with chronic HBV infection were separated routinely, stimulated by PMA, ionomycin and monensin, and the production of IL-4, IFN-γ and TGF-β by CD4+ T cells was observed by flow cytometry(FACS). Results: The percentages of the T cells producing IFN-γ, IL-4 or TGF-β ranged from 2.3% to 18.6%, 1.1% to 8.7% and 0.7% to 7.1% respectively among CD4+ cells from non-infected individuals. The majority of CD4+ T cells in PBMCs from individuals with chronic HBV infection were Th0 cells. The proportion of Th1 cells in patients with active chronic hepatitis B was higher than that in patients at inactive stage of the disease (P<0.05), indicating a significant elevation of Thl cells with the hepatic inflammation activity. The percentage of Th2 cells in individuals with HBV infection was higher than that in controls (P<0.05),but showed no difference between different patients (P>0.05). The percentage of Th3 cells was higher in asymptomatic HBV carriers than that in patients with chronic hepatitis B and in healthy controls (P<0.05). Conclusions: Th1-type cytokines are related with hepatic inflammation activity of chronic hepatitis B, and Th2 cells may be associated with the persistence of HBV infection. Th3 cells cooperating with Th2 cells are likely to function as negative immunoregulator, and may be responsible for the immune tolerance state of chronic HBV infection.

  11. Parameter extraction of different fuel cell models with transferred adaptive differential evolution

    International Nuclear Information System (INIS)

    To improve the design and control of FC (fuel cell) models, it is important to extract their unknown parameters. Generally, the parameter extraction problems of FC models can be transformed as nonlinear and multi-variable optimization problems. To extract the parameters of different FC models exactly and fast, in this paper, we propose a transferred adaptive DE (differential evolution) framework, in which the successful parameters of the adaptive DE solving previous problems are properly transferred to solve new optimization problems in the similar problem-domains. Based on this framework, an improved adaptive DE method (TRADE, in short) is presented as an illustration. To verify the performance of our proposal, TRADE is used to extract the unknown parameters of two types of fuel cell models, i.e., PEMFC (proton exchange membrane fuel cell) and SOFC (solid oxide fuel cell). The results of TRADE are also compared with those of other state-of-the-art EAs (evolutionary algorithms). Even though the modification is very simple, the results indicate that TRADE can extract the parameters of both PEMFC and SOFC models exactly and fast. Moreover, the V–I characteristics obtained by TRADE agree well with the simulated and experimental data in all cases for both types of fuel cell models. Also, it improves the performance of the original adaptive DE significantly in terms of both the quality of final solutions and the convergence speed in all cases. Additionally, TRADE is able to provide better results compared with other EAs. - Highlights: • A framework of transferred adaptive differential evolution is proposed. • Based on the framework, an improved differential evolution (TRADE) is presented. • TRADE obtains very promising results to extract the parameters of PEMFC and SOFC models

  12. Mixed T helper cell signatures in chronic rhinosinusitis with and without polyps.

    Directory of Open Access Journals (Sweden)

    Lara Derycke

    Full Text Available In chronic rhinosinusitis (CRS different phenotypes have been reported based on cytokine profile and inflammatory cell patterns. The aim of this study was to characterize the intracytoplasmatic cytokines of T cells infiltrating the inflamed sinonasal mucosa.Infiltrated T cells and tissue homogenates from sinonasal mucosal samples of 7 healthy subjects, 9 patients with CRS without nasal polyp (CRSsNP, 15 with CRS with nasal polyps (CRSwNP and 5 cystic fibrosis patients (CF-NP were analyzed for cytokine expression using flow cytometry and multiplex analysis respectively. Intracytoplasmic cytokinesin T cells were analyzed after stimulation of nasal polyps with Staphylococcus aureus enterotoxin B for 24 hours.The number of T cells per total living cells was significantly higher in patients with CRSwNP vs. CRSsNP and controls. 85% of the CD4(+ T cells showed to be memory T cells. The effector T cells present in all tissues have a predominant Th1 phenotype. Only in CRSwNP, a significant fraction of T cells produced the Th2 cytokines IL-4 and IL-5, while nasal polyps from CF patients were characterized by a higher CD4/CD8 T cell ratio and an increased number of Th17 cells. 24 h stimulation with SEB resulted in a significant induction of CD4(+ T cells producing IL-10 (Tr1 cells.T cell cytokine patterns in healthy and inflamed sinonasal mucosa revealed that Th2 cells (IL-4 and IL-5 producing cells are significantly increased in CRSwNP mucosal inflammation. Exposure to SEB stimulates Tr1 cells that may contribute to the Th2 bias in CRSwNP.

  13. Olfactory ensheathing cell transplantation improves sympathetic skin responses in chronic spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    Zuncheng Zheng; Guifeng Liu; Yuexia Chen; Shugang Wei

    2013-01-01

    Forty-three patients with chronic spinal cord injury for over 6 months were transplanted with bryonic olfactory ensheathing cells, 2-4 × 106, into multiple sites in the injured area under the sur-gical microscope. The sympathetic skin response in patients was measured with an electromyo-graphy/evoked potential instrument 1 day before transplantation and 3-8 weeks after trans-tion. Spinal nerve function of patients was assessed using the American Spinal Injury Association impairment scale. The sympathetic skin response was elicited in 32 cases before olfactory en-sheathing celltransplantation, while it was observed in 34 cases after transplantation. tantly, sympathetic skin response latency decreased significantly and amplitude increased cantly after transplantation. Transplantation of olfactory ensheathing cells also improved American Spinal Injury Association scores for movement, pain and light touch. Our findings indicate that factory ensheathing celltransplantation improves motor, sensory and autonomic nerve functions in patients with chronic spinal cord injury.

  14. [Phospholipids and structural modification of tissues and cell membranes for adaptation in high altitude mountains].

    Science.gov (United States)

    Iakovlev, V M; Vishnevskiĭ, A A; Shanazarov, A S

    2012-01-01

    The nature of the impact of physical factors of high altitudes (3200 m) on the lipids of tissues and membranes of animals was researched. It was established that the adaptation process in Wistar rats was followed by peroxide degradation and subsequent modification of the phospholipids' structure of tissues and microsomal membranes. Adaptive phospholipids reconstruction takes place in microsomal membranes in the tissues of the lungs, brain, liver and skeletal muscles. Together with this, the amount of phosphatidylinositol and phosphatidic acid accumulates, indicating that the hydrolysis of phosphatidylinositol-4, 5 biphosphate to diacylglycerol and secondary messenger--inositol triphosphate, occurs. A decrease in temperature adaptation (+10 degrees C) leads to a more noticeable shift in peroxide oxidation of lipids, phospholipid structure in the tissues and membranes rather than adaptation in thermoneutral conditions (+30 degrees C). Modification of lipid composition of tissues and cell membranes in the highlands obviously increases the adaptive capabilities of cells of the whole body: physical performance and resistance to hypoxia increases in animals. PMID:22586936

  15. [Phospholipids and structural modification of tissues and cell membranes for adaptation in high altitude mountains].

    Science.gov (United States)

    Iakovlev, V M; Vishnevskiĭ, A A; Shanazarov, A S

    2012-01-01

    The nature of the impact of physical factors of high altitudes (3200 m) on the lipids of tissues and membranes of animals was researched. It was established that the adaptation process in Wistar rats was followed by peroxide degradation and subsequent modification of the phospholipids' structure of tissues and microsomal membranes. Adaptive phospholipids reconstruction takes place in microsomal membranes in the tissues of the lungs, brain, liver and skeletal muscles. Together with this, the amount of phosphatidylinositol and phosphatidic acid accumulates, indicating that the hydrolysis of phosphatidylinositol-4, 5 biphosphate to diacylglycerol and secondary messenger--inositol triphosphate, occurs. A decrease in temperature adaptation (+10 degrees C) leads to a more noticeable shift in peroxide oxidation of lipids, phospholipid structure in the tissues and membranes rather than adaptation in thermoneutral conditions (+30 degrees C). Modification of lipid composition of tissues and cell membranes in the highlands obviously increases the adaptive capabilities of cells of the whole body: physical performance and resistance to hypoxia increases in animals.

  16. Relation of spontaneous transformation in cell culture to adaptive growth and clonal heterogeneity.

    Science.gov (United States)

    Rubin, A L; Yao, A; Rubin, H

    1990-01-01

    Cell transformation in culture is marked by the appearance of morphologically altered cells that continue to multiply to form discrete foci in confluent sheets when the surrounding cells are inhibited. These foci occur spontaneously in early-passage NIH 3T3 cells grown to confluency in 10% calf serum (CS) but are not seen in cultures grown to confluency in 2% CS. However, repeated passage of the cells at low density in 2% CS gives rise to an adapted population that grows to increasingly higher saturation densities and produces large numbers of foci in 2% CS. The increased saturation density of the adapted population in 2% CS is retained upon repeated passage in 10% CS, but the number and size of the foci produced in 2% CS gradually decrease under this regime. Clonal analysis confirms that the focus-forming potential of most if not all of the cells in a population increases in response to a continuously applied growth constraint, although only a small fraction of the population may actually form foci in a given assay. The acquired capacity for focus formation varies widely in clones derived from the adapted population and changes in diverse ways upon further passage of the clones. We propose that the adaptive changes result from progressive selection of successive phenotypic variations in growth capacity that occur spontaneously. The process designated progressive state selection resolves the apparent dichotomy between spontaneous mutation with selection on the one hand and induction on the other, by introducing selection among fluctuating states or metabolic patterns rather than among genetically altered cells.

  17. Olfactory ensheathing cell transplantation improves sympathetic skin responses in chronic spinal cord injury

    OpenAIRE

    Zheng, Zuncheng; Liu, Guifeng; Chen, Yuexia; Wei, Shugang

    2013-01-01

    Forty-three patients with chronic spinal cord injury for over 6 months were transplanted with bryonic olfactory ensheathing cells, 2–4 × 106, into multiple sites in the injured area under the surgical microscope. The sympathetic skin response in patients was measured with an electromyography/evoked potential instrument 1 day before transplantation and 3–8 weeks after transtion. Spinal nerve function of patients was assessed using the American Spinal Injury Association impairment scale. The sy...

  18. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    OpenAIRE

    Sara Chiappalupi; Giovanni De Luca; Francesca Mancuso; Luca Madaro; Francesca Fallarino; Carmine Nicoletti; Mario Calvitti; Iva Arato; Giulia Falabella; Laura Salvadori; Antonio Di Meo; Antonello Bufalari; Stefano Giovagnoli; Riccardo Calafiore; Rosario Donato

    2015-01-01

    We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data ...

  19. Production of interferon-γ by natural killer cells and aging in chronic human schistosomiasis

    Directory of Open Access Journals (Sweden)

    E. Speziali

    2004-01-01

    Full Text Available BACKGROUNG: Aging is associated with several alterations in the phenotype, repertoire and activation status of lymphocytes as well as in the cytokine profile produced by these cells. As a lifelong condition, chronic parasitic diseases such as human schistosomiasis overlaps with the aging process and no systematic study has yet addressed the changes in immune response during infection with Schistosoma mansoni in older individuals.

  20. Chronic kidney disease after liver, cardiac, lung, heart–lung, and hematopoietic stem cell transplant

    OpenAIRE

    Hingorani, Sangeeta

    2008-01-01

    Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosc...

  1. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

    OpenAIRE

    Tucker DL; Rule SA

    2015-01-01

    David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, ...

  2. Exercise ameliorates chronic kidney disease–induced defects in muscle protein metabolism and progenitor cell function

    OpenAIRE

    Wang, Xiaonan H.; Du, Jie; Klein, Janet D.; Bailey, James L; Mitch, William E.

    2009-01-01

    Chronic kidney disease (CKD) impairs muscle protein metabolism leading to muscle atrophy, and exercise can counteract this muscle wasting. Here we evaluated how resistance exercise (muscle overload) and endurance training (treadmill running) affect CKD-induced abnormalities in muscle protein metabolism and progenitor cell function using mouse plantaris muscle. Both exercise models blunted the increase in disease-induced muscle proteolysis and improved phosphorylation of Akt and the forkhead t...

  3. Induced Resistance to Ofatumumab Mediated Cell Clearance Mechanisms, Including Complement Dependent Cytotoxicity, in Chronic Lymphocytic Leukemia

    OpenAIRE

    Baig, Nisar A.; Taylor, Ronald P.; Lindorfer, Margaret A.; Church, Amy K.; LaPlant, Betsy R.; Pettinger, Adam M.; Shanafelt, Tait D.; Nowakowski, Grzegorz S.; Zent, Clive S.

    2014-01-01

    Ofatumumab (OFA), a human CD20 targeting mAb, kills B-lymphocytes utilizing the innate immune system including complement dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients under...

  4. Increased osteoclast formation and activity by peripheral blood mononuclear cells in chronic liver disease patients with osteopenia

    NARCIS (Netherlands)

    B.J. Olivier; A.M. Schoenmaker; R.E. Mebius; V. Everts; C.J. Mulder; K.M.J. van Nieuwkerk; T.J. de Vries; S.W. van der Merwe

    2008-01-01

    Osteoporosis is a common complication of chronic liver disease, and the underlying mechanisms are not understood. We aimed to determine if osteoclasts develop from osteoclast precursors in peripheral blood mononuclear cells (PBMCs) of chronic liver disease patients with osteopenia compared with cont

  5. DISTINCT PHENOTYPES OF INFILTRATING CELLS DURING ACUTE AND CHRONIC LUNG REJECTION IN HUMAN HEART-LUNG TRANSPLANTS

    NARCIS (Netherlands)

    WINTER, JB; CLELLAND, C; GOUW, ASH; PROP, J

    1995-01-01

    To differentiate between acute and chronic lung rejection in an early stage, phenotypes of infiltrating inflammatory cells were analyzed in 34 transbronchial biopsies (TBBs) of 24 patients after heart-lung transplantation. TBBs were taken during during acute lung rejection and chronic lung rejection

  6. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-feng LI; You-zhi ZHANG; Yan-qin LIU; Heng-lin WANG; Li YUAN; Zhi-pu LUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μmol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  7. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-fengLI; You-zhiZHANG; Yan-qinLIU; Heng-linWANG; LiYUAN; Zhi-puLUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC 12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μnol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40 mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  8. The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures.

    Science.gov (United States)

    Anyanwu, Ebere; Campbell, Andrew W; Jones, Joseph; Ehiri, John E; Akpan, Akpan I

    2003-11-13

    Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC) activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40 degrees C (104 degrees F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range

  9. The Neurological Significance of Abnormal Natural Killer Cell Activity in Chronic Toxigenic Mold Exposures

    Directory of Open Access Journals (Sweden)

    Ebere Anyanwu

    2003-01-01

    Full Text Available Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40�C (104�F, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide

  10. Effect of Homoharringtonine on Bone Morrow CD34+CD7+ Cells in Chronic Granulocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    LI Yu-feng; DENG Zhi-kui; XUAN Heng-bao; CHEN Bao-an

    2007-01-01

    Objective: To explore the effect of homoharringtonine (HHT) on bone morrow CD34+CD7+ cells in chronic granulocytic leukemia (CGL). Methods: The changes of bone morrow CD34+CD7+ cells were observed after the treatment of HHT in 23 cases with CGL. The proliferation and apoptosis of CD34+CD7+ cells treated with HHT in vitro were studied. Results: The proportion of CD34+CD7+ cells in CGL (0.145±0.021) was higher than that of normal control (0.052±0.013). The proportion of CD34+CD7+ cells in patients who got cytogenetic responses to HHT (0.072±0.020) decreased remarkably, but not in those patients who did not got cytogenetic responses to HHT, (0.137±0.023). the proliferation of CD34+ cells was inhibited and the proportion of CD34+CD7+ cells decreased after cultured with HHT (0.134 in 24 h, 0.126 in 48 h and 0.102 in 72). The apoptosis rate of CD34+CD7+ cells was higher than that in CD34+CD7- cells (35.39%±4.39% versus 24.57%(4.01%, P<0.05) 72 h after culture with HHT. Conclusion: The proportion of CD34+CD7+ cells in CGL was higher than that of normal control and HHT may inhibit the proliferation and induce apoptosis of bone marrow CD34+CD7+ cells.

  11. Effects of low-dose heavy ion irradiation on male germ cell adaptation and genetics

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hong; LI Wen-Jian; ZHENG Rong-Liang

    2005-01-01

    The heavy ions with high linear energy transfer and high relative biological effectiveness are much more deleterious on the male germ cells, ones of the most radiosensitive cells of the body, than low-LET ionizing radiation such as X-ray or gamma-ray. The effects of low-dose heavy ion irradiation on male germ cell adaptation and genetics and the possible mechanism of this adaptation are summarized in our laboratory. Our results showed that the heavy ion irradiation significantly increased the frequencies of chromosomal aberrations in spermatogonia and spermatocytes of mice, the low dose heavy ion irradiation could induce significant adaptative response on mouse testes and human sperm, and pre-exposure of mouse testes with low-dose heavy ion can markedly alleviate damage effects induced by subsequent high-dose irradiation. The increase of SOD activity and decrease of lipid peroxidation levels induced by low-dose ionizing radiation may be involved in this adaptative response mechanism. These studies may provide useful theoretical and clinical bases for radioprotection of reproductive potential and assessment of genetic risks for human exposed to heavy ions in radiotherapy and in outer space environment.

  12. Fine tuning of the threshold of T cell selection by the Nck adapters.

    Science.gov (United States)

    Roy, Edwige; Togbe, Dieudonnée; Holdorf, Amy; Trubetskoy, Dmitry; Nabti, Sabrina; Küblbeck, Günter; Schmitt, Sabine; Kopp-Schneider, Annette; Leithäuser, Frank; Möller, Peter; Bladt, Friedhelm; Hämmerling, Günter J; Arnold, Bernd; Pawson, Tony; Tafuri, Anna

    2010-12-15

    Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire. PMID:21078909

  13. Two adaptation processes in auditory hair cells together can provide an active amplifier

    CERN Document Server

    Vilfan, A; Vilfan, Andrej; Duke, Thomas

    2003-01-01

    The hair cells of the vertebrate inner ear convert mechanical stimuli to electrical signals. Two adaptation mechanisms are known to modify the ionic current flowing through the transduction channels of the hair bundles: a rapid process involves calcium ions binding to the channels; and a slower adaptation is associated with the movement of myosin motors. We present a mathematical model of the hair cell which demonstrates that the combination of these two mechanisms can produce `self-tuned critical oscillations', i.e. maintain the hair bundle at the threshold of an oscillatory instability. The characteristic frequency depends on the geometry of the bundle and on the calcium dynamics, but is independent of channel kinetics. Poised on the verge of vibrating, the hair bundle acts as an active amplifier. However, if the hair cell is sufficiently perturbed, other dynamical regimes can occur. These include slow relaxation oscillations which resemble the hair bundle motion observed in some experimental preparations.

  14. Synchronization of cells with activator-inhibitor pathways through adaptive environment-mediated coupling

    Science.gov (United States)

    Ghomsi, P. Guemkam; Moukam Kakmeni, F. M.; Tchawoua, C.; Kofane, T. C.

    2015-11-01

    In this paper, we report the synchronized dynamics of cells with activator-inhibitor pathways via an adaptive environment-mediated coupling scheme with feedbacks and control mechanisms. The adaptive character of the extracellular medium is modeled via its damping parameter as a physiological response aiming at annihilating the cellular differentiation existing between the chaotic biochemical pathways of the cells, in order to preserve homeostasis. We perform an investigation on the existence and stability of the synchronization manifold of the coupled system under the proposed coupling pattern. Both mathematical and computational tools suggest the accessibility of conducive prerequisites (conditions) for the emergence of a robust synchronous regime. The relevance of a phase-synchronized dynamics is appraised and several numerical indicators advocate for the prevalence of this fascinating phenomenon among the interacting cells in the phase space.

  15. Fine tuning of the threshold of T cell selection by the Nck adapters.

    Science.gov (United States)

    Roy, Edwige; Togbe, Dieudonnée; Holdorf, Amy; Trubetskoy, Dmitry; Nabti, Sabrina; Küblbeck, Günter; Schmitt, Sabine; Kopp-Schneider, Annette; Leithäuser, Frank; Möller, Peter; Bladt, Friedhelm; Hämmerling, Günter J; Arnold, Bernd; Pawson, Tony; Tafuri, Anna

    2010-12-15

    Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire.

  16. Metabolic Plasticity of Metastatic Breast Cancer Cells: Adaptation to Changes in the Microenvironment

    Directory of Open Access Journals (Sweden)

    Rui V. Simões

    2015-08-01

    Full Text Available Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of 13C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells, leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1 provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2 lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.

  17. Adaptive model predictive control of the hybrid dynamics of a fuel cell system

    OpenAIRE

    Fiacchini, Mirko; Alamo, Teodoro; Albea-Sanchez, Carolina; Fernandez Camacho, Eduardo

    2007-01-01

    International audience In this paper, an adaptive control scheme for the safe operation of a fuel cell system is presented. The aim of the control design is to guarantee that the oxygen ratio do not reach dangerous values. A first level of control is given by a feedforward control. An improved behavior is obtained using an adaptive predictive controller to determine the voltage to be applied to the air compressor. An admissible robust control invariant set for the PWA model of the system i...

  18. Altered distribution of peripheral blood memory B cells in humans chronically infected with Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Esteban R Fernández

    Full Text Available Numerous abnormalities of the peripheral blood T cell compartment have been reported in human chronic Trypanosoma cruzi infection and related to prolonged antigenic stimulation by persisting parasites. Herein, we measured circulating lymphocytes of various phenotypes based on the differential expression of CD19, CD4, CD27, CD10, IgD, IgM, IgG and CD138 in a total of 48 T. cruzi-infected individuals and 24 healthy controls. Infected individuals had decreased frequencies of CD19+CD27+ cells, which positively correlated with the frequencies of CD4+CD27+ cells. The contraction of CD19+CD27+ cells was comprised of IgG+IgD-, IgM+IgD- and isotype switched IgM-IgD- memory B cells, CD19+CD10+CD27+ B cell precursors and terminally differentiated CD19+CD27+CD138+ plasma cells. Conversely, infected individuals had increased proportions of CD19+IgG+CD27-IgD- memory and CD19+IgM+CD27-IgD+ transitional/naïve B cells. These observations prompted us to assess soluble CD27, a molecule generated by the cleavage of membrane-bound CD27 and used to monitor systemic immune activation. Elevated levels of serum soluble CD27 were observed in infected individuals with Chagas cardiomyopathy, indicating its potentiality as an immunological marker for disease progression in endemic areas. In conclusion, our results demonstrate that chronic T. cruzi infection alters the distribution of various peripheral blood B cell subsets, probably related to the CD4+ T cell deregulation process provoked by the parasite in humans.

  19. Altered distribution of peripheral blood memory B cells in humans chronically infected with Trypanosoma cruzi.

    Science.gov (United States)

    Fernández, Esteban R; Olivera, Gabriela C; Quebrada Palacio, Luz P; González, Mariela N; Hernandez-Vasquez, Yolanda; Sirena, Natalia María; Morán, María L; Ledesma Patiño, Oscar S; Postan, Miriam

    2014-01-01

    Numerous abnormalities of the peripheral blood T cell compartment have been reported in human chronic Trypanosoma cruzi infection and related to prolonged antigenic stimulation by persisting parasites. Herein, we measured circulating lymphocytes of various phenotypes based on the differential expression of CD19, CD4, CD27, CD10, IgD, IgM, IgG and CD138 in a total of 48 T. cruzi-infected individuals and 24 healthy controls. Infected individuals had decreased frequencies of CD19+CD27+ cells, which positively correlated with the frequencies of CD4+CD27+ cells. The contraction of CD19+CD27+ cells was comprised of IgG+IgD-, IgM+IgD- and isotype switched IgM-IgD- memory B cells, CD19+CD10+CD27+ B cell precursors and terminally differentiated CD19+CD27+CD138+ plasma cells. Conversely, infected individuals had increased proportions of CD19+IgG+CD27-IgD- memory and CD19+IgM+CD27-IgD+ transitional/naïve B cells. These observations prompted us to assess soluble CD27, a molecule generated by the cleavage of membrane-bound CD27 and used to monitor systemic immune activation. Elevated levels of serum soluble CD27 were observed in infected individuals with Chagas cardiomyopathy, indicating its potentiality as an immunological marker for disease progression in endemic areas. In conclusion, our results demonstrate that chronic T. cruzi infection alters the distribution of various peripheral blood B cell subsets, probably related to the CD4+ T cell deregulation process provoked by the parasite in humans.

  20. [Mast cells, their adenosine receptors and reactive oxygen species in chronic inflammatory pathologies of childhood].

    Science.gov (United States)

    Renke, Joanna; Popadiuk, Stefan; Wozniak, Michał; Szlagatys-Sidorkiewicz, Agnieszka; Hansdorfer-Korzon, Rita

    2006-01-01

    Mast cells were described by Erhlich at the end of XIX-th century. Their role was deeply investigated in asthma and allergy. The massive degranulation of mast cells in allergy can lead to anaphylactic shock. Recently, mast cells have been recognized again as a very interesting topic for investigation, due to their possible role in chronic inflammation. Moreover, through adenosine receptors, mast cells can be activated or inactivated. That is why these cells are regarded as a potential target of new drugs. It has been reported, that mast cells generate intracellular reactive oxygen species (ROS) in response to stimulation with divergent physiologically relevant stimulants. The intensification of ROS production may be measured by the level of carbonyl groups, as a marker of protein peroxidation. However, the role of mast cells in other than asthma diseases with chronic inflammation needs further investigation. It was found out that the information about mast cell distribution in colonic mucosa may serve as help in differentiation between inflammatory bowel disease and collagenous colitis. Moreover, its accumulation in focal active gastritis was confirmed in patients with Crohn's disease. An important role in regulation of inflammatory process seems to be reserved for adenosine receptors present on mastocytes. The activation of mast cells through the adenosine receptor is connected with 11-8 release, which stimulate the migration of leukocytes and oxidation reactions. The detection of mast cells in tissues should not be limited only to the simple histologic examination. It should be completed by the detection of products of degranulation, e.g. tryptase. This is the way to find out their actual function and state of activation. PMID:17203808

  1. An engineered approach to stem cell culture: automating the decision process for real-time adaptive subculture of stem cells.

    Science.gov (United States)

    Ker, Dai Fei Elmer; Weiss, Lee E; Junkers, Silvina N; Chen, Mei; Yin, Zhaozheng; Sandbothe, Michael F; Huh, Seung-il; Eom, Sungeun; Bise, Ryoma; Osuna-Highley, Elvira; Kanade, Takeo; Campbell, Phil G

    2011-01-01

    Current cell culture practices are dependent upon human operators and remain laborious and highly subjective, resulting in large variations and inconsistent outcomes, especially when using visual assessments of cell confluency to determine the appropriate time to subculture cells. Although efforts to automate cell culture with robotic systems are underway, the majority of such systems still require human intervention to determine when to subculture. Thus, it is necessary to accurately and objectively determine the appropriate time for cell passaging. Optimal stem cell culturing that maintains cell pluripotency while maximizing cell yields will be especially important for efficient, cost-effective stem cell-based therapies. Toward this goal we developed a real-time computer vision-based system that monitors the degree of cell confluency with a precision of 0.791±0.031 and recall of 0.559±0.043. The system consists of an automated phase-contrast time-lapse microscope and a server. Multiple dishes are sequentially imaged and the data is uploaded to the server that performs computer vision processing, predicts when cells will exceed a pre-defined threshold for optimal cell confluency, and provides a Web-based interface for remote cell culture monitoring. Human operators are also notified via text messaging and e-mail 4 hours prior to reaching this threshold and immediately upon reaching this threshold. This system was successfully used to direct the expansion of a paradigm stem cell population, C2C12 cells. Computer-directed and human-directed control subcultures required 3 serial cultures to achieve the theoretical target cell yield of 50 million C2C12 cells and showed no difference for myogenic and osteogenic differentiation. This automated vision-based system has potential as a tool toward adaptive real-time control of subculturing, cell culture optimization and quality assurance/quality control, and it could be integrated with current and developing robotic cell

  2. Context and location dependence of adaptive Foxp3+ regulatory T cell formation during immunopathological conditions

    OpenAIRE

    Heiber, Joshua F.; Geiger, Terrence L.

    2012-01-01

    Circulating Foxp3+ regulatory T cells (Treg) may arise in the thymus (natural Treg, nTreg) or through the adaptive upregulation of Foxp3 after T cell activation (induced Treg, iTreg). In this brief review, we explore evidence for the formation and function of iTreg during pathologic conditions. Determining the ontogeny and function of Treg populations has relied on the use of manipulated systems in which either iTreg or nTreg are absent, or lineage tracing of T cell clones through repertoire ...

  3. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity.

    Science.gov (United States)

    Winning, Sandra; Fandrey, Joachim

    2016-01-01

    Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity.

  4. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity

    Directory of Open Access Journals (Sweden)

    Sandra Winning

    2016-01-01

    Full Text Available Dendritic cells (DCs are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate immunity.

  5. The number of granule cells in rat hippocampus is reduced after chronic mild stress and re-established after chronic escitalopram treatment

    DEFF Research Database (Denmark)

    Jayatissa, Magdalena N; Bisgaard, Christina; West, Mark J;

    2008-01-01

    Stress and depression cause structural changes in the hippocampal formation. Some of these can be reversed by chronic antidepressant treatment. In the present study, we examined the changes in the total number of granule cells and the volume of the granule cell layer after exposing rats to chronic...... changes, indicating a decrease in sensitivity to a reward, were assessed in terms of sucrose consumption. We found a significant 22.4% decrease in the total number of granule cells in the stressed rats. This decrease was reversed in the stressed escitalopram treated rats that responded to the treatment...... shows that the anhedonia-like state in the CMS rats is associated with a reduced number of granule cells. We conclude that escitalopram acts on specific cellular targets during neuronal differentiation and that recovery from anhedonia-like behavior in rats may be the consequence of an escitalopram...

  6. A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Aysun Adan Gökbulut

    2015-06-01

    Full Text Available INTRODUCTION: The aims of this study were to examine the cytotoxic and apoptotic effects of KL-21, a novel plant product (produced by Naturin Natural Products, İzmir, Turkey, on 232B4 chronic lymphocytic leukemia (CLL cells and to determine the cytotoxic effects on healthy BEAS-2B human bronchial epithelial cells. METHODS: The cytotoxic effect of KL-21 was determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using the caspase-3 colorimetric assay. Changes in mitochondrial membrane potential were determined using the JC-1 dye-based method. Annexin V-FITC/PI double staining was performed to measure the apoptotic cell population. Effects of KL-21 on cell cycle profiles of CLL cells were investigated by flow cytometry. RESULTS: We detected time- and concentration-dependent increases in the cytotoxic effect of KL-21 on 232B4 CLL cells. However, we also showed that, especially at higher concentrations, KL-21 was less cytotoxic towards BEAS-2B healthy cells than towards CLL cells. Annexin-V/PI double staining results showed that the apoptotic cell population increased in 232B4 cells. Increasing concentrations of KL-21 increased caspase-3 enzyme activity and induced loss of mitochondrial membrane potential. KL-21 administration resulted in small increases in the percentage of the cells in the G0/G1 phase while it decreased the S phase cell population up to 1 mg/mL. At the highest concentration, most of the cells accumulated in the G0/G1 phase. DISCUSSION AND CONCLUSION: KL-21 has a growth-inhibitory effect on 232B4 CLL cells. KL-21 causes apoptosis and cell cycle arrest at G0/G1.

  7. 46. Micronuclei induced by chronical treatment of SO2 inhalation in mouse bone marrow cells

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    In the chronical experiment of treating with sulfur dioxide(SO2) inhalation, Micronuclei(MN) frequencies in the polychromatophilic erythroblasts(PCE) of mouse bone marrow and the frequencies of cells with MN were significantly increased in dose-dependent manner. There is a significant difference between the male and the female animals. The results also showed that SO2 inhibited urethone-induced MN formation, it is a antagonistic joint action to Urethone. These results furtherly confirm that SO2 inhalation is a clastogenetic and genotoxic agent to mammalian cells, and the combination roles of SO2 and other mutagens are complexity.

  8. Effects of lamivudine on the function of dendritic cells derived from patients with chronic hepatitis B virus infection

    OpenAIRE

    Zheng, Peng-Yuan; Zhang, Dong-Yun; Lu, Gao-Feng; Yang, Ping-Chang; Qi, Yuan-Ming; Wang, Bai-Sheng

    2007-01-01

    AIM: To investigate if the nucleoside analogue lamivudine (LAM), a potent inhibitor of HBV replication, could restore the function of dendritic cells derived from patients with chronic hepatitis B (CHB) in an Asian population.

  9. The level of circulating endothelial progenitor cells may be associated with the occurrence and recurrence of chronic subdural hematoma

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    Yan Song

    2013-01-01

    Full Text Available OBJECTIVES: The onset of chronic subdural hematoma may be associated with direct or indirect minor injuries to the head or a poorly repaired vascular injury. Endothelial progenitor cells happen to be one of the key factors involved in hemostasis and vascular repair. This study was designed to observe the levels of endothelial progenitor cells, white blood cells, platelets, and other indicators in the peripheral blood of patients diagnosed with chronic subdural hematoma to determine the possible relationship between the endothelial progenitor cells and the occurrence, development, and outcomes of chronic subdural hematoma. METHOD: We enrolled 30 patients with diagnosed chronic subdural hematoma by computer tomography scanning and operating procedure at Tianjin Medical University General Hospital from July 2009 to July 2011. Meanwhile, we collected 30 cases of peripheral blood samples from healthy volunteers over the age of 50. Approximately 2 ml of blood was taken from veins of the elbow to test the peripheral blood routine and coagulation function. The content of endothelial progenitor cells in peripheral blood mononuclear cells was determined by flow cytometry. RESULTS: The level of endothelial progenitor cells in peripheral blood was significantly lower in preoperational patients with chronic subdural hematomas than in controls. There were no significant differences between the two groups regarding the blood routine and coagulation function. However, the levels of circulating endothelial progenitor cells were significantly different between the recurrent group and the non-recurrent group. CONCLUSIONS: The level of circulating endothelial progenitor cells in chronic subdural hematoma patients was significantly lower than the level in healthy controls. Meanwhile, the level of endothelial progenitor cells in recurrent patients was significantly lower than the level in patients without recurrence. Endothelial progenitor cells may be related to the

  10. Prolactin mediates effects of chronic psychological stress on induction of fibrofatty cells in the heart.

    Science.gov (United States)

    Song, Jiangping; Wang, Mangyuan; Chen, Xiao; Liu, Li; Chen, Liang; Song, Zhizhao; Teng, Xiao; Xing, Yong; Chen, Kai; Zhao, Kun; Hou, Jianfeng; Yang, Pingchang

    2016-01-01

    Cardiocyte apoptosis plays an important role in the pathogenesis of heart diseases. The mechanism is unclear. It is reported that prolactin (PRL) is involved in cardiac disorders. This study aims to investigate the role of PRL in mediating the psychological stress-induced fibrofatty cell differentiation in the heart. In this study, BALB/c mice were treated with a 30-day restraint stress. The heart tissue was processed by paraffin embedding and hematoxylin and eosin. The expression of Sca1 in NIH3T3 cells was assessed by cell culture, flow cytometry and Western blotting. The results showed that chronic stress induced fibrofatty cells in the mouse heart and high serum PRL levels. The induction of fibrofatty cell was mimicked by administration with recombinant PRL. The stress also induced the expression of Sca1 in the mouse heart. Exposure of NIH3T3 cells (a fibroblast cell line) to PRL in the culture enhanced the expression of stem cell antigen-1 (Sca1), phosphorylation of signal transducer and activator of transcription 3 (STAT3) and expression of adipocyte-related protein molecules, including adiponectin, fatty acid binding protein (aP2), peroxisome proliferator activated receptor-g (PPARg) and CCAAT/enhancer binding protein (C/EBP)α, in the cells. We conclude that psychological stress-derived PRL induces fibroblasts to differentiate into fibrofatty cells in the heart.

  11. Active and passive biomonitoring suggest metabolic adaptation in blue mussels (Mytilus spp.) chronically exposed to a moderate contamination in Brest harbor (France).

    Science.gov (United States)

    Lacroix, Camille; Richard, Gaëlle; Seguineau, Catherine; Guyomarch, Julien; Moraga, Dario; Auffret, Michel

    2015-05-01

    oxidative stress and energy-related biomarkers were observed compared to native harbor mussels. Overall, these results suggested mussels chronically exposed to contamination have set up metabolic adaptation, which may contribute to their survival in the moderately contaminated harbor of Brest. Whether these adaptive traits result from phenotypic plasticity or genetic adaptation needs to be further investigated.

  12. Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice.

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    Marina Burgos-Silva

    Full Text Available Acute and chronic kidney injuries (AKI and CKI constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs in an experimental model of nephrotoxicity induced by folic acid (FA in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

  13. Effect of low-dose X-ray radiation on adaptive response in gastric cancer cell

    Institute of Scientific and Technical Information of China (English)

    Shukai Wang; Gang Jiang; Hongsheng Yu; Xiangping Liu; Chang Xu

    2013-01-01

    Objective: We aimed to study the effect and mechanism of low-dose radiation (LDR) on adaptive response of gastric cancer cell. Methods: SGC7901 cells were cultured in vitro, and divided into 4 groups: control group (D0 group), low-dose radiation group (D1 group, 75 mGy), high-dose radiation group (D2 group, 2 Gy), low-dose plus high-dose radiation group (D1 + D2 group, 75 mGy + 2 Gy, the interval of low and high-dose radiation being 8 h). Cell inhibition rate was detected by cytometry and CCK8 method; the proportion of cell cycle at different times after irradiation was determined by using a flow cytometry. The ATM mRNA levels were detected by using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Results: There was no significant different between groups D0 and D1, groups D2 and D1 + D2 cell inhibition rate (P > 0.05). There was a significant increase G2/M arrest in groups D2 and D1 + D2 than groups D0 and D1 after 6 h of radiation and did not recover at 48 h (P 0.05). Conclusion: LDR cannot induce adaptive response in SGC7901 cells in vitro, which may be associated the regulation of cell cycle, and its ATM mRNA expression cannot be affected by 75 mGy X-ray radiation.

  14. Low power proton exchange membrane fuel cell system identification and adaptive control

    Science.gov (United States)

    Yang, Yee-Pien; Wang, Fu-Cheng; Chang, Hsin-Ping; Ma, Ying-Wei; Weng, Biing-Jyh

    This paper proposes a systematic method of system identification and control of a proton exchange membrane (PEM) fuel cell. This fuel cell can be used for low-power communication devices involving complex electrochemical reactions of nonlinear and time-varying dynamic properties. From a system point of view, the dynamic model of PEM fuel cell is reduced to a configuration of two inputs, hydrogen and air flow rates, and two outputs, cell voltage and current. The corresponding transfer functions describe linearized subsystem dynamics with finite orders and time-varying parameters, which are expressed as discrete-time auto-regression moving-average with auxiliary input models for system identification by the recursive least square algorithm. In the experiments, a pseudo-random binary sequence of hydrogen or air flow rate is fed to a single fuel cell device to excite its dynamics. By measuring the corresponding output signals, each subsystem transfer function of reduced order is identified, while the unmodeled, higher-order dynamics and disturbances are described by the auxiliary input term. This provides a basis of adaptive control strategy to improve the fuel cell performance in terms of efficiency, as well as transient and steady state specifications. Simulation shows that adaptive controller is robust to the variation of fuel cell system dynamics, and it has proved promising from the experimental results.

  15. [Proliferation characteristics of a PK-15 cell-adapted strain of porcine parvovirus].

    Science.gov (United States)

    Wu, Yun-Fei; Zhu, Ling; Xu, Zhi-Wen; Fu, Meng-Jin; Chen, Lei; Yang, Ai-Guo; Guo, Wan-Zhu

    2013-06-01

    To study the proliferation characteristics of PPV in differently infected way and the variance of concentrations in different cells. A strain of porcine parvovirus(PPV) was adapted to PK-15 cells, and a Real-time fluorescent quantitative PCR (FQ-PCR) assay was developed based on the specific region of the NS1 gene of PPV to quantify the PPV. The FQ-PCR was used to measure the viral concentration of virus-infected cells by simultaneous or step by step inoculation and plot one-step growth curves. The proliferation characteristics of PPV strain in different cells lines (HeLa, MDBK, PK-15 ,ST, F81, BHK-21 and Marc-145) was also compared. The results showed the PK-15 cell -adapted strain of PPV produced CPE after 12 passages, and maintained stable CPE at the following 10 messages. The one-step growth curve showed that the virus concentration of simultaneous inoculation was higher than that of the step-by-step inoculation, and the proliferation cycle of step-by-step inoculation was shorter. The proliferation ability of PPV strain in different cells showed that CPE appeared first inPK-15, followed by ST, HeLa and MDBK, and the virus concentration was highest in ST, followed byPK-15, MDBK and HeLa. NO proliferation was observed in F81, BHK-21 and Marc-145 cells. These findings lay a material foundation for the basic researches on PPV and the development of vaccine.

  16. Mechanical anisotropy and adaptation of metastatic cells probed by magnetic microbeads

    Science.gov (United States)

    Zhang, Zhipeng; Shi, Yanhui; Jhiang, Sissy M.; Menq, Chia-Hsiang

    2010-02-01

    Metastatic cells have the ability to break through the basal lamina, enter the blood vessels, circulate through the vasculature, exit at distant sites, and form secondary tumors. This multi-step process, therefore, clearly indicates the inherent ability of metastatic cells to sense, process, and adapt to the mechanical forces in different surrounding environments. We describe a magnetic probing device that is useful in characterizing the mechanical properties of cells along arbitrary two-dimensional directions. Magnetic force, with the advantages of biocompatibility and specificity, was produced by magnetic poles placed in an octupole configuration and applied to fibronectin-coated magnetic microbeads attached on cell membrane. Cell deformation in response to the applied force was then recorded through the displacement of the microbeads. The motion of the beads was measured by computer processing the video images acquired by a high-speed CMOS camera. Rotating force vectors with constant magnitude while pointing to directions of all 360 degrees were applied to study the mechanical anisotropy of metastatic breast cancer cells MDA-MB-231. The temporal changes in magnitude and directionality of the cellular responses were then analyzed to investigate the cellular adaptation to force stimulation. This probing technology thus has the potential to provide us a better understanding of the mechano-signatures of cells.

  17. Distribution of Th17 cells and Th1 cells in peripheral blood and cerebrospinal fluid in chronic inflammatory demyelinating polyradiculoneuropathy.

    Science.gov (United States)

    Chi, Li Jun; Xu, Wan Hai; Zhang, Zong Wen; Huang, Hui Tao; Zhang, Li Ming; Zhou, Jin

    2010-12-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system. Th17 and Th1 cells contribute to the pathogenesis of most autoimmune diseases, but little is known about their distribution and reciprocal relationship in CIDP. In this study, we analyzed the distribution of Th17, Th1, and Th17/Th1 cells in the peripheral blood and cerebrospinal fluid (CSF). The results showed that the frequency of Th17 cells was significantly higher in the peripheral blood mononuclear cell (PBMCs) and CSF of active CIDP in comparison with remitting CIDP or to other non-inflammatory neurological diseases (ONDs), accompanied by similar findings for Th17/Th1 cells. Both active and remitting CIDP have higher percentage of Th1 cells in the CSF than OND. CSF protein levels positively correlated with the frequencies of Th17 cells either in the PBMCs or CSF of active CIDP, while there was no significant correlation with Th1 cells. In line with these observations, the levels of interleukin-17 (IL-17) in plasma and transcript factors retinoic acid receptor-related orphan receptor (ROR)γt expressed by PBMCs were significantly higher in the active CIDP than remitting CIDP or OND. In summary, our preliminary findings suggest that elevated numbers of inflammatory T cells, especially for Th17 cells, might be an important determinant in the evolution of CIDP.

  18. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

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    Tokiko Ishida

    Full Text Available The pathogenesis of renal impairment in chronic liver diseases (CLDs has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy, autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the

  19. The 3 major types of innate and adaptive cell-mediated effector immunity.

    Science.gov (United States)

    Annunziato, Francesco; Romagnani, Chiara; Romagnani, Sergio

    2015-03-01

    The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet(+) IFN-γ-producing group 1 ILCs (ILC1 and natural killer cells), CD8(+) cytotoxic T cells (TC1), and CD4(+) TH1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3(+) ILC2s, TC2 cells, and TH2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid-related orphan receptor γt(+) ILC3s, TC17 cells, and TH17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases. PMID:25528359

  20. Adaptation to cell culture induces functional differences in measles virus proteins

    Directory of Open Access Journals (Sweden)

    Rota Paul A

    2008-10-01

    Full Text Available Abstract Background Live, attenuated measles virus (MeV vaccine strains were generated by adaptation to cell culture. The genetic basis for the attenuation of the vaccine strains is unknown. We previously reported that adaptation of a pathogenic, wild-type MeV to Vero cells or primary chicken embryo fibroblasts (CEFs resulted in a loss of pathogenicity in rhesus macaques. The CEF-adapted virus (D-CEF contained single amino acid changes in the C and matrix (M proteins and two substitutions in the shared amino terminal domain of the phosphoprotein (P and V protein. The Vero-adapted virus (D-VI had a mutation in the cytoplasmic tail of the hemagglutinin (H protein. Results In vitro assays were used to test the functions of the wild-type and mutant proteins. The substitution in the C protein of D-CEF decreased its ability to inhibit mini-genome replication, while the wild-type and mutant M proteins inhibited replication to the same extent. The substitution in the cytoplasmic tail of the D-VI H protein resulted in reduced fusion in a quantitative fusion assay. Co-expression of M proteins with wild-type fusion and H proteins decreased fusion activity, but the mutation in the M protein of D-CEF did not affect this function. Both mutations in the P and V proteins of D-CEF reduced the ability of these proteins to inhibit type I and II interferon signaling. Conclusion Adaptation of a wild-type MeV to cell culture selected for genetic changes that caused measurable functional differences in viral proteins.

  1. Dissecting the dendritic cell controversy in chronic hepatitis B virus infection.

    Science.gov (United States)

    Gehring, Adam J; Ann D'Angelo, June

    2015-05-01

    Therapeutic vaccines to boost endogenous T-cell immunity rely on the stimulatory capacity of dendritic cells (DCs). The functionality of DCs in chronic hepatitis B virus (HBV) infection has been a long-standing debate. Therefore, we have attempted to summarize multiple studies investigating DC function in chronic HBV patients to determine whether common observations can be drawn. We found that the frequency and function of ex vivo-tested myeloid and plasmacytoid DCs were largely intact in patients with HBV infection and similar to those of healthy donor DCs. The main exception was reduced IFN-α production by plasmacytoid DC from chronic HBV patients. This reduced IFN-α production correlated with liver inflammation in multiple studies but not with viral load, suggesting that viral antigens have little effect on DC function. The majority of the confusion about DC function arises from studies reporting the reduced function of healthy donor DCs exposed to various sources of HBV in vitro. These direct effects of viral antigens are in contrast to data from HBV-infected patients. The variations in the assays used and areas that require further investigation are also covered. PMID:25363524

  2. Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma.

    Science.gov (United States)

    Firinci, Fatih; Karaman, Meral; Baran, Yusuf; Bagriyanik, Alper; Ayyildiz, Zeynep Arikan; Kiray, Muge; Kozanoglu, Ilknur; Yilmaz, Osman; Uzuner, Nevin; Karaman, Ozkan

    2011-08-01

    Asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. Mesenchymal stem cells (MSCs) are promising for the development of novel therapies in regenerative medicine. This study aimed to examine the efficacy of MSCs on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: Group 1 (control group, n=6), Group 2 (ovalbumin induced asthma only, n=10), Group 3 (ovalbumin induced asthma + MSCs, n=10), and Group 4 (MSCs only, n=10). Histological findings (basement membrane, epithelium, subepithelial smooth muscle thickness, numbers of goblet and mast cells) of the airways and MSC migration were evaluated by light, electron, and confocal microscopes. In Group 3, all early histopathological changes except epithelial thickness and all of the chronic changes were significantly ameliorated when compared with Group 2. Evaluation with confocal microscopy showed that no noteworthy amount of MSCs were present in the lung tissues of Group 4 while significant amount of MSCs was detected in Group 3. Serum NO levels in Group 3, were significantly lower than Group 2. The results of this study revealed that MSCs migrated to lung tissue and ameliorated bronchial asthma in murine model. Further studies are needed to evaluate the efficacy of MSCs for the treatment of asthma. PMID:21439399

  3. Induction of apoptosis by homoharringtonine in G1 phase human chronic myeloid leukemic cells

    Institute of Scientific and Technical Information of China (English)

    MAI Wen-yuan; LIN Mao-fang

    2005-01-01

    Background Homoharringtonine (HHT) is a cephalotaxine ester derived from an evergreen tree found wildely throughout southern China, which has antileukemic activities against a variety of acute myeloid leukemic cells. For the sake of illustrating the mechanisms of HHT in the treatment of leukemia, we assessed the effect of HHT on the apoptosis of human chronic myeloid leukemic cell line K562.Methods The apoptosis of K562 cells induced by HHT was analyzed by transmission electron microscopy, agarose gel electrophoresis of DNA, flow cytometry and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick labeling.Results Characteristic apoptosis-related features emerged in K562 cells after exposed to HHT at a concentration 0.05-100 μg/ml. Transmission electron microscopy of HHT treated K562 cells displayed chromatin condensation and aggregation under the nuclear membrane, nuclear fragmentation and apoptosis body formation. Typical DNA ladder in agarose gel electrophoresis was observed in the cells exposed to HHT. The cell cycle analysis measured by flow cytometry showed G1 phase cells decreased with the increase of S phase cells while apoptosis was induced by HHT in K562 cells. The percentage of apoptotic cells in K562 cells treated with 50 μg/ml of HHT decreased significantly when pretreated with 1 μg/ml of cycloheximide, 0.05 μg/ml of Actinomycin D respectively.Conclusions HHT has apoptotic effects on K562 cells. The HHT induced apoptosis mainly of the cells in G1 phase and this process required RNA transcription and protein synthesis.

  4. Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70.

    Science.gov (United States)

    Lafarge, Sandrine T; Hou, Sen; Pauls, Samantha D; Johnston, James B; Gibson, Spencer B; Marshall, Aaron J

    2015-07-01

    Chronic lymphocytic leukemia is a malignancy driven by abberant B cell signaling and survival. Leukemic B cells accumulate in the peripheral blood and the lymphoid organs where contact with stromal cells and T cells provide critical survival signals. Clinical severity of CLL is associated with several prognostic markers including expression of the kinase ZAP-70. ZAP-70 expression enhances signaling via the B cell antigen receptor and is associated with increased cell adhesion and migration capacity. Here we report that ZAP-70-positive CLL patients display significantly higher expression of the TNF superfamily receptor and memory marker CD27 than do ZAP-70 negative patients. CD27 expression by CLL was acutely elevated upon BCR cross-linking, or upon ectopic expression of ZAP-70. CD27 expression correlated with functional capacity to adhere to stromal cells and antibody blockade of CD27 impaired CLL binding to stroma. These results provide the first evidence for differential expression of CD27 among CLL prognostic groups, suggest a role for ZAP-70 dependent signaling in CD27 induction and implicate CD27 in cell-cell interactions with the lymphoid tissue microenvironment.

  5. Therapeutic activities of engrafted neural stem/precursor cells are not dormant in the chronically injured spinal cord.

    Science.gov (United States)

    Kumamaru, Hiromi; Saiwai, Hirokazu; Kubota, Kensuke; Kobayakawa, Kazu; Yokota, Kazuya; Ohkawa, Yasuyuki; Shiba, Keiichiro; Iwamoto, Yukihide; Okada, Seiji

    2013-08-01

    The transplantation of neural stem/precursor cells (NSPCs) is a promising therapeutic strategy for many neurodegenerative disorders including spinal cord injury (SCI) because it provides for neural replacement or trophic support. This strategy is now being extended to the treatment of chronic SCI patients. However, understanding of biological properties of chronically transplanted NSPCs and their surrounding environments is limited. Here, we performed temporal analysis of injured spinal cords and demonstrated their multiphasic cellular and molecular responses. In particular, chronically injured spinal cords were growth factor-enriched environments, whereas acutely injured spinal cords were enriched by neurotrophic and inflammatory factors. To determine how these environmental differences affect engrafted cells, NSPCs transplanted into acutely, subacutely, and chronically injured spinal cords were selectively isolated by flow cytometry, and their whole transcriptomes were compared by RNA sequencing. This analysis revealed that NSPCs produced many regenerative/neurotrophic molecules irrespective of transplantation timing, and these activities were prominent in chronically transplanted NSPCs. Furthermore, chronically injured spinal cords permitted engrafted NSPCs to differentiate into neurons/oligodendrocytes and provided more neurogenic environment for NSPCs than other environments. Despite these results demonstrate that transplanted NSPCs have adequate capacity in generating neurons/oligodendrocytes and producing therapeutic molecules in chronic SCI microenvironments, they did not improve locomotor function. Our results indicate that failure in chronic transplantation is not due to the lack of therapeutic activities of engrafted NSPCs but the refractory state of chronically injured spinal cords. Environmental modulation, rather modification of transplanting cells, will be significant for successful translation of stem cell-based therapies into chronic SCI patients.

  6. Molecular mechanisms of Saccharomyces cerevisiae stress adaptation and programmed cell death in response to acetic acid

    Directory of Open Access Journals (Sweden)

    Sergio eGiannattasio

    2013-02-01

    Full Text Available Beyond its classical biotechnological applications such as food and beverage production or as a cell factory, the yeast Saccharomyces cerevisiae is a valuable model organism to study fundamental mechanisms of cell response to stressful environmental changes. Acetic acid is a physiological product of yeast fermentation and it is a well-known food preservative due to its antimicrobial action. Acetic acid has recently been shown to cause yeast cell death and aging. Here we shall focus on the molecular mechanisms of S. cerevisiae stress adaptation and programmed cell death in response to acetic acid. We shall elaborate on the intracellular signaling pathways involved in the cross-talk of pro-survival and pro-death pathways underlying the importance of understanding fundamental aspects of yeast cell homeostasis to improve the performance of a given yeast strain in biotechnological applications.

  7. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.

    Science.gov (United States)

    Paggetti, Jerome; Haderk, Franziska; Seiffert, Martina; Janji, Bassam; Distler, Ute; Ammerlaan, Wim; Kim, Yeoun Jin; Adam, Julien; Lichter, Peter; Solary, Eric; Berchem, Guy; Moussay, Etienne

    2015-08-27

    Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected α-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts.

  8. Blood Dendritic Cells: Canary in the Coal Mine to Predict Chronic Inflammatory Disease?

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    Brodie eMiles

    2014-01-01

    Full Text Available The majority of risk factors for chronic inflammatory diseases are unknown. This makes personalized medicine for assessment, prognosis, and choice of therapy very difficult. It is becoming increasingly clear, however, that low-grade subclinical infections may be an underlying cause of many chronic inflammatory diseases and thus may contribute to secondary outcomes (e.g. cancer. Many diseases are now categorized as inflammatory-mediated diseases that stem from a dysregulation in host immunity. There is a growing need to study the links between low-grade infections, the immune responses they elicit, and how this impacts overall health. One such link explored in detail here is the extreme sensitivity of myeloid dendritic cells (mDC in peripheral blood to chronic low-grade infections and the role that these mDCs play in arbitrating the resulting immune responses. We find that emerging evidence supports a role for pathogen-induced mDCs in chronic inflammation leading to increased risk of secondary clinical disease. The mDCs that are elevated in the blood as a result of low-grade bacteremia often do not trigger a productive immune response, but can disseminate the pathogen throughout the host. This aberrant trafficking of mDCs can accelerate systemic inflammatory disease progression. Conversely, restoration of DC homeostasis may aid in pathogen elimination and minimize dissemination. Thus it would seem prudent when assessing chronic inflammatory disease risk to consider blood mDC numbers, and the microbial content (microbiome and activation state of these mDCs. These may provide important clues (the canary in the coal mine of high inflammatory disease risk. This will facilitate development of novel immunotherapies to eliminate such smoldering infections in atherosclerosis, cancer, rheumatoid arthritis, and pre-eclampsia.

  9. Adaptive Cell Segmentation and Tracking for Volumetric Confocal Microscopy Images of a Developing Plant Meristem

    Institute of Scientific and Technical Information of China (English)

    Min Liu; Anirban Chakraborty; Damanpreet Singh; Ram Kishor Yadav; Gopi Meenakshisundaram; G. Venugopala Reddy; Amit Roy-Chowdhury

    2011-01-01

    Automated segmentation and tracking of cells in actively developing tissues can provide high-throughput and quantitative spatiotemporal measurements of a range of cell behaviors; cell expansion and cell-division kinetics leading to a better understanding of the underlying dynamics of morphogenesis.Here,we have studied the problem of constructing cell lineages in time-lapse volumetric image stacks obtained using Confocal Laser Scanning Microscopy (CLSM).The novel contribution of the work lies in its ability to segment and track cells in densely packed tissue,the shoot apical meristem (SAM),through the use of a close-loop,adaptive segmentation,and tracking approach.The tracking output acts as an indicator of the quality of segmentation and,in turn,the segmentation can be improved to obtain better tracking results.We construct an optimization function that minimizes the segmentation error,which is,in turn,estimated from the tracking results.This adaptive approach significantly improves both tracking and segmentation when compared to an open loop framework in which segmentation and tracking modules operate separately.

  10. THE EFFECT OF MICROWAVE AND BANDAGING TREATMENT ON SKIN IMMUNOLOGICAL CELLS IN CHRONIC LIMB LYMPHEDEMA

    Institute of Scientific and Technical Information of China (English)

    曹卫刚; 张涤生; 干季良

    2000-01-01

    Objective To clarify the characteristics of immunological reactions in skin tissues of non - filarial lymphedema patients with or without skin bacterial infection. Methods Avidin-biotin peroxidase (ABC)immunohistochemical method was used to examine the local skin tissue infiltrating inflammatory cells in 16chronic limb lymphedema patients before and after two courses of microwave and bandaging treatment. Results There was a significant increase of T lymphocyte infiltration in lymphedematous skin tissues; after two courses of microwave treatment, T lymphocyte infiltration was greatly resolved whereas the number of macrophages, which can lyse the stagnant proteins in lymphedematous tissues through proteolysis increased. Conclusion Microwave and bandaging treatment can promote regression of extremity edema by reducing chronic inflammation and enhancing the stagnant protein lysis capability in lymphedematous skin tissues.

  11. Identification of candidate T-cell epitopes and molecular mimics in chronic Lyme disease.

    Science.gov (United States)

    Hemmer, B; Gran, B; Zhao, Y; Marques, A; Pascal, J; Tzou, A; Kondo, T; Cortese, I; Bielekova, B; Straus, S E; McFarland, H F; Houghten, R; Simon, R; Pinilla, C; Martin, R

    1999-12-01

    Elucidating the cellular immune response to infectious agents is a prerequisite for understanding disease pathogenesis and designing effective vaccines. In the identification of microbial T-cell epitopes, the availability of purified or recombinant bacterial proteins has been a chief limiting factor. In chronic infectious diseases such as Lyme disease, immune-mediated damage may add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both Borrelia burgdorferi and the host. We also found that the antigen specificity of a single T-cell clone can be degenerate and yet the clone can preferentially recognize different peptides derived from the same organism, thus demonstrating that flexibility in T-cell recognition does not preclude specificity. This approach has potential applications in the identification of ligands in infectious diseases, tumors and autoimmune diseases.

  12. Chronic alcohol consumption potentiates the development of diabetes through pancreatic β-cell dysfunction

    Institute of Scientific and Technical Information of China (English)

    Ji; Yeon; Kim; Dae; Yeon; Lee; Yoo; Jeong; Lee; Keon; Jae; Park; Kyu; Hee; Kim; Jae; Woo; Kim; Won-Ho; Kim

    2015-01-01

    Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes(T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcoholconsumption and the development of T2 D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic β-cell and the exact mechanisms associated with ethanolmediated β-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-tomoderate ethanol consumption may protect against T2 D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2 D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2 D, particularly with respect to pancreatic β-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanolproduced peroxynitrite contributes to pancreatic β-cell dysfunction and metabolic syndrome.

  13. Adherence and invasion of mouse-adapted H pylori in different epithelial cell lines

    Institute of Scientific and Technical Information of China (English)

    Mao-Jun Zhang; Fan-Liang Meng; Xiao-Yun Ji; Li-Hua He; Jian-Zhong Zhang

    2007-01-01

    AIM: To assess the adhesion and invasion abilities of different mouse adapted H pylori strains in different cell lines in vitro and investigate their effects on the virulence factors cagA and vacA.METHODS: The adherence and invasion abilities of different H pylori strains in different epithelial cell lines were examined by the gentamycin protection assay. The null mutants of cagA and vacA were processed by direct PCR mutation method. The morphologic changes of different cell lines after H pylori attachment were examined by microscopy.RESULTS: The densities of adherence to and invasion into cells in vitro were different from those in the mouse infection experiments. 88-3887 strain could invade and adhere to cells stronger than SSI and X47. All tested strains had better adhering and invasive abilities in SCG-7901 cell. CagA and vacA minus mutants had the same invasion and adherent abilities as their wild types. In all strains and cell lines tested, only AGS cell had the significant hummingbird phenotype after inoculation with the 88-3887 wild-type.CONCLUSION: Both the host cells and the bacteria play important parts in the invasion and adhesion abilities of H pylori. CagA and VacA are not related to the ability of invasion and adhesion of Hpylori in different cell lines in vitro.

  14. Exercise-Induced Skeletal Muscle Adaptations Alter the Activity of Adipose Progenitor Cells

    OpenAIRE

    Daniel Zeve; Millay, Douglas P.; Jin Seo; Graff, Jonathan M.

    2016-01-01

    Exercise decreases adiposity and improves metabolic health; however, the physiological and molecular underpinnings of these phenomena remain unknown. Here, we investigate the effect of endurance training on adipose progenitor lineage commitment. Using mice with genetically labeled adipose progenitors, we show that these cells react to exercise by decreasing their proliferation and differentiation potential. Analyses of mouse models that mimic the skeletal muscle adaptation to exercise indicat...

  15. [Acquired angioedema with C1-INH deficiency and accompanying chronic spontaneous urticaria in a patient with chronic lymphatic B cell leukemia].

    Science.gov (United States)

    Klossowski, N; Braun, S A; von Gruben, V; Losem, C; Plewe, D; Homey, B; Meller, S

    2015-10-01

    Acquired angioedema due to C1 inhibitor deficiency (C1-INH-AAE) is characterized by recurrent edema of the subcutaneous and/or submucosal tissue without wheals and negative family history of angioedema. Here, we present the case of a patient with a chronic lymphatic B cell leukemia who suffered from both C1-INH-AAE and chronic spontaneous urticaria. Oral corticosteroids, antihistamines, and the anti-IgE antibody omalizumab were applied to treat the chronic urticaria in combination with the plasma-derived C1 esterase inhibitor concentrate Berinert® and the bradykinin B2 receptor antagonist icatibant, but the symptoms did not improved significantly. Thus, polychemotherapy targeting the slow-growing lymphoproliferative disease including rituximab was initiated, which resulted in remission of both the urticaria and the angioedema.

  16. Elevated pulse pressure is associated with hemolysis, proteinuria and chronic kidney disease in sickle cell disease.

    Directory of Open Access Journals (Sweden)

    Enrico M Novelli

    Full Text Available A seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n  =  661 enrolled in a multicenter international sickle cell trial. Markers of hemolysis were analyzed as independent variables and as a previously validated hemolytic index that includes multiple variables. We found that pulse pressure, not systolic, diastolic or mean arterial pressure, independently correlated with high reticulocyte count (beta  =  2.37, p  =  0.02 and high hemolytic index (beta  =  1.53, p = 0.002 in patients with homozygous sickle cell disease in two multiple linear regression models which include the markers of hemolysis as independent variables or the hemolytic index, respectively. Pulse pressure was also independently associated with elevated serum creatinine (beta  =  3.21, p  =  0.02, and with proteinuria (beta  =  2.52, p  =  0.04. These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be a risk factor for clinical complications of vascular dysfunction in sickle cell disease. Longitudinal and mechanistic studies should be conducted to confirm these hypotheses.

  17. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Xing-Xiang Peng; Amit K. Tiwari; Hsiang-Chun Wu; Zhe-Sheng Chen

    2012-01-01

    Imatinib,a breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) tyrosine kinase inhibitor (TKI),has revolutionized the treatment of chronic myelogenous leukemia (CML).However,development of multidrug resistance(MDR) limits the use of imatinib.In the present study,we aimed to investigate the mechanisms of cellular resistance to imatinib in CML.Therefore,we established an imatinib-resistant human CML cell line (K562-imatinib) through a stepwise selection process.While characterizing the phenotype of these cells,we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells.In addition,these cells were cross-resistant to second- and third-generation BCR-ABL TKIs.Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein (P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells.In addition,accumulation of [14C]6-mercaptopurine (6-MP) was decreased,whereas the ATP-dependent efflux of [14C] 6-MP and [3H]methotrexate transport were increased in K562-imatinib cells.These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.

  18. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells.

    Science.gov (United States)

    Snyder, Christopher M; Cho, Kathy S; Bonnett, Elizabeth L; van Dommelen, Serani; Shellam, Geoffrey R; Hill, Ann B

    2008-10-17

    During persistent murine cytomegalovirus (MCMV) infection, the T cell response is maintained at extremely high intensity for the life of the host. These cells closely resemble human CMV-specific cells, which compose a major component of the peripheral T cell compartment in most people. Despite a phenotype that suggests extensive antigen-driven differentiation, MCMV-specific T cells remain functional and respond vigorously to viral challenge. We hypothesized that a low rate of antigen-driven proliferation would account for the maintenance of this population. Instead, we found that most of these cells divided only sporadically in chronically infected hosts and had a short half-life in circulation. The overall population was supported, at least in part, by memory T cells primed early in infection, as well as by recruitment of naive T cells at late times. Thus, these data show that memory inflation is maintained by a continuous replacement of short-lived, functional cells during chronic MCMV infection.

  19. Experimental Evaluation of Interference Suppression Receivers and Rank Adaptation in 5G Small Cells

    DEFF Research Database (Denmark)

    Assefa, Dereje; Berardinelli, Gilberto; Catania, Davide;

    2015-01-01

    Advanced receivers are a key component of the 5th Generation (5G) ultra-dense small cells concept given their capability of efficiently dealing with the ever-increasing problem of inter-cell interference. In this paper, we evaluate the potential of interference suppression receivers in real network...... the Interference Rejection Combining (IRC) and Successive Interference Cancellation (SIC) receivers and different rank adaptation approaches. Each node in our software defined radio (SDR) testbed features a 22 MIMO transceiver built with the USRP N200 hardware by Ettus Research. Our experimental results confirm...

  20. Effect of chronic low dose natural radiation in human peripheral blood mononuclear cells: Evaluation of DNA damage and repair using the alkaline comet assay

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, P.R. Vivek, E-mail: prvkumar06@gmail.com [Low Level Radiation Research Laboratory, Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, IRE Campus, Beach Road, Kollam 691 001, Kerala (India); Seshadri, M. [Low Level Radiation Research Section, Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India); Jaikrishan, G. [Low Level Radiation Research Laboratory, Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, IRE Campus, Beach Road, Kollam 691 001, Kerala (India); Das, Birajalaxmi [Low Level Radiation Research Section, Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India)

    2015-05-15

    Highlights: • Effect of chronic low dose natural radiation in radio adaptive response studied. • PBMCs of subjects from NLNRA and HLNRA were challenged with gamma radiation. • DNA damage and repair in PBMCs was compared using the alkaline comet assay. • Significant reduction in DNA damage in subjects of high dose group from HLNRA noted. • Probable induction of an in vivo radio adaptive response in subjects from HLNRA. - Abstract: This study investigates whether peripheral blood mononuclear cells (PBMCs) from inhabitants of Kerala in southwest India, exposed to chronic low dose natural radiation in vivo (>1 mSv year{sup −1}), respond with a radioadaptive response to a challenging dose of gamma radiation. Toward this goal, PBMCs isolated from 77 subjects from high-level natural radiation areas (HLNRA) and 37 subjects from a nearby normal level natural radiation area (NLNRA) were challenged with 2 Gy and 4 Gy gamma radiation. Subjects from HLNRA were classified based on the mean annual effective dose received, into low dose group (LDG) and high dose group (HDG) with mean annual effective doses of 2.69 mSv (N = 43, range 1.07 mSv year{sup −1} to 5.55 mSv year{sup −1}) and 9.62 mSv (N = 34, range 6.07 mSv year{sup −1} to17.41 mSv year{sup −1}), respectively. DNA strand breaks and repair kinetics (at 7 min, 15 min and 30 min after 4 Gy) were evaluated using the alkaline single cell gel electrophoresis (comet) assay. Initial levels of DNA strand breaks observed after either a 2 Gy or a 4 Gy challenging dose were significantly lower in subjects of the HDG from HLNRA compared to subjects of NLNRA (2 Gy, P = 0.01; 4 Gy, P = 0.02) and LDG (2 Gy P = 0.01; 4 Gy, P = 0.05). Subjects of HDG from HLNRA showed enhanced rejoining of DNA strand breaks (HDG/NLNRA, P = 0.06) during the early stage of repair (within 7 min). However at later times a similar rate of rejoining of strand breaks was observed across the groups (HDG, LDG and NLNRA). Preliminary results from

  1. Effect of chronic low dose natural radiation in human peripheral blood mononuclear cells: Evaluation of DNA damage and repair using the alkaline comet assay

    International Nuclear Information System (INIS)

    Highlights: • Effect of chronic low dose natural radiation in radio adaptive response studied. • PBMCs of subjects from NLNRA and HLNRA were challenged with gamma radiation. • DNA damage and repair in PBMCs was compared using the alkaline comet assay. • Significant reduction in DNA damage in subjects of high dose group from HLNRA noted. • Probable induction of an in vivo radio adaptive response in subjects from HLNRA. - Abstract: This study investigates whether peripheral blood mononuclear cells (PBMCs) from inhabitants of Kerala in southwest India, exposed to chronic low dose natural radiation in vivo (>1 mSv year−1), respond with a radioadaptive response to a challenging dose of gamma radiation. Toward this goal, PBMCs isolated from 77 subjects from high-level natural radiation areas (HLNRA) and 37 subjects from a nearby normal level natural radiation area (NLNRA) were challenged with 2 Gy and 4 Gy gamma radiation. Subjects from HLNRA were classified based on the mean annual effective dose received, into low dose group (LDG) and high dose group (HDG) with mean annual effective doses of 2.69 mSv (N = 43, range 1.07 mSv year−1 to 5.55 mSv year−1) and 9.62 mSv (N = 34, range 6.07 mSv year−1 to17.41 mSv year−1), respectively. DNA strand breaks and repair kinetics (at 7 min, 15 min and 30 min after 4 Gy) were evaluated using the alkaline single cell gel electrophoresis (comet) assay. Initial levels of DNA strand breaks observed after either a 2 Gy or a 4 Gy challenging dose were significantly lower in subjects of the HDG from HLNRA compared to subjects of NLNRA (2 Gy, P = 0.01; 4 Gy, P = 0.02) and LDG (2 Gy P = 0.01; 4 Gy, P = 0.05). Subjects of HDG from HLNRA showed enhanced rejoining of DNA strand breaks (HDG/NLNRA, P = 0.06) during the early stage of repair (within 7 min). However at later times a similar rate of rejoining of strand breaks was observed across the groups (HDG, LDG and NLNRA). Preliminary results from our study suggest in vivo

  2. Reversible adaptive plasticity: A mechanism for neuroblastoma cell heterogeneity and chemo-resistance

    Directory of Open Access Journals (Sweden)

    Lina eChakrabarti

    2012-08-01

    Full Text Available We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD or sphere forming, anchorage independent (AI growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, β-catenin and PDGFRβ enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

  3. Regulatory T-Cells in Chronic Lymphocytic Leukemia and Autoimmune Diseases

    Science.gov (United States)

    D’Arena, Giovanni; Rossi, Giovanni; Vannata, Barbara; Deaglio, Silvia; Mansueto, Giovanna; D’Auria, Fiorella; Statuto, Teodora; Simeon, Vittorio; De Martino, Laura; Marandino, Aurelio; Del Poeta8, Giovanni; De Feo, Vincenzo; Musto, Pellegrino

    2012-01-01

    Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in cancer and autoimmune disorders, as well. PMID:22973497

  4. Effects of chronic whole-body gamma irradiation on cell mediated immunity

    International Nuclear Information System (INIS)

    The whole blood lymphocyte stimulation test has been used to estimate the effects of chronic, whole-body, gamma irradiation in the dog. At lower dose levels, 0.07 and 0.33 R/day to cumulative dose of about 50 and 250 R, there was no change in cell mediated immunity. Dogs at high dose levels were affected. Dogs which succumbed to aplastic anemia at high doses had reduced immunological responses. Dogs which survived these high doses showed a temporary depression. When aplastic anemia was initially noted, there was a differential response to PHA and Con-A stimulation. The response to the former mitogen was profoundly reduced, but Con-A stimulated cells were unaffected, indicative of the development of radioresistant cell lines. As the dogs progressed toward aplastic anemia, all T lympocytes were negatively affected

  5. Th17 cells confer long-term adaptive immunity to oral mucosal Candida albicans infections.

    Science.gov (United States)

    Hernández-Santos, N; Huppler, A R; Peterson, A C; Khader, S A; McKenna, K C; Gaffen, S L

    2013-09-01

    Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. Despite its prevalence, little is known about C. albicans-specific immunity in the oral mucosa. Vaccines against Candida generate both T helper type 1 (Th1) and Th17 responses, and considerable evidence implicates interleukin (IL)-17 in immunity to OPC. However, IL-17 is also produced by innate immune cells that are remarkably similar to Th17 cells, expressing the same markers and localizing to similar mucosal sites. To date, the relative contribution(s) of Th1, Th17, and innate IL-17-producing cells in OPC have not been clearly defined. Here, we sought to determine the nature and function of adaptive T-cell responses to OPC, using a new recall infection model. Mice subjected to infection and re-challenge with Candida mounted a robust and stable antigen-specific IL-17 response in CD4+ but not CD8+ T cells. There was little evidence for Th1 or Th1/Th17 responses. The Th17 response promoted accelerated fungal clearance, and Th17 cells could confer protection in Rag1-/- mice upon adoptive transfer. Surprisingly, CD4 deficiency did not cause OPC but was instead associated with compensatory IL-17 production by Tc17 and CD3+CD4-CD8- cells. Therefore, classic CD4+Th17 cells protect from OPC but can be compensated by other IL-17-producing cells in CD4-deficient hosts. PMID:23250275

  6. A fully automatic framework for cell segmentation on non-confocal adaptive optics images

    Science.gov (United States)

    Liu, Jianfei; Dubra, Alfredo; Tam, Johnny

    2016-03-01

    By the time most retinal diseases are diagnosed, macroscopic irreversible cellular loss has already occurred. Earlier detection of subtle structural changes at the single photoreceptor level is now possible, using the adaptive optics scanning light ophthalmoscope (AOSLO). This work aims to develop a fully automatic segmentation framework to extract cell boundaries from non-confocal split-detection AOSLO images of the cone photoreceptor mosaic in the living human eye. Significant challenges include anisotropy, heterogeneous cell regions arising from shading effects, and low contrast between cells and background. To overcome these challenges, we propose the use of: 1) multi-scale Hessian response to detect heterogeneous cell regions, 2) convex hulls to create boundary templates, and 3) circularlyconstrained geodesic active contours to refine cell boundaries. We acquired images from three healthy subjects at eccentric retinal regions and manually contoured cells to generate ground-truth for evaluating segmentation accuracy. Dice coefficient, relative absolute area difference, and average contour distance were 82±2%, 11±6%, and 2.0±0.2 pixels (Mean±SD), respectively. We find that strong shading effects from vessels are a main factor that causes cell oversegmentation and false segmentation of non-cell regions. Our segmentation algorithm can automatically and accurately segment photoreceptor cells on non-confocal AOSLO images, which is the first step in longitudinal tracking of cellular changes in the individual eye over the time course of disease progression.

  7. Diabetic beta-cells can achieve self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses.

    Directory of Open Access Journals (Sweden)

    Grégory Lacraz

    Full Text Available BACKGROUND: Oxidative stress (OS, through excessive and/or chronic reactive oxygen species (ROS, is a mediator of diabetes-related damages in various tissues including pancreatic beta-cells. Here, we have evaluated islet OS status and beta-cell response to ROS using the GK/Par rat as a model of type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Localization of OS markers was performed on whole pancreases. Using islets isolated from 7-day-old or 2.5-month-old male GK/Par and Wistar control rats, 1 gene expression was analyzed by qRT-PCR; 2 insulin secretion rate was measured; 3 ROS accumulation and mitochondrial polarization were assessed by fluorescence methods; 4 antioxidant contents were quantified by HPLC. After diabetes onset, OS markers targeted mostly peri-islet vascular and inflammatory areas, and not islet cells. GK/Par islets revealed in fact protected against OS, because they maintained basal ROS accumulation similar or even lower than Wistar islets. Remarkably, GK/Par insulin secretion also exhibited strong resistance to the toxic effect of exogenous H(2O(2 or endogenous ROS exposure. Such adaptation was associated to both high glutathione content and overexpression (mRNA and/or protein levels of a large set of genes encoding antioxidant proteins as well as UCP2. Finally, we showed that such a phenotype was not innate but spontaneously acquired after diabetes onset, as the result of an adaptive response to the diabetic environment. CONCLUSIONS: The GK/Par model illustrates the effectiveness of adaptive response to OS by beta-cells to achieve self-tolerance. It remains to be determined to what extend such islet antioxidant defenses upregulation might contribute to GK/Par beta-cell secretory dysfunction.

  8. Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiao-Yun; Yang, Yue-Feng; Wu, Chu-Tse; Xiao, Feng-Jun; Zhang, Qun-Wei [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Ma, Xiao-Ni [Lanzhou University of Technology, Lanzhou 730050 (China); Li, Qing-Fang; Yan, Jun [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Wang, Hua, E-mail: wanghualjh@gmail.com [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Wang, Li-Sheng, E-mail: wangls@nic.bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China)

    2010-03-19

    Spreds, a recently established class of negative regulators of the Ras-ERK (extracellular signal-regulated kinase) pathway, are involved in hematogenesises, allergic disorders and tumourigenesis. However, their role in hematologic neoplasms is largely unknown. Possible effects of Spreds on other signal pathways closely related to Ras-ERK have been poorly investigated. In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras-ERK cascade, adenovirus-mediated Spred2 over-expression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras-ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potential targets for selective therapy of CML.

  9. Lapatinib induces autophagy, apoptosis and megakaryocytic differentiation in chronic myelogenous leukemia K562 cells.

    Directory of Open Access Journals (Sweden)

    Huey-Lan Huang

    Full Text Available Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6, ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.

  10. Sensitivity of chronic lymphocytic leukemia cells to small targeted therapeutic molecules: An in vitro comparative study.

    Science.gov (United States)

    Sylvan, Sandra Eketorp; Skribek, Henriette; Norin, Stefan; Muhari, Orsolya; Österborg, Anders; Szekely, Laszlo

    2016-01-01

    New drugs targeting important cellular signaling pathways are currently being developed for chronic lymphocytic leukemia (CLL). It is therefore of interest to analyze their in vitro killing capacity in manufacturer-independent, comparative experiments. We here report on the sensitivity of CLL cells to a panel of emerging targeted therapeutics using high-throughput screening based on an automated fluorescence digital scanning system. Fresh CLL cells from 42 patients with indolent or progressive CLL were cultured for 72 hours on microtiter plates in a unique primary cell culture medium. Antitumor effects of 31 small therapeutic molecules (and, as controls, 29 cytostatic agents) at equimolar concentration were compared in a fluorescence survival assay. In vitro sensitivity to each drug exhibited considerable interpatient variability. The highest mean direct killing was observed for one survivin inhibitor (YM-155), two bcl-2 inhibitors (ABT-199, ABT-737), and one selective CDK inhibitor (dinaciclib). Their killing capacity was, in contrast to most cytostatic agents, similarly high in refractory versus untreated CLL patients and was significantly higher on cells with the 17p deletion/TP53 mutation than on cells with other cytogenetic abnormalities (p = 0.02). Sensitivity of bone marrow and lymph node cells was highly correlated with that of blood cells. Even though direct killing may not be the only therapeutic effector function in vivo, results from this head-to-head comparison may help to identify drugs of particular interest for intensified clinical development. PMID:26325331

  11. Metabolic Adaptations of Azospirillum brasilense to Oxygen Stress by Cell-to-Cell Clumping and Flocculation

    Science.gov (United States)

    Bible, Amber N.; Khalsa-Moyers, Gurusahai K.; Mukherjee, Tanmoy; Green, Calvin S.; Mishra, Priyanka; Purcell, Alicia; Aksenova, Anastasia; Hurst, Gregory B.

    2015-01-01

    The ability of bacteria to monitor their metabolism and adjust their behavior accordingly is critical to maintain competitiveness in the environment. The motile microaerophilic bacterium Azospirillum brasilense navigates oxygen gradients by aerotaxis in order to locate low oxygen concentrations that can support metabolism. When cells are exposed to elevated levels of oxygen in their surroundings, motile A. brasilense cells implement an alternative response to aerotaxis and form transient clumps by cell-to-cell interactions. Clumping was suggested to represent a behavior protecting motile cells from transiently elevated levels of aeration. Using the proteomics of wild-type and mutant strains affected in the extent of their clumping abilities, we show that cell-to-cell clumping represents a metabolic scavenging strategy that likely prepares the cells for further metabolic stresses. Analysis of mutants affected in carbon or nitrogen metabolism confirmed this assumption. The metabolic changes experienced as clumping progresses prime cells for flocculation, a morphological and metabolic shift of cells triggered under elevated-aeration conditions and nitrogen limitation. The analysis of various mutants during clumping and flocculation characterized an ordered set of changes in cell envelope properties accompanying the metabolic changes. These data also identify clumping and early flocculation to be behaviors compatible with the expression of nitrogen fixation genes, despite the elevated-aeration conditions. Cell-to-cell clumping may thus license diazotrophy to microaerophilic A. brasilense cells under elevated oxygen conditions and prime them for long-term survival via flocculation if metabolic stress persists. PMID:26407887

  12. Metabolic adaptations of Azospirillum brasilense to oxygen stress by cell-to-cell clumping and flocculation.

    Science.gov (United States)

    Bible, Amber N; Khalsa-Moyers, Gurusahai K; Mukherjee, Tanmoy; Green, Calvin S; Mishra, Priyanka; Purcell, Alicia; Aksenova, Anastasia; Hurst, Gregory B; Alexandre, Gladys

    2015-12-01

    The ability of bacteria to monitor their metabolism and adjust their behavior accordingly is critical to maintain competitiveness in the environment. The motile microaerophilic bacterium Azospirillum brasilense navigates oxygen gradients by aerotaxis in order to locate low oxygen concentrations that can support metabolism. When cells are exposed to elevated levels of oxygen in their surroundings, motile A. brasilense cells implement an alternative response to aerotaxis and form transient clumps by cell-to-cell interactions. Clumping was suggested to represent a behavior protecting motile cells from transiently elevated levels of aeration. Using the proteomics of wild-type and mutant strains affected in the extent of their clumping abilities, we show that cell-to-cell clumping represents a metabolic scavenging strategy that likely prepares the cells for further metabolic stresses. Analysis of mutants affected in carbon or nitrogen metabolism confirmed this assumption. The metabolic changes experienced as clumping progresses prime cells for flocculation, a morphological and metabolic shift of cells triggered under elevated-aeration conditions and nitrogen limitation. The analysis of various mutants during clumping and flocculation characterized an ordered set of changes in cell envelope properties accompanying the metabolic changes. These data also identify clumping and early flocculation to be behaviors compatible with the expression of nitrogen fixation genes, despite the elevated-aeration conditions. Cell-to-cell clumping may thus license diazotrophy to microaerophilic A. brasilense cells under elevated oxygen conditions and prime them for long-term survival via flocculation if metabolic stress persists.

  13. Autophagy in retinal ganglion cells in a rhesus monkey chronic hypertensive glaucoma model.

    Directory of Open Access Journals (Sweden)

    Shuifeng Deng

    Full Text Available Primary open angle glaucoma (POAG is a neurodegenerative disease characterized by physiological intraocular hypertension that causes damage to the retinal ganglion cells (RGCs. In the past, RGC damage in POAG was suggested to have been attributed to RGC apoptosis. However, in the present study, we applied a model closer to human POAG through the use of a chronic hypertensive glaucoma model in rhesus monkeys to investigate whether another mode of progressive cell death, autophagy, was activated in the glaucomatous retinas. First, in the glaucomatous retinas, the levels of LC3B-II, LC3B-II/LC3B-I and Beclin 1 increased as demonstrated by Western blot analyses, whereas early or initial autophagic vacuoles (AVi and late or degraded autophagic vacuoles (AVd accumulated in the ganglion cell layer (GCL and in the inner plexiform layer (IPL as determined by transmission electron microscopy (TEM analysis. Second, lysosome activity and autophagosome-lysosomal fusion increased in the RGCs of the glaucomatous retinas, as demonstrated by Western blotting against lysosome associated membrane protein-1 (LAMP1 and double labeling against LC3B and LAMP1. Third, apoptosis was activated in the glaucomatous eyes with increased levels of caspase-3 and cleaved caspase-3 and an increased number of TUNEL-positive RGCs. Our results suggested that autophagy was activated in RGCs in the chronic hypertensive glaucoma model of rhesus monkeys and that autophagy may have potential as a new target for intervention in glaucoma treatment.

  14. Underground Adaptation to a Hostile Environment: Acute Myeloid Leukemia vs. Natural Killer Cells

    Science.gov (United States)

    Dulphy, Nicolas; Chrétien, Anne-Sophie; Khaznadar, Zena; Fauriat, Cyril; Nanbakhsh, Arash; Caignard, Anne; Chouaib, Salem; Olive, Daniel; Toubert, Antoine

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which incidence increases with age. The disease affects the differentiation of hematopoietic stem or precursor cells in the bone marrow and can be related to abnormal cytogenetic and/or specific mutational patterns. AML blasts can be sensitive to natural killer (NK) cell antitumor response. However, NK cells are frequently defective in AML patients leading to tumor escape. NK cell defects affect not only the expression of the activating NK receptors, including the natural cytotoxicity receptors, the NK group 2, member D, and the DNAX accessory molecule-1, but also cytotoxicity and IFN-γ release. Such perturbations in NK cell physiology could be related to the adaptation of the AML to the immune pressure and more generally to patient’s clinical features. Various mechanisms are potentially involved in the inhibition of NK-cell functions in AML, including defects in the normal lymphopoiesis, reduced expression of activating receptors through cell-to-cell contacts, and production of immunosuppressive soluble agents by leukemic blasts. Therefore, the continuous cross-talk between AML and NK cells participates to the leukemia immune escape and eventually to patient’s relapse. Methods to restore or stimulate NK cells seem to be attractive strategies to treat patients once the complete remission is achieved. Moreover, our capacity in stimulating the NK cell functions could lead to the development of preemptive strategies to eliminate leukemia-initiating cells before the emergence of the disease in elderly individuals presenting preleukemic mutations in hematopoietic stem cells. PMID:27014273

  15. Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies.

    Science.gov (United States)

    Sandri, Sara; Bobisse, Sara; Moxley, Kelly; Lamolinara, Alessia; De Sanctis, Francesco; Boschi, Federico; Sbarbati, Andrea; Fracasso, Giulio; Ferrarini, Giovanna; Hendriks, Rudi W; Cavallini, Chiara; Scupoli, Maria Teresa; Sartoris, Silvia; Iezzi, Manuela; Nishimura, Michael I; Bronte, Vincenzo; Ugel, Stefano

    2016-05-01

    Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2-restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self-MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540-51. ©2016 AACR.

  16. Autologous stem cell therapy to treat chronic ulcer in heifer- A case study

    Directory of Open Access Journals (Sweden)

    Jayakrushna Das

    Full Text Available Aim: The study was conducted to reveal the efficacy of Bone marrow derived mesenchymal stem cells (BM-MSCs based therapy in healing of chronic non-healing and ulcerative wound in bovine species. Materials and Methods: One 2 years old Jersey heifer affected with chronic ulcerative wound involving full thickness skin and under lying muscle at dorsal side of lumbar region since four months at the time of presentation. Bone marrow was collected from tibia, cultured and grown and after achievement of optimum confluence it was applied at the site. Different parameters of clinical, physiological, haematological, biochemical, histochemical, histological, tensile strength and photographic evaluations were done during the study period. Results: The estimated values of above mentioned parameters on zero day and after healing (18 days showed significant difference (P<0.05 in relation to collagen content, tensile strength and physical characteristics of wound like extent of wound, size of wound, type of exudates and photography. But clinical, haematological and biochemical data showed no significant difference. Conclusion: The BM-MSCs were the main pioneers to bring the chronic ulcerative wound towards healing. The procedure is simple, safe and effective in bringing out healing without showing any adverse effect on host. [Vet World 2012; 5(12.000: 771-774

  17. Disrupted NOS signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow.

    Science.gov (United States)

    Datar, Sanjeev A; Gong, Wenhui; He, Youping; Johengen, Michael; Kameny, Rebecca J; Raff, Gary W; Maltepe, Emin; Oishi, Peter E; Fineman, Jeffrey R

    2016-07-01

    Associated abnormalities of the lymphatic circulation are well described in congenital heart disease. However, their mechanisms remain poorly elucidated. Using a clinically relevant ovine model of a congenital cardiac defect with chronically increased pulmonary blood flow (shunt), we previously demonstrated that exposure to chronically elevated pulmonary lymph flow is associated with: 1) decreased bioavailable nitric oxide (NO) in pulmonary lymph; and 2) attenuated endothelium-dependent relaxation of thoracic duct rings, suggesting disrupted lymphatic endothelial NO signaling in shunt lambs. To further elucidate the mechanisms responsible for this altered NO signaling, primary lymphatic endothelial cells (LECs) were isolated from the efferent lymphatic of the caudal mediastinal node in 4-wk-old control and shunt lambs. We found that shunt LECs (n = 3) had decreased bioavailable NO and decreased endothelial nitric oxide synthase (eNOS) mRNA and protein expression compared with control LECs (n = 3). eNOS activity was also low in shunt LECs, but, interestingly, inducible nitric oxide synthase (iNOS) expression and activity were increased in shunt LECs, as were total cellular nitration, including eNOS-specific nitration, and accumulation of reactive oxygen species (ROS). Pharmacological inhibition of iNOS reduced ROS in shunt LECs to levels measured in control LECs. These data support the conclusion that NOS signaling is disrupted in the lymphatic endothelium of lambs exposed to chronically increased pulmonary blood and lymph flow and may contribute to decreased pulmonary lymphatic bioavailable NO.

  18. Therapeutic Potential of Cell Penetrating Peptides (CPPs) and Cationic Polymers for Chronic Hepatitis B

    DEFF Research Database (Denmark)

    Ndeboko, Bénédicte; Lemamy, Guy Joseph; Nielsen, Peter E;

    2015-01-01

    hepatitis B virus (DHBV), a reference model for human HBV infection. The in vivo administration of PNA-CPP conjugates to neonatal ducklings showed that they reached the liver and inhibited DHBV replication. Interestingly, our results indicated also that a modified CPP (CatLip) alone, in the absence of its......Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. Because current anti-HBV treatments are only virostatic, there is an urgent need for development of alternative antiviral approaches. In this context, cell-penetrating peptides (CPPs) and cationic polymers...

  19. Practical Aspects of Allogeneic Hematopoietic Cell Transplantation for Patients with Poor-Risk Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Julio Delgado

    2011-01-01

    Full Text Available Allogeneic hematopoietic cell transplantation has become a viable option for younger patients with poor-risk chronic lymphocytic leukemia. The results obtained with either conventional or reduced-intensity conditioning regimens have been recently evaluated and compared with alternative nontransplant strategies. This manuscript deals with practical aspects of the procedure, including patient and donor selection, conditioning regimen, GVHD prophylaxis, disease monitoring, infectious and noninfectious complications, and timing of the procedure. Finally, we speculate on how we could improve the results obtained with the procedure and new advances currently in clinical trials.

  20. Cardiac cell damage: a primary myocardial disease in streptozotocin-induced chronic diabetes.

    OpenAIRE

    Seager, M. J.; Singal, P. K.; Orchard, R.; Pierce, G. N.; Dhalla, N S

    1984-01-01

    Ultrastructural changes in heart muscle due to chronic diabetes subsequent to a single injection of streptozotocin (65 mg/kg body wt, i.v.) were studied in rats. Presence of diabetes was indicated by hyperglycaemia (plasma glucose, control, 120 +/- 7; diabetic, 448 +/- 21 mg/dl) as well as hypo-insulinaemia (plasma insulin, control, 25.6 +/- 5.2; diabetic, 11.2 +/- 0.5 microU/ml). After 8 weeks of diabetes, the hearts were processed for electron microscopic examination. Cardiac muscle cells i...

  1. Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection.

    Science.gov (United States)

    Harari, Alexandre; Rizzardi, G Paolo; Ellefsen, Kim; Ciuffreda, Donatella; Champagne, Patrick; Bart, Pierre-Alexandre; Kaufmann, Daniel; Telenti, Amalio; Sahli, Roland; Tambussi, Giuseppe; Kaiser, Laurent; Lazzarin, Adriano; Perrin, Luc; Pantaleo, Giuseppe

    2002-08-15

    CD4 T-cell-specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1- and CMV-specific interferon-gamma-secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1-specific CD4 T-cell responses. A substantial proportion of CD4(+)CCR7(-) T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

  2. A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control

    Directory of Open Access Journals (Sweden)

    Gang Xin

    2015-11-01

    Full Text Available Control of chronic viral infections by CD8 T cells is critically dependent on CD4 help. In particular, helper-derived IL-21 plays a key role in sustaining the CD8 T cell response; however, the molecular pathways by which IL-21 sustains CD8 T cell immunity remain unclear. We demonstrate that IL-21 causes a phenotypic switch of transcription factor expression in CD8 T cells during chronic viral infection characterized by sustained BATF expression. Importantly, BATF expression during chronic infection is both required for optimal CD8 T cell persistence and anti-viral effector function and sufficient to rescue “unhelped” CD8 T cells. Mechanistically, BATF sustains the response by cooperating with IRF4, an antigen-induced transcription factor that is also critically required for CD8 T cell maintenance, to preserve Blimp-1 expression and thereby sustain CD8 T cell effector function. Collectively, these data suggest that CD4 T cells “help” the CD8 response during chronic infection via IL-21-induced BATF expression.

  3. Adaptive and Pathogenic Responses to Stress by Stem Cells during Development

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    Daniel A. Rappolee

    2012-12-01

    Full Text Available Cellular stress is the basis of a dose-dependent continuum of responses leading to adaptive health or pathogenesis. For all cells, stress leads to reduction in macromolecular synthesis by shared pathways and tissue and stress-specific homeostatic mechanisms. For stem cells during embryonic, fetal, and placental development, higher exposures of stress lead to decreased anabolism, macromolecular synthesis and cell proliferation. Coupled with diminished stem cell proliferation is a stress-induced differentiation which generates minimal necessary function by producing more differentiated product/cell. This compensatory differentiation is accompanied by a second strategy to insure organismal survival as multipotent and pluripotent stem cells differentiate into the lineages in their repertoire. During stressed differentiation, the first lineage in the repertoire is increased and later lineages are suppressed, thus prioritized differentiation occurs. Compensatory and prioritized differentiation is regulated by at least two types of stress enzymes. AMP-activated protein kinase (AMPK which mediates loss of nuclear potency factors and stress-activated protein kinase (SAPK that does not. SAPK mediates an increase in the first essential lineage and decreases in later lineages in placental stem cells. The clinical significance of compensatory and prioritized differentiation is that stem cell pools are depleted and imbalanced differentiation leads to gestational diseases and long term postnatal pathologies.

  4. Adaptive and Pathogenic Responses to Stress by Stem Cells during Development.

    Science.gov (United States)

    Mansouri, Ladan; Xie, Yufen; Rappolee, Daniel A

    2012-01-01

    Cellular stress is the basis of a dose-dependent continuum of responses leading to adaptive health or pathogenesis. For all cells, stress leads to reduction in macromolecular synthesis by shared pathways and tissue and stress-specific homeostatic mechanisms. For stem cells during embryonic, fetal, and placental development, higher exposures of stress lead to decreased anabolism, macromolecular synthesis and cell proliferation. Coupled with diminished stem cell proliferation is a stress-induced differentiation which generates minimal necessary function by producing more differentiated product/cell. This compensatory differentiation is accompanied by a second strategy to insure organismal survival as multipotent and pluripotent stem cells differentiate into the lineages in their repertoire. During stressed differentiation, the first lineage in the repertoire is increased and later lineages are suppressed, thus prioritized differentiation occurs. Compensatory and prioritized differentiation is regulated by at least two types of stress enzymes. AMP-activated protein kinase (AMPK) which mediates loss of nuclear potency factors and stress-activated protein kinase (SAPK) that does not. SAPK mediates an increase in the first essential lineage and decreases in later lineages in placental stem cells. The clinical significance of compensatory and prioritized differentiation is that stem cell pools are depleted and imbalanced differentiation leads to gestational diseases and long term postnatal pathologies.

  5. A review of adaptive mechanisms in cell responses towards oxidative stress caused by dental resin monomers.

    Science.gov (United States)

    Krifka, Stephanie; Spagnuolo, Gianrico; Schmalz, Gottfried; Schweikl, Helmut

    2013-06-01

    Dental composite resins are biomaterials commonly used to aesthetically restore the structure and function of teeth impaired by caries, erosion, or fracture. Residual monomers released from resin restorations as a result of incomplete polymerization processes interact with living oral tissues. Monomers like triethylene glycol dimethacrylate (TEGDMA) or 2-hydroxylethyl methacrylate (HEMA) are cytotoxic via apoptosis, induce genotoxic effects, and delay the cell cycle. Monomers also influence the response of cells of the innate immune system, inhibit specific odontoblast cell functions, or delay the odontogenic differentiation and mineralization processes in pulp-derived cells including stem cells. These observations indicate that resin monomers act as environmental stressors which inevitably disturb regulatory cellular networks through interference with signal transduction pathways. We hypothesize that an understanding of the cellular mechanisms underlying these phenomena will provide a better estimation of the consequences associated with dental therapy using composite materials, and lead to innovative therapeutic strategies and improved materials being used at tissue interfaces within the oral cavity. Current findings strongly suggest that monomers enhance the formation of reactive oxygen species (ROS), which is most likely the cause of biological reactions activated by dental composites and resin monomers. The aim of the present review manuscript is to discuss adaptive cell responses to oxidative stress caused by monomers. The particular significance of a tightly controlled network of non-enzymatic as well as enzymatic antioxidants for the regulation of cellular redox homeostasis and antioxidant defense in monomer-exposed cells will be addressed. The expression of ROS-metabolizing antioxidant enzymes like superoxide dismutase (SOD1), glutathione peroxidase (GPx1/2), and catalase in cells exposed to monomers will be discussed with particular emphasis on the role

  6. Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome

    Science.gov (United States)

    Medina-Gomez, Gema; Yetukuri, Laxman; Velagapudi, Vidya; Campbell, Mark; Blount, Margaret; Jimenez-Linan, Mercedes; Ros, Manuel; Orešič, Matej; Vidal-Puig, Antonio

    2009-01-01

    SUMMARY The events that contribute to the expansion of β-cell mass and enhanced β-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that β-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of β cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the β cells, (2) identify molecular effectors that contribute to increasing β-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate β-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of β-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult β cells contribute to the failure of the POKO β cell. Our results indicate that the rapid development of insulin resistance and β-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and β-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in β cells with

  7. Neural Stem Cell or Human Induced Pluripotent Stem Cell-Derived GABA-ergic Progenitor Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy.

    Science.gov (United States)

    Upadhya, Dinesh; Hattiangady, Bharathi; Shetty, Geetha A; Zanirati, Gabriele; Kodali, Maheedhar; Shetty, Ashok K

    2016-01-01

    Grafting of neural stem cells (NSCs) or GABA-ergic progenitor cells (GPCs) into the hippocampus could offer an alternative therapy to hippocampal resection in patients with drug-resistant chronic epilepsy, which afflicts >30% of temporal lobe epilepsy (TLE) cases. Multipotent, self-renewing NSCs could be expanded from multiple regions of the developing and adult brain, human embryonic stem cells (hESCs), and human induced pluripotent stem cells (hiPSCs). On the other hand, GPCs could be generated from the medial and lateral ganglionic eminences of the embryonic brain and from hESCs and hiPSCs. To provide comprehensive methodologies involved in testing the efficacy of transplantation of NSCs and GPCs in a rat model of chronic TLE, NSCs derived from the rat medial ganglionic eminence (MGE) and MGE-like GPCs derived from hiPSCs are taken as examples in this unit. The topics comprise description of the required materials, reagents and equipment, methods for obtaining rat MGE-NSCs and hiPSC-derived MGE-like GPCs in culture, generation of chronically epileptic rats, intrahippocampal grafting procedure, post-grafting evaluation of the effects of grafts on spontaneous recurrent seizures and cognitive and mood impairments, analyses of the yield and the fate of graft-derived cells, and the effects of grafts on the host hippocampus. © 2016 by John Wiley & Sons, Inc. PMID:27532817

  8. The effect of radio-adaptive doses on HT29 and GM637 cells

    Directory of Open Access Journals (Sweden)

    Hell Roswitha

    2008-04-01

    Full Text Available Abstract Background The shape of the dose-response curve at low doses differs from the linear quadratic model. The effect of a radio-adaptive response is the centre of many studies and well known inspite that the clinical applications are still rarely considered. Methods We studied the effect of a low-dose pre-irradiation (0.03 Gy – 0.1 Gy alone or followed by a 2.0 Gy challenging dose 4 h later on the survival of the HT29 cell line (human colorectal cancer cells and on the GM637 cell line (human fibroblasts. Results 0.03 Gy given alone did not have a significant effect on both cell lines, the other low doses alone significantly reduced the cell survival. Applied 4 h before the 2.0 Gy fraction, 0.03 Gy led to a significant induced radioresistance in GM637 cells, but not in HT29 cells, and 0.05 Gy led to a significant hyperradiosensitivity in HT29 cells, but not in GM637 cells. Conclusion A pre-irradiation with 0.03 Gy can protect normal fibroblasts, but not colorectal cancer cells, from damage induced by an irradiation of 2.0 Gy and the application of 0.05 Gy prior to the 2.0 Gy fraction can enhance the cell killing of colorectal cancer cells while not additionally damaging normal fibroblasts. If these findings prove to be true in vivo as well this may optimize the balance between local tumour control and injury to normal tissue in modern radiotherapy.

  9. Three-dimensional hierarchical cultivation of human skin cells on bio-adaptive hybrid fibers.

    Science.gov (United States)

    Planz, Viktoria; Seif, Salem; Atchison, Jennifer S; Vukosavljevic, Branko; Sparenberg, Lisa; Kroner, Elmar; Windbergs, Maike

    2016-07-11

    The human skin comprises a complex multi-scale layered structure with hierarchical organization of different cells within the extracellular matrix (ECM). This supportive fiber-reinforced structure provides a dynamically changing microenvironment with specific topographical, mechanical and biochemical cell recognition sites to facilitate cell attachment and proliferation. Current advances in developing artificial matrices for cultivation of human cells concentrate on surface functionalizing of biocompatible materials with different biomolecules like growth factors to enhance cell attachment. However, an often neglected aspect for efficient modulation of cell-matrix interactions is posed by the mechanical characteristics of such artificial matrices. To address this issue, we fabricated biocompatible hybrid fibers simulating the complex biomechanical characteristics of native ECM in human skin. Subsequently, we analyzed interactions of such fibers with human skin cells focusing on the identification of key fiber characteristics for optimized cell-matrix interactions. We successfully identified the mediating effect of bio-adaptive elasto-plastic stiffness paired with hydrophilic surface properties as key factors for cell attachment and proliferation, thus elucidating the synergistic role of these parameters to induce cellular responses. Co-cultivation of fibroblasts and keratinocytes on such fiber mats representing the specific cells in dermis and epidermis resulted in a hierarchical organization of dermal and epidermal tissue layers. In addition, terminal differentiation of keratinocytes at the air interface was observed. These findings provide valuable new insights into cell behaviour in three-dimensional structures and cell-material interactions which can be used for rational development of bio-inspired functional materials for advanced biomedical applications.

  10. Chronic antidiabetic sulfonylureas in vivo: reversible effects on mouse pancreatic beta-cells.

    Directory of Open Access Journals (Sweden)

    Maria Sara Remedi

    2008-10-01

    Full Text Available BACKGROUND: Pancreatic beta-cell ATP-sensitive potassium (K ATP channels are critical links between nutrient metabolism and insulin secretion. In humans, reduced or absent beta-cell K ATP channel activity resulting from loss-of-function K ATP mutations induces insulin hypersecretion. Mice with reduced K ATP channel activity also demonstrate hyperinsulinism, but mice with complete loss of K ATP channels (K ATP knockout mice show an unexpected insulin undersecretory phenotype. Therefore we have proposed an "inverse U" hypothesis to explain the response to enhanced excitability, in which excessive hyperexcitability drives beta-cells to insulin secretory failure without cell death. Many patients with type 2 diabetes treated with antidiabetic sulfonylureas (which inhibit K ATP activity and thereby enhance insulin secretion show long-term insulin secretory failure, which we further suggest might reflect a similar progression. METHODS AND FINDINGS: To test the above hypotheses, and to mechanistically investigate the consequences of prolonged hyperexcitability in vivo, we used a novel approach of implanting mice with slow-release sulfonylurea (glibenclamide pellets, to chronically inhibit beta-cell K ATP channels. Glibenclamide-implanted wild-type mice became progressively and consistently diabetic, with significantly (p < 0.05 reduced insulin secretion in response to glucose. After 1 wk of treatment, these mice were as glucose intolerant as adult K ATP knockout mice, and reduction of secretory capacity in freshly isolated islets from implanted animals was as significant (p < 0.05 as those from K ATP knockout animals. However, secretory capacity was fully restored in islets from sulfonylurea-treated mice within hours of drug washout and in vivo within 1 mo after glibenclamide treatment was terminated. Pancreatic immunostaining showed normal islet size and alpha-/beta-cell distribution within the islet, and TUNEL staining showed no evidence of apoptosis

  11. Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

    Science.gov (United States)

    Cubas, Rafael; van Grevenynghe, Julien; Wills, Saintedym; Kardava, Lela; Santich, Brian H; Buckner, Clarisa M; Muir, Roshell; Tardif, Virginie; Nichols, Carmen; Procopio, Francesco; He, Zhong; Metcalf, Talibah; Ghneim, Khader; Locci, Michela; Ancuta, Petronella; Routy, Jean-Pierre; Trautmann, Lydie; Li, Yuxing; McDermott, Adrian B; Koup, Rick A; Petrovas, Constantinos; Migueles, Steven A; Connors, Mark; Tomaras, Georgia D; Moir, Susan; Crotty, Shane; Haddad, Elias K

    2015-12-15

    Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

  12. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.

    Science.gov (United States)

    Peppa, Dimitra; Micco, Lorenzo; Javaid, Alia; Kennedy, Patrick T F; Schurich, Anna; Dunn, Claire; Pallant, Celeste; Ellis, Gidon; Khanna, Pooja; Dusheiko, Geoffrey; Gilson, Richard J; Maini, Mala K

    2010-01-01

    NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56(bright) NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/- TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-β blockade. PMID:21187913

  13. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.

    Directory of Open Access Journals (Sweden)

    Dimitra Peppa

    Full Text Available NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB, allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56(bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/- TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-β blockade.

  14. Permissivity of primary human hepatocytes and different hepatoma cell lines to cell culture adapted hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Francois Helle

    Full Text Available Significant progress has been made in Hepatitis C virus (HCV culture since the JFH1 strain cloning. However, developing efficient and physiologically relevant culture systems for all viral genotypes remains an important goal. In this work, we aimed at producing a high titer JFH1 derived virus to test different hepatic cells' permissivity. To this end, we performed successive infections and obtained a JFH1 derived virus reaching high titers. Six potential adaptive mutations were identified (I599V in E2, R1373Q and M1611T in NS3, S2364P and C2441S in NS5A and R2523K in NS5B and the effect of these mutations on HCV replication and infectious particle production was investigated. This cell culture adapted virus enabled us to efficiently infect primary human hepatocytes, as demonstrated using the RFP-NLS-IPS reporter protein and intracellular HCV RNA quantification. However, the induction of a strong type III interferon response in these cells was responsible for HCV inhibition. The disruption of this innate immune response led to a strong infection enhancement and permitted the detection of viral protein expression by western blotting as well as progeny virus production. This cell culture adapted virus also enabled us to easily compare the permissivity of seven hepatoma cell lines. In particular, we demonstrated that HuH-7, HepG2-CD81, PLC/PRF/5 and Hep3B cells were permissive to HCV entry, replication and secretion even if the efficiency was very low in PLC/PRF/5 and Hep3B cells. In contrast, we did not observe any infection of SNU-182, SNU-398 and SNU-449 hepatoma cells. Using iodixanol density gradients, we also demonstrated that the density profiles of HCV particles produced by PLC/PRF/5 and Hep3B cells were different from that of HuH-7 and HepG2-CD81 derived virions. These results will help the development of a physiologically relevant culture system for HCV patient isolates.

  15. Stressful Presentations: Mild Chronic Cold Stress in Mice Influences Baseline Properties of Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Kathleen Marie Kokolus

    2014-02-01

    Full Text Available The ability of dendritic cells to stimulate and regulate T cells is critical to effective anti-tumor immunity. Therefore, it is important to fully recognize any inherent factors which may influence DC function under experimental conditions, especially in laboratory mice since they are used so heavily to study immune responses. Physiological stress is well recognized to impair several arms of immune protection. The goals of this report are to briefly summarize previous work revealing how DCs respond to various forms of physiologically relevant stress and to present new data highlighting the potential for chronic mild cold stress inherent in mice housed at standard ambient temperatures required for laboratory mice to influence baseline DCs properties. Since recent data from our group shows that CD8+ T cell function is altered by mild chronic cold stress and since DC function is crucial for CD8+ T cell activation, we wondered whether mild cold stress may also be influencing DC properties. We found increased numbers of splenic DCs (CD11c+ in cold stressed mice compared to mice housed at a thermoneutral temperature, which significantly reduces cold stress. However, many of the DCs which are expanded in cold stressed mice express an immature phenotype. We also found that antigen presentation and ability of splenocytes to activate T cells were impaired compared to that seen in DCs isolated from mice at thermoneutrality. The new data presented here strongly suggest that the housing temperature of mice can affect fundamental properties of DC function which in turn could be influencing the response of DCs to added experimental stressors or other treatments.

  16. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Tucker DL

    2015-06-01

    Full Text Available David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL and chronic lymphocytic leukemia (CLL, small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which functions by irreversible inhibition of the downstream signaling pathway of the B-cell receptor, which normally promotes cell survival and proliferation. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile even in elderly and multiply pretreated patient cohorts. Although the majority of disease responses tend to be partial, efficacy data have also been encouraging with more than two-thirds of patients with CLL and MCL demonstrating a durable response, even in the high-risk disease setting. Resistance mechanisms are only partially understood and appear to be multifactorial, including the binding site mutation C481S, and escape through other common cell-signaling pathways. This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, both as a single agent and in combination with other therapies, and considers how this drug is likely to be used in future clinical practice. Keywords: ibrutinib, mantle cell lymphoma, chronic lymphocytic leukemia, Bruton’s tyrosine kinase, lymphoproliferative disorders

  17. An engineered approach to stem cell culture: automating the decision process for real-time adaptive subculture of stem cells.

    Directory of Open Access Journals (Sweden)

    Dai Fei Elmer Ker

    Full Text Available Current cell culture practices are dependent upon human operators and remain laborious and highly subjective, resulting in large variations and inconsistent outcomes, especially when using visual assessments of cell confluency to determine the appropriate time to subculture cells. Although efforts to automate cell culture with robotic systems are underway, the majority of such systems still require human intervention to determine when to subculture. Thus, it is necessary to accurately and objectively determine the appropriate time for cell passaging. Optimal stem cell culturing that maintains cell pluripotency while maximizing cell yields will be especially important for efficient, cost-effective stem cell-based therapies. Toward this goal we developed a real-time computer vision-based system that monitors the degree of cell confluency with a precision of 0.791±0.031 and recall of 0.559±0.043. The system consists of an automated phase-contrast time-lapse microscope and a server. Multiple dishes are sequentially imaged and the data is uploaded to the server that performs computer vision processing, predicts when cells will exceed a pre-defined threshold for optimal cell confluency, and provides a Web-based interface for remote cell culture monitoring. Human operators are also notified via text messaging and e-mail 4 hours prior to reaching this threshold and immediately upon reaching this threshold. This system was successfully used to direct the expansion of a paradigm stem cell population, C2C12 cells. Computer-directed and human-directed control subcultures required 3 serial cultures to achieve the theoretical target cell yield of 50 million C2C12 cells and showed no difference for myogenic and osteogenic differentiation. This automated vision-based system has potential as a tool toward adaptive real-time control of subculturing, cell culture optimization and quality assurance/quality control, and it could be integrated with current and

  18. Modification of immunocytochemical ZAP-70 assay for potential clinical application in B-cell chronic lymphocytic leukemia

    OpenAIRE

    Jerzy Kawiak; Jacek Roliński; Agnieszka Bojarska-Junak

    2011-01-01

    The ZAP-70 protein is a member of the Syk/ZAP protein tyrosine kinase family, normally expressed in T cells and NK cells but not found in normal, mature B cells. The protein plays a critical role in the initiation of T-cell signaling. Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) that expressed nonmutated immunoglobulin V genes were found to express levels of ZAP-70 protein that were comparable to those detected in T cells of healthy adults. The ZAP-70 protein ...

  19. Trisomy 12 in chronic lymphocytic leukemia and hairy cell leukemia: a cytogenetic and interphase cytogenetic study.

    Science.gov (United States)

    Cuneo, A; Bigoni, R; Balboni, M; Carli, M G; Piva, N; Fagioli, F; Latorraca, A; Wlodarska, I; van den Berghe, H; Castoldi, G

    1994-09-01

    Fluorescent in situ hybridization (FISH) with a chromosome 12-specific pericentromeric probe was performed in 42 patients with B-cell chronic lymphocytic leukemia (CLL) and in 10 patients with hairy cell leukemia (HCL). In all cases, a normal karyotype in more than 10 metaphase cells was obtained by conventional chromosome study. FISH documented that 6/42 patients with CLL in fact had trisomy 12 in 15-49% interphase cells. Sequential FISH studies were performed in 2 cases, showing an increase of percentage of trisomic cells over a 2-month to 4-year period. Two out of 10 patients with HCL, one of whom had morphologic features consistent with a diagnosis of HCL variant, showed 5.5 and 10% interphase nuclei with three fluorescent signals, a finding suggestive of the presence of trisomy 12. Combined immunophenotyping and FISH staining in these patients with HCL documented that trisomic cells were CD11c-positive, CD13-negative, and CD2-negative. We conclude that FISH is a sensitive technique allowing for the detection of trisomy 12 in a fraction of cytogenetically normal patients affected with CLL and HCL. PMID:7858495

  20. Characterization of miRNomes in Acute and Chronic Myeloid Leukemia Cell Lines

    Institute of Scientific and Technical Information of China (English)

    Qian Xiong; Jiangwei Yan; Songnian Hu; Xiangdong Fang; Yadong Yang; Hai Wang; Jie Li; Shaobin Wang; Yanming Li; Yaran Yang; Kan Cai; Xiuyan Ruan

    2014-01-01

    Myeloid leukemias are highly diverse diseases and have been shown to be associated with microRNA (miRNA) expression aberrations. The present study involved an in-depth miRNome analysis of two human acute myeloid leukemia (AML) cell lines, HL-60 and THP-1, and one human chronic myeloid leukemia (CML) cell line, K562, via massively parallel signature sequenc-ing. mRNA expression profiles of these cell lines that were established previously in our lab facil-itated an integrative analysis of miRNA and mRNA expression patterns. miRNA expression profiling followed by differential expression analysis and target prediction suggested numerous miRNA signatures in AML and CML cell lines. Some miRNAs may act as either tumor suppres-sors or oncomiRs in AML and CML by targeting key genes in AML and CML pathways. Expres-sion patterns of cell type-specific miRNAs could partially reflect the characteristics of K562, HL-60 and THP-1 cell lines, such as actin filament-based processes, responsiveness to stimulus and phag-ocytic activity. miRNAs may also regulate myeloid differentiation, since they usually suppress dif-ferentiation regulators. Our study provides a resource to further investigate the employment of miRNAs in human leukemia subtyping, leukemogenesis and myeloid development. In addition, the distinctive miRNA signatures may be potential candidates for the clinical diagnosis, prognosis and treatment of myeloid leukemias.

  1. Restoration of Innate and Adaptive Immune Responses by HCV Viral Inhibition with an Induction Approach Using Natural Interferon-Beta in Chronic Hepatitis C

    Directory of Open Access Journals (Sweden)

    Y. Kishida

    2012-01-01

    Full Text Available Chronic hepatitis C (CHC is a serious medical problem necessitating more effective treatment. This study investigated the hypothesis that an induction approach with nIFN-beta for 24 weeks followed by PEG-IFN-alpha+ribavirin (standard of care: SOC for 48 weeks (novel combination treatment: NCT would increase the initial virologic response rate and restore innate and adaptive immune responses in CHC. Seven CHC patients with a high viral load and genotype 1b were treated with NCT. Serum cytokine and chemokine levels were evaluated during NCT. NCT prevented viral escape and breakthrough resulting in persistent viral clearance of HCVRNA. IL-15 was increased at the end of induction therapy in both early virologic responders (EAVRs and late virologic responders (LAVRs; CXCL-8, CXCL-10, and CCL-4 levels were significantly decreased (<0.05 in EAVR but not in LAVR during NCT, and IL-12 increased significantly (<0.05 and CXCL-8 decreased significantly (<0.05 after the end of NCT in EAVR but not in LAVR. NCT prevented viral breakthrough with viral clearance leading to improvement of innate and adaptive immunity resulting in a sustained virologic response (SVR. NCT (=8 achieved a higher SVR rate than SOC (=8 in difficult-to-treat CHC patients with genotype 1 and high viral loads.

  2. DNA DAMAGE IN BUCCAL EPITHELIAL CELLS FROM INDIVIDUALS CHRONICALLY EXPOSED TO ARSENIC VIA DRINKING WATER IN INNER MONGOLIA, CHINA

    Science.gov (United States)

    The purpose of this pilot study was to assess DNA damage in buccal cells from individuals chronically exposed to arsenic via drinking water in Ba Men, Inner Mongolia. Buccal cells were collected from 19 Ba Men residents exposed to arsenic at 527.5 ? 23.7 g/L (mean ? SEM) and ...

  3. Expression of mitochondrial fission protein locus Fisl and ultrastructural changes in the renal cells of rats with chronic fluorosis

    Institute of Scientific and Technical Information of China (English)

    秦双立

    2013-01-01

    Objective To observe the expression of mitochondrial fission protein locus Fis1 and ultrastructural changes in the renal cells of rats with chronic fluorosis,and to reveal the mechanism in mitochondrial damage of the renal cells.Methods Sixty SD rats were randomly divided into 3 groups according

  4. Comparison of mesenchymal stromal cells from young healthy donors and patients with severe chronic coronary artery disease

    DEFF Research Database (Denmark)

    Friis, Tina; Haack-Sørensen, Mandana; Hansen, Susanne Kofoed;

    2011-01-01

    It has been questioned whether bone marrow-derived mesenchymal stromal cells (MSCs) from patients with ischemic heart disease are suitable for use in regenerative stem cell therapy. We compared MSCs from patients with chronic coronary artery disease (CAD) and MSCs from young healthy donors...

  5. Comparison of mesenchymal stromal cells from young healthy donors and patients with severe chronic coronary artery disease

    DEFF Research Database (Denmark)

    Friis, Tina; Haack-Sørensen, Mandana; Hansen, Susanne Kofoed;

    2011-01-01

    It has been questioned whether bone marrow-derived mesenchymal stromal cells (MSCs) from patients with ischemic heart disease are suitable for use in regenerative stem cell therapy. We compared MSCs from patients with chronic coronary artery disease (CAD) and MSCs from young healthy donors with r...

  6. Temperature modeling and control of Direct Methanol Fuel Cell based on adaptive neural fuzzy technology

    Institute of Scientific and Technical Information of China (English)

    Qi Zhidong; Zhu Xinjian; Cao Guangyi

    2006-01-01

    Aiming at on-line controlling of Direct Methanol Fuel Cell (DMFC) stack, an adaptive neural fuzzy inference technology is adopted in the modeling and control of DMFC temperature system. In the modeling process, an Adaptive Neural Fuzzy Inference System (ANFIS) identification model of DMFC stack temperature is developed based on the input-output sampled data, which can avoid the internal complexity of DMFC stack. In the controlling process, with the network model trained well as the reference model of the DMFC control system, a novel fuzzy genetic algorithm is used to regulate the parameters and fuzzy rules of a neural fuzzy controller. In the simulation, compared with the nonlinear Proportional Integral Derivative (PID) and traditional fuzzy algorithm, the improved neural fuzzy controller designed in this paper gets better performance, as demonstrated by the simulation results.

  7. In-cell adaptive touch technology for a flexible e-paper display

    Science.gov (United States)

    Lee, Jong-Kwon; Kim, Sang-Soo; Park, Yong-In; Kim, Chang-Dong; Hwang, Yong-Kee

    2011-02-01

    In-cell adaptive touch technology for use in an electrophoretic display (EPD) has been developed and implemented in 11.5 in. UXGA flexible electronic paper display. Here, two types of a-Si:H photo-sensor arrays fabricated on a stainless steel substrate at the process temperature of 250 °C have been used along with an overall capacitive sensor formed on top of the flexible panel. Thus, we can resolve the sensing issue of normal photo-sensor array as well as maintain the feature of low power consumption in the EPD. Moreover, new touch algorithm adapted depending upon the amount of light intensity has been applied to enhance touch sensitivity regardless of environmental light conditions.

  8. Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments

    Science.gov (United States)

    Cardoso, Ana Carolina Ferreira; Andrade, Luciana Nogueira de Sousa; Bustos, Silvina Odete; Chammas, Roger

    2016-01-01

    Galectin-3 is a member of the β-galactoside-binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein found in the nucleus and in the cytoplasm, under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (e.g., hypoxia and nutrient deprivation) galectin-3 is upregulated, through the activity of transcription factors, such as HIF-1α and NF-κB. Here, we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins, and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell, and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocytes/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, as (i) it favors tumor cell adaptation for survival in stressed conditions; (ii) upon secretion, galectin-3 induces tumor cell detachment and migration; and (iii) it attracts monocyte/macrophage and endothelial cells to the tumor mass, inducing both directly and indirectly the process of angiogenesis. The two latter activities are potentially targetable, and specific interventions may be designed to counteract the protumoral role of extracellular

  9. The hedgehog receptor patched1 in T cells is dispensable for adaptive immunity in mice.

    Directory of Open Access Journals (Sweden)

    Kai D Michel

    Full Text Available Hedgehog (Hh signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells. In contrast, peripheral T cells were not affected. Proliferation and IFNγ secretion by Ptch-deficient T cells were indistinguishable from controls irrespectively of whether we used strong or suboptimal conditions for stimulation. Analysis of CTL and Treg cell functions did not reveal any differences between both genotypes, and T cell apoptosis induced by glucocorticoids or γ-irradiation was also similar. Surprisingly, absence of Ptch did not lead to an activation of canonic Hh signaling in peripheral T cells as indicated by unaltered expression levels of Gli1 and Gli2. To test whether we could uncover any role of Ptch in T cells in vivo we subjected the mutant mice to three different disease models, namely allogeneic bone marrow transplantation mimicking graft-versus-host disease, allergic airway inflammation as a model of asthma and growth of adoptively transferred melanoma cells as a means to test tumor surveillance by the immune system. Nonetheless, we were neither able to demonstrate any difference in the disease courses nor in any pathogenic parameter in these three models of adaptive immunity. We therefore conclude that the Hh receptor Ptch is dispensable for T cell function in vitro as well as in vivo.

  10. Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments.

    Science.gov (United States)

    Cardoso, Ana Carolina Ferreira; Andrade, Luciana Nogueira de Sousa; Bustos, Silvina Odete; Chammas, Roger

    2016-01-01

    Galectin-3 is a member of the β-galactoside-binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein found in the nucleus and in the cytoplasm, under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (e.g., hypoxia and nutrient deprivation) galectin-3 is upregulated, through the activity of transcription factors, such as HIF-1α and NF-κB. Here, we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins, and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell, and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocytes/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, as (i) it favors tumor cell adaptation for survival in stressed conditions; (ii) upon secretion, galectin-3 induces tumor cell detachment and migration; and (iii) it attracts monocyte/macrophage and endothelial cells to the tumor mass, inducing both directly and indirectly the process of angiogenesis. The two latter activities are potentially targetable, and specific interventions may be designed to counteract the protumoral role of extracellular

  11. ALLOIMMUNIZATION IN SICKLE CELL DISEASE: CHANGING ANTIBODY SPECIFICITIES AND ASSOCIATION WITH CHRONIC PAIN AND DECREASED SURVIVAL

    Science.gov (United States)

    Telen, Marilyn J.; Afenyi-Annan, Araba; Garrett, Melanie E.; Combs, Martha Rae; Orringer, Eugene P.; Ashley-Koch, Allison E.

    2014-01-01

    BACKGROUND: Alloimmunization remains a significant complication of transfusion and has been associated with multiple factors, including inflammation, an important pathophysiologic mechanism in sickle cell disease (SCD). We explored whether alloimmunization is associated with disease severity in SCD. STUDY DESIGN AND METHODS Adult SCD patients were enrolled in a study of outcome modifying genes in SCD. Historical records of patients with SCD at two participating institutions were reviewed for data on antigen phenotype and alloimmunization. Differences in demographic, clinical and laboratory findings, end organ damage, and overall disease severity were then compared between alloimmunized and non-alloimmunized patients. RESULTS Of 319 patients, 87 (27%) were alloimmunized. Alloantibody specificities differed from those previously described, especially due to the significantly higher frequency of anti-S. Although alloimmunization was not associated with frequency of vaso-occlusive episodes, a higher percentage of alloimmunized patients had chronic pain, as defined by daily use of short acting narcotics (p=0.006), long acting narcotics (p=0.013), or both (p=0.03). Additionally, alloimmunized patients had poorer survival (HR=1.92, p=0.01) and were more likely to have avascular necrosis (p=0.024), end-organ damage (p=0.049) and red cell autoantibodies (p<0.001), even after controlling for the effects of age, gender, and hemoglobin diagnosis. Alloimmunization was not associated with other SCD related complications, such as acute chest syndrome or stroke. CONCLUSIONS Alloimmunization in SCD may be associated with chronic pain, risk of end-organ damage, and shorter survival. These novel findings suggest new directions for the investigation of immune response-mediated pathways common to alloimmunization and chronic pain. PMID:25444611

  12. Apoptosis of gingival connective tissue cells in diabetic individuals with chronic periodontitis

    Directory of Open Access Journals (Sweden)

    Farin Kiani Yazdy

    2013-05-01

    Full Text Available   Background and Aims: Apoptosis or programmed cell death plays an important role in the pathogenesis of many diseases. Previous studies suggest that apoptosis is involved in the pathogenesis of periodontal disease, on the other hand it is also suggested that diabetes mellitus enhances apoptosis of connective tissue cells. Thus, we measured expression of proteins which are relevant to apoptosis in the gingival tissue of diabetic patients with chronic periodontitis in comparison to non diabetic individuals.   Materials and Methods: 25 patients with diabetes and chronic periodontitis and 16 non diabetic controls were included in this study. 4 weeks after scaling and root planning and oral hygiene instructions, periodontal surgery was done and gingival tissues obtained during surgery, were sent to lab to investigate expression of Fas, P53, Bcl-2 and Survivin using real-time PCR technique. Data were analyzed using Mann-Whitney and Chi-squared.   Results: Pro-apoptotic proteins (Fas, P53 were significantly (P<0.05 higher in gingival tissues of diabetics (9.5×10-6, 2.4×10-6, respectively in comparison to non diabetics (9.4×10-7, 5.6×10-7, whereas the difference in expression of anti-apoptotic proteins (Bcl-2, Survivin between 2 groups was not significant (9.7×10-8, 3.5×10-7 in comparison to 1.4×10-7, 3.1×10-7, respectively( P =0.91, P =0.29 respectively.   Conclusion: Apoptosis was increased in gingival connective tissue of diabetic patients with chronic periodontitis in comparison to non diabetic ones. Therefore , intervention in expression or function of pro-apoptotic proteins (Fas, P53 could be a new goal in the treatment of periodontal disease of diabetic patients.

  13. Squamous cell carcinoma of the suprapubic tract: A rare presentation in patients with chronic indwelling urinary catheters.

    Science.gov (United States)

    Massaro, Peter Alexander; Moore, Jonathan; Rahmeh, Tarek; Morse, Michael J

    2014-07-01

    Squamous cell carcinoma (SCC) of the bladder is uncommon, but can arise in the setting of long-term bladder catheterization and chronic inflammation. SCC can arise primarily from the suprapubic catheter tract, but fewer than 10 such cases have been reported. We document 2 cases of SCC arising from the suprapubic tract associated with chronic indwelling urinary catheters. SCC must be differentiated from granulomatous conditions, which are quite common in patients with suprapubic catheters. PMID:25132900

  14. Adaptive rheology and ordering of cell cytoskeleton govern matrix rigidity sensing.

    Science.gov (United States)

    Gupta, Mukund; Sarangi, Bibhu Ranjan; Deschamps, Joran; Nematbakhsh, Yasaman; Callan-Jones, Andrew; Margadant, Felix; Mège, René-Marc; Lim, Chwee Teck; Voituriez, Raphaël; Ladoux, Benoît

    2015-01-01

    Matrix rigidity sensing regulates a large variety of cellular processes and has important implications for tissue development and disease. However, how cells probe matrix rigidity, and hence respond to it, remains unclear. Here, we show that rigidity sensing and adaptation emerge naturally from actin cytoskeleton remodelling. Our in vitro experiments and theoretical modelling demonstrate a biphasic rheology of the actin cytoskeleton, which transitions from fluid on soft substrates to solid on stiffer ones. Furthermore, we find that increasing substrate stiffness correlates with the emergence of an orientational order in actin stress fibres, which exhibit an isotropic to nematic transition that we characterize quantitatively in the framework of active matter theory. These findings imply mechanisms mediated by a large-scale reinforcement of actin structures under stress, which could be the mechanical drivers of substrate stiffness-dependent cell shape changes and cell polarity. PMID:26109233

  15. Evaluation of specific humoral immune response in pigs vaccinated with cell culture adapted classical swine fever vaccine

    OpenAIRE

    Nath, Mrinal K.; Sarma, D. K.; B. C. DAS; Deka, P.; Kalita, D.; Dutta, J. B.; Mahato, G.; S Sarma; Roychoudhury, P

    2016-01-01

    Aim: To determine an efficient vaccination schedule on the basis of the humoral immune response of cell culture adapted live classical swine fever virus (CSFV) vaccinated pigs and maternally derived antibody (MDA) in piglets of vaccinated sows. Materials and Methods: A cell culture adapted live CSFV vaccine was subjected to different vaccination schedule in the present study. Serum samples were collected before vaccination (day 0) and 7, 14, 28, 42, 56, 180, 194, 208, 270, 284 and 298 days af...

  16. Identification of galectin-1 as a novel mediator for chemoresistance in chronic myeloid leukemia cells.

    Science.gov (United States)

    Luo, Wu; Song, Li; Chen, Xi-Lei; Zeng, Xiang-Feng; Wu, Jian-Zhang; Zhu, Cai-Rong; Huang, Tao; Tan, Xiang-Peng; Lin, Xiao-Mian; Yang, Qi; Wang, Ji-Zhong; Li, Xiao-Kun; Wu, Xiao-Ping

    2016-05-01

    Multidrug resistance protein-1 (MDR1) has been proven to be associated with the development of chemoresistance to imatinib (Glivec, STI571) which displays high efficacy in treatment of BCR-ABL-positive chronic myelogenous leukemia (CML). However, the possible mechanisms of MDR1 modulation in the process of the resistance development remain to be defined. Herein, galectin-1 was identified as a candidate modulator of MDR1 by proteomic analysis of a model system of leukemia cell lines with a gradual increase of MDR1 expression and drug resistance. Coincidently, alteration of galectin-1 expression triggers the change of MDR1 expression as well as the resistance to the cytotoxic drugs, suggesting that augment of MDR1 expression engages in galectin-1-mediated chemoresistance. Moreover, we provided the first data showing that NF-κB translocation induced by P38 MAPK activation was responsible for the modulation effect of galectin-1 on MDR1 in the chronic myelogenous leukemia cells. Galectin-1 might be considered as a novel target for combined modality therapy for enhancing the efficacy of CML treatment with imatinib. PMID:27050374

  17. CD8 positive T cells express IL-17 in patients with chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Eidelman David H

    2011-04-01

    Full Text Available Abstract Background Chronic obstructive pulmonary disease (COPD is a progressive and irreversible chronic inflammatory disease of the lung. The nature of the immune reaction in COPD raises the possibility that IL-17 and related cytokines may contribute to this disorder. This study analyzed the expression of IL-17A and IL-17F as well as the phenotype of cells producing them in bronchial biopsies from COPD patients. Methods Bronchoscopic biopsies of the airway were obtained from 16 COPD subjects (GOLD stage 1-4 and 15 control subjects. Paraffin sections were used for the investigation of IL-17A and IL-17F expression in the airways by immunohistochemistry, and frozen sections were used for the immunofluorescence double staining of IL-17A or IL-17F paired with CD4 or CD8. In order to confirm the expression of IL-17A and IL-17F at the mRNA level, a quantitative RT-PCR was performed on the total mRNA extracted from entire section or CD8 positive cells selected by laser capture microdissection. Results IL-17F immunoreactivity was significantly higher in the bronchial biopsies of COPD patients compared to control subjects (P P P P Conclusion These findings support the notion that Th17 cytokines could play important roles in the pathogenesis of COPD, raising the possibility of using this mechanism as the basis for novel therapeutic approaches.

  18. Noncultured Autologous Adipose-Derived Stem Cells Therapy for Chronic Radiation Injury

    Directory of Open Access Journals (Sweden)

    Sadanori Akita

    2010-01-01

    Full Text Available Increasing concern on chronic radiation injuries should be treated properly for life-saving improvement of wound management and quality of life. Recently, regenerative surgical modalities should be attempted with the use of noncultured autologous adipose-derived stem cells (ADSCs with temporal artificial dermis impregnated and sprayed with local angiogenic factor such as basic fibroblast growth factor, and secondary reconstruction can be a candidate for demarcation and saving the donor morbidity. Autologous adipose-derived stem cells, together with angiogenic and mitogenic factor of basic fibroblast growth factor and an artificial dermis, were applied over the excised irradiated skin defect and tested for Patients who were uneventfully healed with minimal donor-site morbidity, which lasts more than 1.5 years.

  19. The water channel aquaporin-1 contributes to renin cell recruitment during chronic stimulation of renin production

    DEFF Research Database (Denmark)

    Tinning, Anne Robdrup; Jensen, Boye L; Schweda, Frank;

    2014-01-01

    Processing and release of secretory granules involve water movement across granule membranes. It was hypothesized that the water channel aquaporin-1 (AQP-1) contributes directly to recruitment of renin-positive cells in the afferent arteriole. AQP1(-/-) and (+/+) mice were fed a low NaCl diet (LS...... to (+/+) mice. Tissue renin concentration was higher in AQP1(-/-) mice and renin mRNA level was not different between genotypes. Mean arterial blood pressure was not different at baseline and during low salt diet but decreased significantly in both genotypes after addition of ACEI; the response was faster...... for acutely stimulated renin secretion in vivo and from isolated perfused kidney, whereas recruitment of renin-positive cells in response to chronic stimulation is attenuated or delayed in AQP1(-/-) mice....

  20. Autoimmunity in chronic obstructive pulmonary disease: clinical and experimental evidence

    OpenAIRE

    Kheradmand, Farrah; Shan, Ming; Xu, Chuang; Corry, David B.

    2012-01-01

    Over the past few decades, neutrophils and macrophages had co-occupied center stage as the critical innate immune cells underlying the pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease and lung parenchymal destruction (i.e., emphysema). While chronic exposure to smoke facilitates the recruitment of innate immune cells into the lung, a clear role for adaptive immunity in emphysema has emerged. Evidence from human studies specifically point to a role for recruitment ...

  1. The Role of Plasmacytoid Dendritic Cells in Innate and Adaptive Immune Responses against Alpha Herpes Virus Infections

    Directory of Open Access Journals (Sweden)

    Philipp Schuster

    2011-01-01

    Full Text Available In 1999, two independent groups identified plasmacytoid dendritic cells (PDC as major type I interferon- (IFN- producing cells in the blood. Since then, evidence is accumulating that PDC are a multifunctional cell population effectively coordinating innate and adaptive immune responses. This paper focuses on the role of different immune cells and their interactions in the surveillance of alpha herpes virus infections, summarizes current knowledge on PDC surface receptors and their role in direct cell-cell contacts, and develops a risk factor model for the clinical implications of herpes simplex and varicella zoster virus reactivation. Data from studies involving knockout mice and cell-depletion experiments as well as human studies converge into a “spider web”, in which the direct and indirect crosstalk between many cell populations tightly controls acute, latent, and recurrent alpha herpes virus infections. Notably, cells involved in innate immune regulations appear to shape adaptive immune responses more extensively than previously thought.

  2. Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis.

    Science.gov (United States)

    Wild, J; Schmiedel, B J; Maurer, A; Raab, S; Prokop, L; Stevanović, S; Dörfel, D; Schneider, P; Salih, H R

    2015-08-01

    Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies.

  3. Clinical significance of peripheral blood CD4 + natural killer T cells in chronic hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    JIANG Rong-long; LU Qiao-sheng; FENG Xiao-rong; LUO Kang-xian; HOU Jin-lin; FU Ning

    2001-01-01

    To understand the clinical significance of CD4+ natural killer T (NK-T) cells in chronic hepatitis B virus (HBV) infection. Methods: Peripheral blood mononuclear cells (PBMCs) from individuals with chronic HBV infection were separated routinely. After Induction with IL-12/IL-2 for 12 d, the proportion of CD4+NK-T cells in peripheral blood was determined by fluorescence activated cell sorter (FACS) analysis, and the cytotoxicity of peripheral blood lymphocytes (PBLs) was tested with a 4 h 51Cr release assay. Results: After IL-12/IL-2 induction, the proportion of CD4+ NK-T cells was (18.1±4.20)%, (6.95±2.85)% and (1.50±1.30)% in the healthy control, CAH and AsC respectively. That in the peripheral blood of chronic HBV infected individuals was lower than that in the healthy control. CD8+ NK-T cells was (2.70±1.10)%, (2.20±1.40)% and (3.10±0.70)%respectively. In vitro cytotoxicity assays against Wish cells revealed that the PBLs cytotoxicity reduced in chronic HBV infected individuals (P<0.05), and that in AsC group was significantly lower in comparison with CHB and healthy control groups. The cytotoxicity of CD4+ NK-T cells against Wish cells could be abolished by treating PBLs with either anti-CD4 Ab or anti-CD56 Ab and complement, and partially depleted by anti-CD8 Ab. Conclusion:The abnormal cellular immune function of chronic HBV infected individuals may be associated with the deficiency of CD4+ NK-T cells.

  4. A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells.

    Science.gov (United States)

    Medves, Sandrine; Auchter, Morgan; Chambeau, Laetitia; Gazzo, Sophie; Poncet, Delphine; Grangier, Blandine; Verney, Aurélie; Moussay, Etienne; Ammerlaan, Wim; Brisou, Gabriel; Morjani, Hamid; Géli, Vincent; Palissot, Valérie; Berchem, Guy; Salles, Gilles; Wenner, Thomas

    2016-07-01

    Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e. C-circle concentration, an extra-chromosomal telomere repeat (ECTR), and the level of telomeric sister chromatid exchange (T-SCE) rate. Patients showed relative homogenous telomere length although almost no TERT transcript and nearly no C-circle were evidenced. Nevertheless, compared with normal B cells, B-CLL cells showed an increase in T-SCE rate that was correlated with a strong down-regulation of the topoisomerase III alpha (TOP3A) expression, involved in the dissolution of Holliday Junctions (HJ), together with an increased expression of SLX1A, SLX4, MUS81 and GEN1, involved in the resolution of HJ. Altogether, our results suggest that the telomere maintenance mechanism of B-CLL cells do not preferentially use telomerase or ALT. Rather, the rupture of the dissolvasome/resolvasome balance may increase telomere shuffling that could homogenize telomere length, slowing telomere erosion in this disease. PMID:26970083

  5. Effect of mesenchymal stem cells on inhibiting airway remodeling and airway inflammation in chronic asthma.

    Science.gov (United States)

    Ge, Xiahui; Bai, Chong; Yang, Jianming; Lou, Guoliang; Li, Qiang; Chen, Ruohua

    2013-07-01

    Previous studies proved that bone marrow-derived mesenchymal stem cells (BMSCs) could improve a variety of immune-mediated disease by its immunomodulatory properties. In this study, we investigated the effect on airway remodeling and airway inflammation by administrating BMSCs in chronic asthmatic mice. Forty-eight female BALB/c mice were randomly distributed into PBS group, BMSCs treatment group, BMSCs control group, and asthmatic group. The levels of cytokine and immunoglobulin in serum and bronchoalveolar lavage fluid were detected by enzyme-linked immunosorbent assay. The number of CD4(+) CD25(+) regulatory T cells and morphometric analysis was determined by flow cytometry, hematoxylin-eosin, immunofluorescence staining, periodic-acid Schiff, and masson staining, respectively. We found that airway remodeling and airway inflammation were evident in asthmatic mice. Moreover, low level of IL-12 and high levels of IL-13, IL-4, OVA-specific IgG1, IgE, and IgG2a and the fewer number of CD4(+) CD25(+) regulatory T cells were present in asthmatic group. However, transplantation of BMSCs significantly decreased airway inflammation and airway remodeling and level of IL-4, OVA-specific IgE, and OVA-specific IgG1, but elevated level of IL-12 and the number of CD4 + CD25 + regulatory T cells in asthma (P cells in asthma, but not contribution to lung regeneration. PMID:23334934

  6. Translation, cross-cultural adaptation, and validity of the Korean version of the pain sensitivity questionnaire in chronic pain patients.

    Science.gov (United States)

    Kim, Ho-Joong; Ruscheweyh, Ruth; Yeo, Ji-Hyun; Cho, Hyeon-Guk; Yi, Je-Min; Chang, Bong-Soon; Lee, Choon-Ki; Yeom, Jin S

    2014-11-01

    The purpose of this study was to translate pain sensitivity questionnaires (PSQ) into the Korean language, perform a cross-cultural adaption of the PSQ, and validate the Korean version of PSQ in patients with degenerative spinal disease. The PSQ was translated forward and backward, cross-culturally adapted by 2 independent translators, and approved by an expert committee. The final Korean version of the PSQ was tested on 72 patients with degenerative spinal disease. Test-retest reliability was evaluated for 60 patients (83%) who completed the second assessment in an interval of 4 weeks. The mean PSQ-minor, PSQ-moderate, and PSQ-total (standard deviation [SD]) were 5.40 (2.02), 6.46 (1.98), and 5.93 (1.93), respectively. The PSQ-total, PSQ-minor, and PSQ-moderate of the Korean version showed very good internal consistencies determined by the Cronbach's α of 0.926, 0.869, and 0.877, respectively. For convergent validity, the PSQ scores of the Korean version showed significant correlations with pain catastrophizing scale (PCS) (r = 0.377, P = 0.002; r = 0.365, P = 0.003; r = 0.362, P = 0.003 for PSQ-total, PSQ-minor, and PSQ-moderate of the Korean version, respectively). For test-retest reliability, the intraclass correlation coefficients were 0.782 for PSQ-total, 0.752 for PSQ-minor, and 0.793 for PSQ-moderate. In conclusion, the validated Korean version of PSQ is a transculturally equivalent, reliable, and valid tool to assess individual pain sensitivity.

  7. Adaptive regulation of taurine and beta-alanine uptake in a human kidney cell line from the proximal tubule

    DEFF Research Database (Denmark)

    Jessen, H; Jacobsen, Christian

    1997-01-01

    1. The underlying mechanisms involved in the adaptive regulation of beta-amino acid uptake in the human proximal tubule were examined by use of an immortalized human embryonic kidney epithelial cell line (IHKE). 2. The results indicated that the adaptive response to maintain whole-body taurine...... interferes with microtubule organization, was capable of blocking the response to alterations of taurine in cell medium, whereas inhibition of protein and nucleic acid synthesis by cycloheximide and actinomycin D, respectively, did not change the adaptive pattern. 4. Phorbol 12-myristate 13-acetate (PMA...

  8. Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells.

    Science.gov (United States)

    Cerutti, Andrea; Zan, Hong; Kim, Edmund C; Shah, Shefali; Schattner, Elaine J; Schaffer, András; Casali, Paolo

    2002-12-01

    Chronic lymphocytic leukemia (CLL) results from the expansion of malignant CD5(+) B cells that usually express IgD and IgM. These leukemic cells can give rise in vivo to clonally related IgG(+) or IgA(+) elements. The requirements and modalities of this process remain elusive. Here we show that leukemic B cells from 14 of 20 CLLs contain the hallmarks of ongoing Ig class switch DNA recombination (CSR), including extrachromosomal switch circular DNAs and circle transcripts generated by direct S micro -->Sgamma, S micro -->Salpha, and S micro -->Sepsilon as well as sequential Sgamma-->Salpha and Sgamma-->Sepsilon CSR. Similar CLL B cells express transcripts for activation-induced cytidine deaminase, a critical component of the CSR machinery, and contain germline I(H)-C(H) and mature V(H)DJ(H)-C(H) transcripts encoded by multiple Cgamma, Calpha, and Cepsilon genes. Ongoing CSR occurs in only a fraction of the CLL clone, as only small proportions of CD5(+)CD19(+) cells express surface IgG or IgA and lack IgM and IgD. In vivo class-switching CLL B cells down-regulate switch circles and circle transcripts in vitro unless exposed to exogenous CD40 ligand and IL-4. In addition, CLL B cells that do not class switch in vivo activate the CSR machinery and secrete IgG, IgA, or IgE upon in vitro exposure to CD40 ligand and IL-4. These findings indicate that in CLL at least some members of the malignant clone actively differentiate in vivo along a pathway that induces CSR. They also suggest that this process is elicited by external stimuli, including CD40 ligand and IL-4, provided by bystander immune cells.

  9. Ebolavirus evolves in human to minimize the detection by immune cells by accumulating adaptive mutations.

    Science.gov (United States)

    Ramaiah, Arunachalam; Arumugaswami, Vaithilingaraja

    2016-06-01

    The current outbreak of Zaire ebolavirus (EBOV) lasted longer than the previous outbreaks and there is as yet no proven treatment or vaccine available. Understanding host immune pressure and associated EBOV immune evasion that drive the evolution of EBOV is vital for diagnosis as well as designing a highly effective vaccine. The aim of this study was to deduce adaptive selection pressure acting on each amino acid sites of EBOV responsible for the recent 2014 outbreak. Multiple statistical methods employed in the study include SLAC, FEL, REL, IFEL, FUBAR and MEME. Results show that a total of 11 amino acid sites from sGP and ssGP, and 14 sites from NP, VP40, VP24 and L proteins were inferred as positively and negatively selected, respectively. Overall, the function of 11 out of 25 amino acid sites under selection pressure exactly found to be involved in T cell and B-cell epitopes. We identified that the EBOV had evolved through purifying selection pressure, which is a predictor that is known to aid the virus to adapt better to the human host and subsequently reduce the efficiency of existing immunity. Furthermore, computational RNA structure prediction showed that the three synonymous nucleotide mutations in NP gene altered the RNA secondary structure and optimal base-pairing energy, implicating a possible effect on genome replication. Here, we have provided evidence that the EBOV strains involved in the recent 2014 outbreak have evolved to minimize the detection by T and B cells by accumulating adaptive mutations to increase the survival fitness. PMID:27366764

  10. Adaptive Response to ionizing Radiation Induced by Low Doses of Gamma Rays in Human Lymphoblastoid Cell Lines

    International Nuclear Information System (INIS)

    When cells are exposed to low doses of a mutagenic or clastogenic agents, they often become less sensitive to the effects of a higher does administered subsequently. Such adaptive responses were first described in Escherichia coli and mammalian cells to low doses of an alkylating agent. Since most of the studies have been carried out with human lymphocytes, it is urgently necessary to study this effect in different cellular systems. Its relation with inherent cellular radiosensitivity and underlying mechanism also remain to be answered. In this study, adaptive response by 1 cGy of gamma rays was investigated in three human lymphoblastoid cell lines which were derived from ataxia telangiectasia homozygote, ataxia telangiectasia heterozygote, and normal individual. Experiments were carried out by delivering 1 cGy followed by 50 cGy of gamma radiation and chromatid breaks were scored as an endpoint. The results indicate that prior exposure to 1 cGy of gamma rays reduces the number of chromatid breaks induced by subsequent higher does (50 cGy). The expression of this adaptive response was similar among three cell lines despite of their different radiosensitivity. When 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, was added after 50 cGy, adaptive responses were abolished in all the tested cell lines. Therefore it is suggested that the adaptive response can be observed in human lymphoblastoid cell lines. Which was first documented through this study. The expression of adaptive response was similar among the cell lines regardless of their radiosensitivity. The elimination of the adaptive response by 3-aminobenzamide is consistent with the proposal that this adaptive response is the result of the induction of a certain chromosomal repair mechanism

  11. [Changes of heart function after different cell type stem cell transplantation in chronic heart failure].

    Science.gov (United States)

    Fan, Zhongcai; Chen, Mao; Deng, Juelin; Liu, Xiaojing; Zhang, Li; Rao, Li; Yang, Qing; Huang, Dejia

    2006-12-01

    To investigate the feasibility of introcoronary cell infusion into nonischemic heart failure (HF) heart and whether different types of stem cell transplantation would affect heart function to a similar degree. Japanese white ears rabbits were used as HF models by intravenous injection adriamycin. Autologous bone marrow mononuclear cells(BMCs), bone marrow stromal cells (MSCs), skeletal myoblasts (SMs) or culture medium were infused into coronary arteries respectively by occluding the root of ascending aorta. The mortality during and 4 weeks after the procedure the mortality was 7.1% and 16.7% respectively. After 4 weeks, the ejection fraction (EF) in BMCs group had significant improvement (P 0.05). In sham group,the left ventricular endostolic diameter (LVED) had significant enlargement (P 0.05). Immunofluorescence revealed de novo expression of cardiac troponin I in BMCs and MSCs groups, cardiac troponin I was not detected in SMs group. In conclusions, intracoronary cell transplantation could provide effective cell delivery into dilated cardiomyopathy hearts and could be a useful strategy for treating CHF, BMCs cell transplantation may be the first choice in all the above cell types. PMID:17228727

  12. Efficient induction of extrinsic cell death by dandelion root extract in human chronic myelomonocytic leukemia (CMML cells.

    Directory of Open Access Journals (Sweden)

    Pamela Ovadje

    Full Text Available BACKGROUND: Chronic Myelomonocytic Leukemia (CMML is a heterogeneous disease that is not only hard to diagnose and classify, but is also highly resistant to treatment. Available forms of therapy for this disease have not shown significant effects and patients rapidly develop resistance early on in therapy. These factors lead to the very poor prognosis observed with CMML patients, with median survival duration between 12 and 24 months after diagnosis. This study is therefore centered around evaluating the selective efficacy of a natural extract from dandelion roots, in inducing programmed cell death in aggressive and resistant CMML cell lines. METHODOLOGY/PRINCIPAL FINDINGS: To confirm the induction of programmed cell death in three human CMML cell lines, nuclear condensation and externalization of the phosphatidylserine, two main characteristics of apoptosis, were detected using Hoechst staining and annexin-V binding assay. The induction of another mode of cell death, autophagy, was determined using a monodansylcadaverine (MDC stain, to detect the formation of autophagy vacuoles. The results from this study indicate that Dandelion Root Extract (DRE is able to efficiently and selectively induce apoptosis and autophagy in these cell lines in a dose and time dependent manner, with no significant toxicity on non-cancerous peripheral blood mononuclear cells. More importantly, we observed early activation of initiator caspase-8, which led to mitochondrial destabilization and the induction of autophagy, suggesting that DRE acts through the extrinsic pathway of apoptosis. The inability of DRE to induce apoptosis in dominant-negative FADD cells, confirms the mechanism of action of DRE in in vitro models of CMML. CONCLUSION: The results from this study indicate that natural products, in particular Dandelion Root Extract, have great potential, as non-toxic and effective alternatives to conventional modes of chemotherapy available today.

  13. Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide.

    Directory of Open Access Journals (Sweden)

    Irene Amigo-Jiménez

    Full Text Available BACKGROUND: Matrix metalloproteinase-9 (MMP-9 contributes to chronic lymphocytic leukemia (CLL pathology by regulating cell migration and preventing spontaneous apoptosis. It is not known if MMP-9 is involved in CLL cell response to chemotherapy and we address this in the present study, using arsenic trioxide (ATO and fludarabine as examples of cytotoxic drugs. METHODS: We used primary cells from the peripheral blood of CLL patients and MEC-1 cells stably transfected with an empty vector or a vector containing MMP-9. The effect of ATO and fludarabine was determined by flow cytometry and by the MTT assay. Expression of mRNA was measured by RT-PCR and qPCR. Secreted and cell-bound MMP-9 was analyzed by gelatin zymography and flow cytometry, respectively. Protein expression was analyzed by Western blotting and immunoprecipitation. Statistical analyses were performed using the two-tailed Student's t-test. RESULTS: In response to ATO or fludarabine, CLL cells transcriptionally upregulated MMP-9, preceding the onset of apoptosis. Upregulated MMP-9 primarily localized to the membrane of early apoptotic cells and blocking apoptosis with Z-VAD prevented MMP-9 upregulation, thus linking MMP-9 to the apoptotic process. Culturing CLL cells on MMP-9 or stromal cells induced drug resistance, which was overcome by anti-MMP-9 antibodies. Accordingly, MMP-9-MEC-1 transfectants showed higher viability upon drug treatment than Mock-MEC-1 cells, and this effect was blocked by silencing MMP-9 with specific siRNAs. Following drug exposure, expression of anti-apoptotic proteins (Mcl-1, Bcl-xL, Bcl-2 and the Mcl-1/Bim, Mcl-1/Noxa, Bcl-2/Bax ratios were higher in MMP-9-cells than in Mock-cells. Similar results were obtained upon culturing primary CLL cells on MMP-9. CONCLUSIONS: Our study describes for the first time that MMP-9 induces drug resistance by modulating proteins of the Bcl-2 family and upregulating the corresponding anti-apoptotic/pro-apoptotic ratios. This

  14. Effect of betaine on HSP70 expression and cell survival during adaptation to osmotic stress.

    Science.gov (United States)

    Petronini, P G; De Angelis, E M; Borghetti, A F; Wheeler, K P

    1993-07-15

    Induced expression of the HSP70 gene in 3T3 and SV-3T3 cells was monitored by measurements of the synthesis of HSP70 and of the cellular contents of both HSP70 and its mRNA. The presence of betaine (N-trimethylglycine) at concentrations of 2.5-25 mM decreased the induction of HSP70 gene expression caused by incubation of 3T3 and SV-3T3 cells in hypertonic (0.5 osM) medium. This effect was accompanied by an enhancement of SV-3T3 cell adaptation, assayed by colony formation, to the hyperosmotic conditions. In contrast, the presence of betaine did not affect HSP70 gene expression induced in these cells by heat shock. After 6 h incubation with 25 mM betaine under hypertonic (0.5 osM) conditions the intracellular concentration of betaine in SV-3T3 cells was about 195 mM, compared with about 70 mM under isotonic (0.3 osM) conditions. Hence, with this concentration of extracellular betaine, the marked increase in the accumulation of betaine within the cells presumably counteracts the imposed osmotic pressure and eliminates the signal that otherwise initiates increased expression of the HSP70 gene. PMID:8343134

  15. Adaptation of infectious bronchitis virus in primary cells of the chick embryo chorioallantoic membrane

    Directory of Open Access Journals (Sweden)

    M. H. Mohammed

    2013-06-01

    Full Text Available The susceptibility of the primary chick embryo chorioallontoic membrane cells to infectious bronchitis virus was evaluated after twenty consecutive passages in chick embryo chorioallontoic membrane cells. Virus replication was monitored by cytopathic observation, indirect immunoperoxidase, and reverse transcription polymerase chain reaction (RT-PCR. At 72 hours post-infection (p.i. in third passage, the cytopathic effect was characterized by rounding up of cells, monolayer detachment, intracytoplasmic brownish colouration was readily observed by immunoperoxidase from 24 hours p.i in third passage, and at all times the extracted viral RNA from IBV-infected monolayers was demonstrated by RT-PCR. Tissue culture ineffective dose50 (TCID50 was used to measure virus titration performed on primary chick embryo chorioallontoic membrane cells and the titre in twenty passage was 108.6 TCID50/ml. The results obtained in this study suggested that the primary chick embryo chorioallontoic membrane cells can be used for adaptation infectious bronchitis virus (IBV and may be considered a step forward for the use of these cells in the future for IBV vaccine production

  16. Effect of Taurine on Acinar Cell Apoptosis and Pancreatic Fibrosis in Dibutyltin Dichloride-induced Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Sawa,Kiminari

    2012-08-01

    Full Text Available The relationship between pancreatic fibrosis and apoptosis of pancreatic acinar cells has not been fully elucidated. We reported that taurine had an anti-fibrotic effect in a dibutyltin dichloride (DBTC-chronic pancreatitis model. However, the effect of taurine on apoptosis of pancreatic acinar cells is still unclear. Therefore, we examined apoptosis in DBTC-chronic pancreatitis and in the AR42J pancreatic acinar cell line with/without taurine. Pancreatic fibrosis was induced by a single administration of DBTC. Rats were fed a taurine-containing diet or a normal diet and were sacrificed at day 5. The AR42J pancreatic acinar cell line was incubated with/without DBTC with taurine chloramines. Apoptosis was determined by using terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL assay. The expression of Bad and Bcl-2 proteins in the AR42J cells lysates was detected by Western blot analysis. The apoptotic index of pancreatic acinar cells in DBTC-administered rats was significantly increased. Taurine treatment inhibited pancreatic fibrosis and apoptosis of acinar cells induced by DBTC. The number of TUNEL-positive cells in the AR42J pancreatic acinar cell lines was significantly increased by the addition of DBTC. Incubation with taurine chloramines ameliorated these changes. In conclusion, taurine inhibits apoptosis of pancreatic acinar cells and pancreatitis in experimental chronic pancreatitis.

  17. Analysis of leptin signalling in hematopoietic cells using an adapted MAPPIT strategy.

    Science.gov (United States)

    Montoye, T; Piessevaux, J; Lavens, D; Wauman, J; Catteeuw, D; Vandekerckhove, J; Lemmens, I; Tavernier, J

    2006-05-29

    The adipocyte-secreted hormone leptin participates in the regulation of hematopoiesis and enhances proliferation of hematopoietic cells. We used an adaptation of the MAPPIT mammalian two-hybrid method to study leptin signalling in a hematopoietic setting. We confirmed the known interactions of suppressor of cytokine signalling 3 (SOCS3) and STAT5 with the Y985 and Y1077 motifs of the leptin receptor, respectively. We also provide evidence for novel interactions at the Y1077 motif, including phospholipase C gamma and several members of the SOCS protein family, further underscoring the important role of the Y1077 motif in leptin signalling. PMID:16698021

  18. Allosuppressor- and allohelper-T cells in acute and chronic graft-vs. -host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Rolink, A.G.; Gleichmann, E.

    1983-08-01

    Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. We analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. When nonirradiated F1 mice were used as the recipients, we found unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients but were capable of inducing a vigorous formation of SLE-like autoantibodies and severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. The sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and then comparing donor-cell inocula that contained similar numbers of T lymphocytes. Donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients unseparated donor T cells were superior to T cell subsets in inducing LGVHD. In contrast Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells.

  19. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model.

    Directory of Open Access Journals (Sweden)

    Vadivel Parthsarathy

    Full Text Available Neurogenesis is a life long process, but the rate of cell proliferation and differentiation decreases with age. In Alzheimer's patients, along with age, the presence of Aβ in the brain inhibits this process by reducing stem cell proliferation and cell differentiation. GLP-1 is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and the GLP-1 analogue liraglutide has been shown to increase cell proliferation in an Alzheimer's disease (AD mouse model. Here we investigated acute and chronic effects of liraglutide on progenitor cell proliferation, neuroblast differentiation and their subsequent differentiation into neurons in wild type and APP/PS-1 mice at different ages. APP/PS1 and their littermate controls, aged 3, 6, 12, 15 months were injected acutely or chronically with 25 nmol/kg liraglutide. Acute treatment with liraglutide showed an increase in cell proliferation in APP/PS1 mice, but not in controls whereas chronic treatment increased cell proliferation at all ages (BrdU and Ki67 markers. Moreover, numbers of immature neurons (DCX were increased in both acute and chronic treated animals at all ages. Most newly generated cells differentiated into mature neurons (NeuN marker. A significant increase was observed with chronically treated 6, 12, 15 month APP/PS1 and WT groups. These results demonstrate that liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza(TM, increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD.

  20. Human cell chips: adapting DNA microarray spotting technology to cell-based imaging assays.

    Directory of Open Access Journals (Sweden)

    Traver Hart

    Full Text Available Here we describe human spotted cell chips, a technology for determining cellular state across arrays of cells subjected to chemical or genetic perturbation. Cells are grown and treated under standard tissue culture conditions before being fixed and printed onto replicate glass slides, effectively decoupling the experimental conditions from the assay technique. Each slide is then probed using immunofluorescence or other optical reporter and assayed by automated microscopy. We show potential applications of the cell chip by assaying HeLa and A549 samples for changes in target protein abundance (of the dsRNA-activated protein kinase PKR, subcellular localization (nuclear translocation of NFkappaB and activation state (phosphorylation of STAT1 and of the p38 and JNK stress kinases in response to treatment by several chemical effectors (anisomycin, TNFalpha, and interferon, and we demonstrate scalability by printing a chip with approximately 4,700 discrete samples of HeLa cells. Coupling this technology to high-throughput methods for culturing and treating cell lines could enable researchers to examine the impact of exogenous effectors on the same population of experimentally treated cells across multiple reporter targets potentially representing a variety of molecular systems, thus producing a highly multiplexed dataset with minimized experimental variance and at reduced reagent cost compared to alternative techniques. The ability to prepare and store chips also allows researchers to follow up on observations gleaned from initial screens with maximal repeatability.

  1. Pathogenesis of endothelial cell dysfunction in chronic kidney disease: a retrospective and what the future may hold

    OpenAIRE

    Goligorsky, Michael S.

    2015-01-01

    Cardiovascular complications dominate the landscape of chronic kidney diseases (CKD). Endothelial cell dysfunction (ECD) is a well-known culprit of cardiovascular morbidity and it develops in CKD with remarkable frequency. This brief overview of ECD in CKD scans two decades of studies performed in my laboratory, from genetic analyses to proteomic and metabolomics screens. I provide a detailed description of findings related to the premature senescence of endothelial cells, cell transition fro...

  2. Interventions to improve chronic cyclosporine A nephrotoxicity through inhibiting renal cell apoptosis: a systematic review

    Institute of Scientific and Technical Information of China (English)

    XIAO Zheng; LI Cheng-wen; SHAN Juan; LUO Lei; FENG Li; LU Jun; LI Sheng-fu

    2013-01-01

    Objective To reveal interventions for chronic cyclosporine A nephrotoxicity (CCN) and provide new targets for further studies,we analyzed all relevant studies about interventions in renal cell apoptosis.Data sources We collected all relevant studies about interventions for cyclosporine A (CsA)-induced renal cell apoptosis in Medline (1966 to July 2010),Embase (1980 to July 2010) and ISI (1986 to July 2010),evaluated their quality,extracted data following PICOS principles and synthesized the data.Study selection We included all relevant studies about interventions in CsA-induced renal cell apoptosis no limitation of research design and language) and excluded the duplicated articles,meeting abstracts and reviews without specific data.Results There were three kinds of intervention,include anti-oxidant (sulfated polysaccharides,tea polyphenols,apigenin,curcumin,spirulina,etc),biologics (recombinant human erythropoietin (rhEPO),a murine pan-specific transforming growth factor (TGF)-beta-neutralizing monoclonal antibody1D11,cartilage oligomeric matrix protein (COMP)-angiopoietin-1 and hepatocyte growth factor (HGF) gene),and other drugs (spironolactone,rosiglitazone,pirfenidone and colchicine).These interventions significantly improved the CCN,renal cell apoptosis and renal dysfunction through intervening in four apoptotic pathways in animals or protected renal cells from apoptosis induced by CsA and increased cell survival through respectively four pathways in vitro.Conclusions There are three group interventions for CCN.Especially anti-oxidant drugs can significantly improve CCN,renal cell apoptosis and renal dysfunction.Many drugs can improve CCN through intervening in Fas/Fas ligand or mitochondrial pathway with sufficient evidences.Angiotensin Ⅱ,nitric oxide (NO) and endoplasmic reticulum (ER) pathways will be new targets for CCN.

  3. Isolated central nervous system relapse of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Fuchs Mary

    2012-08-01

    Full Text Available Abstract Background This case report highlights the relevance of quantifying the BCR-ABL gene in cerebrospinal fluid of patients with suspected relapse of chronic myeloid leukemia in the central nervous system. Case presentation We report on a female patient with isolated central nervous system relapse of chronic myeloid leukemia (CML during peripheral remission after allogeneic hematopoietic stem cell transplantation. The patient showed a progressive cognitive decline as the main symptom. MRI revealed a hydrocephalus and an increase in cell count in the cerebrospinal fluid (CSF with around 50% immature blasts in the differential count. A highly elevated BCR-ABL/ ABL ratio was detected in the CSF, whilst the ratio for peripheral blood and bone marrow was not altered. On treatment of the malresorptive hydrocephalus with shunt surgery, the patient showed an initial cognitive improvement, followed by a secondary deterioration. At this time, the cranial MRI showed leukemic infiltration of lateral ventricles walls. Hence, intrathecal administration of cytarabine, methotrexate, and dexamethasone was initiated, which caused a significant decrease of cells in the CSF. Soon after, the patient demonstrated significant cognitive improvement with a good participation in daily activities. At a later time point, after the patient had lost the major molecular response of CML, therapy with dasatinib was initiated. In a further follow-up, the patient was neurologically and hematologically stable. Conclusions In patients with treated CML, the rare case of an isolated CNS blast crisis has to be taken into account if neurological symptoms evolve. The analysis of BCR-ABL in the CSF is a further option for the reliable detection of primary isolated relapse of CML in these patients.

  4. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model.

    Science.gov (United States)

    Bonfield, Tracey L; Koloze, Mary; Lennon, Donald P; Zuchowski, Brandon; Yang, Sung Eun; Caplan, Arnold I

    2010-12-01

    Allogeneic human mesenchymal stem cells (hMSCs) introduced intravenously can have profound anti-inflammatory activity resulting in suppression of graft vs. host disease as well as regenerative events in the case of stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of these diseases. hMSCs produce bioactive factors that provide molecular cuing for: 1) immunosuppression of T cells; 2) antiscarring; 3) angiogenesis; 4) antiapoptosis; and 5) regeneration (i.e., mitotic for host-derived progenitor cells). Studies have shown that hMSCs have profound effects on the immune system and are well-tolerated and therapeutically active in immunocompetent rodent models of multiple sclerosis and stroke. Furthermore, intravenous administration of MSCs results in pulmonary localization. Asthma is a major debilitating pulmonary disease that impacts in excess of 150 million people in the world with uncontrolled asthma potentially leading to death. In addition, the socioeconomic impact of asthma-associated illnesses at the pediatric and adult level are in the millions of dollars in healthcare costs and lost days of work. hMSCs may provide a viable multiaction therapeutic for this inflammatory lung disease by secreting bioactive factors or directing cellular activity. Our studies show the effectiveness and specificity of the hMSCs on decreasing chronic airway inflammation associated with the murine ovalbumin model of asthma. In addition, the results from these studies verify the in vivo immunoeffectiveness of hMSCs in rodents and support the potential therapeutic use of hMSCs for the treatment of airway inflammation associated with chronic asthma. PMID:20817776

  5. Distinct morphophenotypic features of chronic B-cell leukaemias identified with CD1c and CD23 antibodies.

    Science.gov (United States)

    Orazi, A; Cattoretti, G; Polli, N; Delia, D; Rilke, F

    1991-07-01

    Morphological criteria usually applied to diagnose various subtypes of B-cell chronic lymphoid leukaemia are largely subjective. Immunophenotyping of 61 relevant cases using a selected panel of monoclonal antibodies (mAb), showed that CD1c and CD23 mAb were able to separate B-cell chronic lymphocytic leukaemia (B-CLL) from other chronic B-cell lymphoproliferative diseases. Lymphocytes of B-CLL were CD1c-, CD23+, whereas those of other types of chronic B-cell leukaemia were CD1c+/-, CD23-, and CD38/-. Non-B-CLL cases had a significantly higher amount of large peroxidase-negative (unstained) cells analyzed with an automated blood cell counter (Technicon H6000). This type of volumetric assessment allowed a separation between typical and "atypical" B-CLL, which otherwise were both CD1c-, and CD23+. These combinations of phenotypic markers corresponded to well-defined haematopathologic entities, conventionally diagnosed on peripheral blood (PB) and bone marrow smears, and on histologic sections of lymph nodes and spleen.

  6. Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche.

    Science.gov (United States)

    Ye, Haobin; Adane, Biniam; Khan, Nabilah; Sullivan, Timothy; Minhajuddin, Mohammad; Gasparetto, Maura; Stevens, Brett; Pei, Shanshan; Balys, Marlene; Ashton, John M; Klemm, Dwight J; Woolthuis, Carolien M; Stranahan, Alec W; Park, Christopher Y; Jordan, Craig T

    2016-07-01

    Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show that a subpopulation of leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36(+) LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and acute myeloid leukemia (AML) cells with similar biological properties. These findings suggest striking interplay between leukemic cells and AT to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation. PMID:27374788

  7. Metabolic Adaptations of Azospirillum brasilense to Oxygen Stress by Cell-to-Cell Clumping and Flocculation

    OpenAIRE

    Bible, Amber N.; Khalsa-Moyers, Gurusahai K.; Mukherjee, Tanmoy; Green, Calvin S.; Mishra, Priyanka; Purcell, Alicia; Aksenova, Anastasia; Gregory B Hurst; Alexandre, Gladys

    2015-01-01

    The ability of bacteria to monitor their metabolism and adjust their behavior accordingly is critical to maintain competitiveness in the environment. The motile microaerophilic bacterium Azospirillum brasilense navigates oxygen gradients by aerotaxis in order to locate low oxygen concentrations that can support metabolism. When cells are exposed to elevated levels of oxygen in their surroundings, motile A. brasilense cells implement an alternative response to aerotaxis and form transient clum...

  8. Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells.

    Science.gov (United States)

    Zhang, Bin; Li, Ling; Ho, Yinwei; Li, Min; Marcucci, Guido; Tong, Wei; Bhatia, Ravi

    2016-03-01

    Chronic myelogenous leukemia (CML) results from transformation of a long-term hematopoietic stem cell (LTHSC) by expression of the BCR-ABL fusion gene. However, BCR-ABL-expressing LTHSCs are heterogeneous in their capacity as leukemic stem cells (LSCs). Although discrepancies in proliferative, self-renewal, and differentiation properties of normal LTHSCs are being increasingly recognized, the mechanisms underlying heterogeneity of leukemic LTHSCs are poorly understood. Using a CML mouse model, we identified gene expression differences between leukemic and nonleukemic LTHSCs. Expression of the thrombopoietin (THPO) receptor MPL was elevated in leukemic LTHSC populations. Compared with LTHSCs with low MPL expression, LTHSCs with high MPL expression showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro and increased leukemogenic capacity in vivo. Although both G0 and S phase subpopulations were increased in LTHSCs with high MPL expression, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSCs reduced THPO-induced JAK/STAT signaling and leukemogenic potential. These same phenotypes were also present in LTHSCs from patients with CML, and patient LTHSCs with high MPL expression had reduced sensitivity to BCR-ABL tyrosine kinase inhibitor treatment but increased sensitivity to JAK inhibitors. Together, our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSCs and suggest that high MPL-expressing CML stem cells are potential targets for therapy. PMID:26878174

  9. Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

    Science.gov (United States)

    Kryeziu, Kushtrim; Pirker, Christine; Englinger, Bernhard; van Schoonhoven, Sushilla; Spitzwieser, Melanie; Mohr, Thomas; Körner, Wilfried; Weinmüllner, Regina; Tav, Koray; Grillari, Johannes; Cichna-Markl, Margit; Berger, Walter; Heffeter, Petra

    2016-01-01

    As an environmental poison, arsenic is responsible for many cancer deaths. Paradoxically, arsenic trioxide (ATO) presents also a powerful therapy used to treat refractory acute promyelocytic leukemia (APL) and is intensively investigated for treatment of other cancer types. Noteworthy, cancer therapy is frequently hampered by drug resistance, which is also often associated with enhancement of tumor aggressiveness. In this study, we analyzed ATO-selected cancer cells (A2780ATO) for the mechanisms underlying their enhanced tumorigenicity and aggressiveness. These cells were characterized by enhanced proliferation and spheroid growth as well as increased tumorigenicity of xenografts in SCID mice. Noteworthy, subsequent studies revealed that overexpression of Met receptor was the underlying oncogenic driver of these effects, as A2780ATO cells were characterized by collateral sensitivity against Met inhibitors. This finding was also confirmed by array comparative genomic hybridization (array CGH) and whole genome gene expression arrays, which revealed that Met overexpression by chronic ATO exposure was based on the transcriptional regulation via activation of AP-1. Finally, it was shown that treatment with the Met inhibitor crizotinib was also effective against A2780ATO cell xenografts in vivo, indicating that targeting of Met presents a promising strategy for the treatment of Met-overexpressing tumors after either arsenic exposure or failure to ATO treatment. PMID:27036042

  10. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells.

    Science.gov (United States)

    Daneshmanesh, A H; Hojjat-Farsangi, M; Khan, A S; Jeddi-Tehrani, M; Akhondi, M M; Bayat, A A; Ghods, R; Mahmoudi, A-R; Hadavi, R; Österborg, A; Shokri, F; Rabbani, H; Mellstedt, H

    2012-06-01

    ROR1 is a receptor tyrosine kinase (RTK) recently identified to be overexpressed at the gene and protein levels in chronic lymphocytic leukemia (CLL). Monoclonal antibodies (MAbs) against RTKs have been successfully applied for therapy of solid tumors. We generated five MAbs against the Ig (n = 1), cysteine-rich (CRD) (n = 2) and kringle (KNG) (n = 2) domains, respectively, of the extracellular part of ROR1. All CLL patients (n = 20) expressed ROR1 on the surface of the leukemic cells. A significantly higher frequency of ROR1 expression was found in patients with progressive versus non-progressive disease, and in those with unmutated versus mutated IgVH genes. All five MAbs alone induced apoptosis in the absence of complement or added effector cells (Annexin-V and MTT, as well as cleavage of poly-(ADP ribose)-polymerase, caspase-8 and caspase-9) of CLL cells but not of normal B cells. Most effective were MAbs against CRD and KNG, significantly superior to rituximab (P < 0.005). Cross-linking of anti-ROR1 MAbs using the F(ab')(2) fragments of anti-Fc antibodies significantly augmented apoptosis. Two of the MAbs induced complement-dependent cytotoxicity (CDC) similar to that of rituximab and one anti-ROR1 MAb (KNG) (IgG1) showed killing activity by antibody-dependent cellular cytotoxicity. The identified ROR1 epitopes may provide a basis for generating human ROR1 MAbs for therapy. PMID:22289919

  11. Outpatient red blood cell transfusion payments among patients on chronic dialysis

    Directory of Open Access Journals (Sweden)

    Gitlin Matthew

    2012-11-01

    Full Text Available Abstract Background Payments for red blood cell (RBC transfusions are separate from US Medicare bundled payments for dialysis-related services and medications. Our objective was to examine the economic burden for payers when chronic dialysis patients receive outpatient RBC transfusions. Methods Using Truven Health MarketScan® data (1/1/02-10/31/10 in this retrospective micro-costing economic analysis, we analyzed data from chronic dialysis patients who underwent at least 1 outpatient RBC transfusion who had at least 6 months of continuous enrollment prior to initial dialysis claim and at least 30 days post-transfusion follow-up. A conceptual model of transfusion-associated resource use based on current literature was employed to estimate outpatient RBC transfusion payments. Total payments per RBC transfusion episode included screening/monitoring (within 3 days, blood acquisition/administration (within 2 days, and associated complications (within 3 days for acute events; up to 45 days for chronic events. Results A total of 3283 patient transfusion episodes were included; 56.4% were men and 40.9% had Medicare supplemental insurance. Mean (standard deviation [SD] age was 60.9 (15.0 years, and mean Charlson comorbidity index was 4.3 (2.5. During a mean (SD follow-up of 495 (474 days, patients had a mean of 2.2 (3.8 outpatient RBC transfusion episodes. Mean/median (SD total payment per RBC transfusion episode was $854/$427 ($2,060 with 72.1% attributable to blood acquisition and administration payments. Complication payments ranged from mean (SD $213 ($168 for delayed hemolytic transfusion reaction to $19,466 ($15,424 for congestive heart failure. Conclusions Payments for outpatient RBC transfusion episodes were driven by blood acquisition and administration payments. While infrequent, transfusion complications increased payments substantially when they occurred.

  12. Role of activation-induced cell death in pathogenesis of patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Chun-Sheng Hou; Gui-Qiang Wang; Shu-Lan Lu; Bei Yue; Ming-Rong Li; Xiao-Yan Wang; Jian-Wu Yu

    2003-01-01

    AIM: To study and compare the difference of activationinduced cell death (AICD) in peripheral blood T-lymphocytes (PBL-Ts) from patients with chronic hepatitis B (CHB) and the normal people in vitro, and to explore the role of AICD in chronic hepatitis B virus (HBV) infection and the pathogenesis of CHB.METHODS: Twenty-five patients and fourteen healthy people were selected for isolation of PBL-Ts. During cultivation, antiCD3 mAb, PMA and ionomycin were used for AICD of PBL-Ts.AICD ratio of PBL-Ts was detected with TdT-mediated dUTP nick end labeling and assessed by flow cytometry.RESULTS: When induced with anti-CD3, PMA and ionomycin in vitro, AICD ratio of PBL-Ts from CHB patients was significantly higher than that from healthy control (17.24±1.21VS. 6.63±1.00, P<0.01) and that from CHB patients without induction (17.24±1.21 VS. 9.88±1.36, P<0.0L). There was a similar AICD ratio of PBL-Ts between induction group and without induction group, but no difference was found before and after induction in healthy control. The density of INF-γ in culture media of induction groups of CHB was lower than that of other groups (P<0.01). There was no difference between these groups in density of IL-10 (P>0.05).CONCLUSION: When induced during cultivation in vitro,PBL-Ts from CHB have AICD very commonly. This phenomenon has a potentially important relation with pathogenesis of CHB and chronicity of HBV infection.

  13. A Computational Approach to Model Vascular Adaptation During Chronic Hemodialysis: Shape Optimization as a Substitute for Growth Modeling

    Science.gov (United States)

    Mahmoudzadeh Akherat, S. M. Javid; Boghosian, Michael; Cassel, Kevin; Hammes, Mary

    2015-11-01

    End-stage-renal disease patients depend on successful long-term hemodialysis via vascular access, commonly facilitated via a Brachiocephalic Fistula (BCF). The primary cause of BCF failure is Cephalic Arch Stenosis (CAS). It is believed that low Wall Shear Stress (WSS) regions, which occur because of the high flow rates through the natural bend in the cephalic vein, create hemodynamic circumstances that trigger the onset and development of Intimal Hyperplasia (IH) and subsequent CAS. IH is hypothesized to be a natural effort to reshape the vessel, aiming to bring the WSS values back to a physiologically acceptable range. We seek to explore the correlation between regions of low WSS and subsequent IH and CAS in patient-specific geometries. By utilizing a shape optimization framework, a method is proposed to predict cardiovascular adaptation that could potentially be an alternative to vascular growth and remodeling. Based on an objective functional that seeks to alter the vessel shape in such a way as to readjust the WSS to be within the normal physiological range, CFD and shape optimization are then coupled to investigate whether the optimal shape evolution is correlated with actual patient-specific geometries thereafter. Supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01 DK90769).

  14. Hematopoietic and mesenchymal stem cells for the treatment of chronic respiratory diseases: role of plasticity and heterogeneity.

    Science.gov (United States)

    Conese, Massimo; Piro, Donatella; Carbone, Annalucia; Castellani, Stefano; Di Gioia, Sante

    2014-01-01

    Chronic lung diseases, such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) are incurable and represent a very high social burden. Stem cell-based treatment may represent a hope for the cure of these diseases. In this paper, we revise the overall knowledge about the plasticity and engraftment of exogenous marrow-derived stem cells into the lung, as well as their usefulness in lung repair and therapy of chronic lung diseases. The lung is easily accessible and the pathophysiology of these diseases is characterized by injury, inflammation, and eventually by remodeling of the airways. Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal (stem) cells (MSCs), encompass a wide array of cell subsets with different capacities of engraftment and injured tissue regenerating potential. Proof-of-principle that marrow cells administered locally may engraft and give rise to specialized epithelial cells has been given, but the efficiency of this conversion is too limited to give a therapeutic effect. Besides the identification of plasticity mechanisms, the characterization/isolation of the stem cell subpopulations represents a major challenge to improving the efficacy of transplantation protocols used in regenerative medicine for lung diseases. PMID:24563632

  15. Hematopoietic and Mesenchymal Stem Cells for the Treatment of Chronic Respiratory Diseases: Role of Plasticity and Heterogeneity

    Directory of Open Access Journals (Sweden)

    Massimo Conese

    2014-01-01

    Full Text Available Chronic lung diseases, such as cystic fibrosis (CF, asthma, and chronic obstructive pulmonary disease (COPD are incurable and represent a very high social burden. Stem cell-based treatment may represent a hope for the cure of these diseases. In this paper, we revise the overall knowledge about the plasticity and engraftment of exogenous marrow-derived stem cells into the lung, as well as their usefulness in lung repair and therapy of chronic lung diseases. The lung is easily accessible and the pathophysiology of these diseases is characterized by injury, inflammation, and eventually by remodeling of the airways. Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells (HSPCs and mesenchymal stromal (stem cells (MSCs, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue regenerating potential. Proof-of-principle that marrow cells administered locally may engraft and give rise to specialized epithelial cells has been given, but the efficiency of this conversion is too limited to give a therapeutic effect. Besides the identification of plasticity mechanisms, the characterization/isolation of the stem cell subpopulations represents a major challenge to improving the efficacy of transplantation protocols used in regenerative medicine for lung diseases.

  16. Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema

    Directory of Open Access Journals (Sweden)

    João Tadeu Ribeiro-Paes

    2011-01-01

    Full Text Available João Tadeu Ribeiro-Paes1, Aldemir Bilaqui2, Oswaldo T Greco2, Milton Artur Ruiz2, Monica Y Marcelino3, Talita Stessuk1, Carolina A de Faria3, Mario R Lago21Universidade Estadual Paulista (UNESP, Campus de Assis, Assis, SP, Brazil; 2Cardiovascular Diseases Institute (IMC, São José do Rio Preto, SP, Brazil; 3Inter-units Biotechnology Post Graduation Program, USP-IPT-I, Butantan, São Paulo, SP, BrazilAbstract: Within the chronic obstructive pulmonary disease (COPD spectrum, lung emphysema presents, as a primarily histopathologic feature, the destruction of pulmonary parenchyma and, accordingly, an increase in the airflow obstruction distal to the terminal bronchiole. Notwithstanding the significant advances in prevention and treatment of symptoms, no effective or curative therapy has been accomplished. In this context, cellular therapy with stem cells (SCs arises as a new therapeutic approach, with a wide application potential. The purpose of this study is to evaluate the safety of SCs infusion procedure in patients with advanced COPD (stage IV dyspnea. After selection, patients underwent clinical examination and received granulocyte colony-stimulating factor, immediately prior to the bone marrow harvest. The bone marrow mononuclear cells (BMMC were isolated and infused into a peripheral vein. The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease. Therefore, the proposed methodology in this study for BMMC cell therapy in sufferers of advanced COPD was demonstrated to be free of significant adverse effects. Although a larger sample and a greater follow-up period are needed, it is possible to infer that BMMC cell therapy introduces an unprecedented change in the course or in the natural history of emphysema, inhibiting or slowing the progression of disease. This clinical trial was registered with ClinicalTrials.gov (NCT

  17. [Outcomes of using autologous peripheral-blood stem cells in patients with chronic lower arterial insufficiency].

    Science.gov (United States)

    Maksimov, A V; Kiiasov, A P; Plotnikov, M V; Maianskaia, S D; Shamsutdinova, I I; Gazizov, I M; Mavlikeev, M O

    2011-01-01

    Presented herein are the outcomes of using autologous peripheral blood stem cells (SCs) in patients with stage II В lower limb chronic obliterating diseases (according to A.V. Pokrovsky's classification). Autologous SCs had previously been stimulated by means of the recombinant granulocytic colony stimulating factor (G-CSF) for five days. On day six, we performed mobilization of the peripheral blood stem cells on the MSC+ unit by means of leukopheresis followed by intramuscular administration of half of the obtained dose into the affected extremity. The mean number of the transplanted mononuclears amounted to 6.73 ± 2.2 x 10(9) cells, with the number of CD34+ cells averaging 2.94 ± 2.312 x 10(7). Assessing the therapeutic outcomes at 3 and 6 months of follow-up showed a statistically significant increase in the ankle-brachial pressure index (ABPI) [being at baseline 0.59 ± 0.04, at 3 months - 0.66 ± 0.04 (P=0.001), and after 6 months - 0.73 ± .08 (P=0.035)], accompanied and followed by improved measures of the treadmill test, with the pain-free walking distance at baseline equalling 102.2 ± 11.55 m, after 3 months - 129 ± 11.13 m (P<0.001), and after 6 months - 140 ± 13.11 m=0.021 vs baseline). The findings of the immunohistochemical study confirmed the development of neoangiogenesis in the skeletal muscle and a 25 percent increase in the capillary-network density following administration of autologous stem cells into the muscle. The method of transplanting peripheral-blood autologous stem cells for treatment of patients presenting with distal forms of chronic obliterating insufficiency of the lower limbs proved safe and efficient. The findings obtained during this study made it possible to recommend extending the indications for its application at the expense of patients with critical ischaemia. PMID:21983456

  18. Dysfunction of peripheral blood dendritic cells from patients with chronic hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    Fu-Sheng Wang1; Li-He Xing; Ming-Xu Liu; Cnuan-Lin Zhu; Hui-Gang Liu; Hui- Fen Wang; Zhou-Yun Lei

    2001-01-01

    AIM To identify the property of dendritic cella (DCs) of peripheral blood monocytes (PBMC) in patlents with chronic HBV infection. METHODS Twenty patients with persistent HBV infectlon were included in this study, 10 healthy subjects being used as a control group. The peripheral blood mononuclear cells (PBMC) of T cell-depleted populations were incubated and induced into mature dendritic cells in the RPMI-1640 medium in the presence of cytokines GMCSF, IL-4, FLt-3, TNF-α and 100 mL@ L-1 of fetal calf serum for a total of 10 - 12 days. The expressions of surface markers on DCs were evaluated using flow cytometric analysis. ELISA method was used to determine the cytokine levels of interleukin-12 (IL-12) and IL-10 in the supernatant produced by DCs. For detection of the stimulatory capacity of DCs to T cell proliferation,mytomycin C-treated DC were incubated with allogenic T cells. RESULTS A typical morphology of mature DCs from healthy subjects and HBV-infected patients was induced in in vitro incubation, but the proliferation ability and cellular number of DCs from HBV-infected patients significantly decreased compared with healthy individuals. In particular, the expression levels of HLADR, CD80 (B7-1) and CD86 (B7-2) on DC surface from patients were also lower than that from healthy individuals (0.46 vs 0.92 for HLA-DR, 0.44 vs 0.88 for CD80 and 0.44 vs 0. 84 for CD86, P< 0.05). The stimulatory capacity and production of IL-12 of DCs from patients in allogenic mixed lymphocyte reaction (AMLR) significantly decreased, but the production level of nitric oxide (NO) by DCa simultaneously increased compared with healthy subjects (86± 15 vs 170±22 μmoI@L 1, P<0.05). CONCLUSION The patients with chronic HBV infection have the defective function and immature phenotype of dendritic cells, which may be associated with the inability of efficient presentation of HBV antigens to host immune system for the clearance of HBV.

  19. Multiple metastatic basal cell carcinoma with concurrent metastatic pleomorphic sarcoma in chronic lymphedema area--case report.

    Science.gov (United States)

    Oliveira, Giuliano da Paz; Girão, Régio José Santiago; Soares, Cléverson Teixeira; Mello Junior, Edgard Jose Franco

    2012-01-01

    Chronic lymphedema presents as interstitial fluid retention due to a failure in the lymphatic system drainage. The affected region becomes more vulnerable immunologically and predisposed to the onset of neoplasms. Basal Cell Carcinoma is the most common sort of neoplasm, nevertheless it rarely metastisizes. Sarcomas are malignant mesenchymal neoplasms, locally aggressive, which can spread. Here is reported an infrequent case of multiple basal cell carcinoma, synchronous to a poorly differentiated pleomorphic sarcoma, both spreading to lymph nodes and arising from tissue compromised by chronic lymphedema. PMID:23197211

  20. Proposal of a new diagnostic algorithm for hepatocellular carcinoma based on the Japanese guidelines but adapted to the Western world for patients under surveillance for chronic liver disease.

    Science.gov (United States)

    Renzulli, Matteo; Golfieri, Rita

    2016-01-01

    To date, despite many scientific evidences, the guidelines of the principal hepatological societies, such as the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver, do not recognize the diagnostic superiority of magnetic resonance imaging (MRI) over computed tomography in the diagnosis of hepatocellular carcinoma (HCC) and, for the most part, do not contemplate the use of hepatospecific contrast media, such as gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB). The aim of this paper was to analyze the recent results of EOB-MRI in the study of chronic liver disease and the differences between the American Association for the Study of Liver Diseases and the Japan Society of Hepatology guidelines, of which the latter represents the most consolidated experience on EOB-MRI use for HCC diagnosis. Finally, a new diagnostic algorithm for HCC in patients under surveillance for chronic liver disease was formulated, which contemplates the use of EOB. This new diagnostic algorithm is based on the Japan Society of Hepatology algorithm but goes beyond it by adapting it to the Western world, taking into account both the difference between the two and the latest results concerning the diagnosis of HCC. This new diagnostic algorithm for HCC is proposed in order to provide useful diagnostic tools to all those Western countries where the use of EOB (more expensive than extracellular contrast media) is widespread but in which common strategies to manage the nodules that this new contrast agent allows identifying have not been available to date. PMID:26312574

  1. Imaging human retinal pigment epithelium cells using adaptive optics optical coherence tomography

    Science.gov (United States)

    Liu, Zhuolin; Kocaoglu, Omer P.; Turner, Timothy L.; Miller, Donald T.

    2016-03-01

    Retinal pigment epithelium (RPE) cells are vital to health of the outer retina, but are often compromised in ageing and major ocular diseases that lead to blindness. Early manifestation of RPE disruption occurs at the cellular level, and while biomarkers at this scale hold considerable promise, RPE cells have proven extremely challenging to image in the living human eye. We present a novel method based on optical coherence tomography (OCT) equipped with adaptive optics (AO) that overcomes the associated technical obstacles. The method takes advantage of the 3D resolution of AO-OCT, but more critically sub-cellular segmentation and registration that permit organelle motility to be used as a novel contrast mechanism. With this method, we successfully visualized RPE cells and characterized their 3D reflectance profile in every subject and retinal location (3° and 7° temporal to the fovea) imaged to date. We have quantified RPE packing geometry in terms of cell density, cone-to-RPE ratio, and number of nearest neighbors using Voronoi and power spectra analyses. RPE cell density (cells/mm2) showed no significant difference between 3° (4,892+/-691) and 7° (4,780+/-354). In contrast, cone-to- RPE ratio was significantly higher at 3° (3.88+/-0.52:1) than 7° (2.31+/- 0.23:1). Voronoi analysis also showed most RPE cells have six nearest neighbors, which was significantly larger than the next two most prevalent associations: five and seven. Averaged across the five subjects, prevalence of cells with six neighbors was 51.4+/-3.58% at 3°, and 54.58+/-3.01% at 7°. These results are consistent with histology and in vivo studies using other imaging modalities.

  2. Restored Circulating Invariant NKT Cells Are Associated with Viral Control in Patients with Chronic Hepatitis B

    Science.gov (United States)

    Jiang, Xiaotao; Zhang, Mingxia; Lai, Qintao; Huang, Xuan; Li, Yongyin; Sun, Jian; Abbott, William G.H.; Ma, Shiwu; Hou, Jinlin

    2011-01-01

    Invariant NKT (iNKT) cells are involved in the pathogenesis of various infectious diseases. However, their role in hepatitis B virus (HBV) infection is not fully understood, especially in human species. In this study, 35 chronic hepatitis B (CHB) patients, 25 inactive carriers (IC) and 36 healthy controls (HC) were enrolled and the proportions of circulating iNKT cells in fresh isolated peripheral blood mononuclear cells (PBMC) were detected by flow cytometry. A longitudinal analysis was also conducted in 19 CHB patients who received antiviral therapy with telbivudine. Thereafter, the immune functions of iNKT cells were evaluated by cytokine secretion and a two-chamber technique. The median frequency of circulating iNKT cells in CHB patients (0.13%) was lower than that in HC (0.24%, P = 0.01) and IC (0.19%, P = 0.02), and increased significantly during antiviral therapy with telbivudine (P = 0.0176). The expressions of CC chemokine receptor 5 (CCR5) and CCR6 were dramatically higher on iNKT cells (82.83%±9.87%, 67.67%±16.83% respectively) than on conventional T cells (30.5%±5.65%, 14.02%±5.92%, both P<0.001) in CHB patients. Furthermore, iNKT cells could migrate toward the CC chemokine ligand 5. Patients with a high ratio (≥1.0) of CD4−/CD4+ iNKT cells at baseline had a higher rate (58.33%) of HBeAg seroconversion than those with a low ratio (<1.0, 0%, P = 0.0174). In conclusion, there is a low frequency of peripheral iNKT cells in CHB patients, which increases to normal levels with viral control. The ratio of CD4−/CD4+ iNKT cells at baseline may be a useful predictor for HBeAg seroconversion in CHB patients on telbivudine therapy. PMID:22194934

  3. Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification.

    Science.gov (United States)

    Dono, M; Hashimoto, S; Fais, F; Trejo, V; Allen, S L; Lichtman, S M; Schulman, P; Vinciguerra, V P; Sellars, B; Gregersen, P K; Ferrarini, M; Chiorazzi, N

    1996-02-15

    Peripheral blood mononuclear cells from five patients with IgG+ B-type chronic lymphocytic leukemia (B-CLL) were analyzed for the presence of clone-specific Ig H chain variable region gene mRNA transcripts linked to C mu and/or C alpha. This was assessed by (1) comparing the lengths of portions of the VHDJH of the IgG+ CLL clones with those of the mu and alpha isotype-expressing B cells, (2) performing clone-specific endonuclease digestion studies, and (3) determining the DNA sequences of the mu and alpha isotype-expressing cDNA. Thus, when B-cell mRNA from these five patients were reverse transcribed with C gamma-specific primers and then amplified by polymerase chain reaction, dominant cDNA were found with lengths corresponding to those of the IgG+ CLL B cell. In addition, in four cases, cDNA of lengths identical to those of the CLL B cell were detected when mRNA was reverse transcribed and amplified using c mu- and/or C alpha-specific primers, strongly suggesting clonal relatedness. These CLL-related mu- and alpha-expressing cDNA were present in greater amounts that unrelated (non-CLL) mu- and alpha-expressing cDNA from normal B cells that used genes of the same VH family. When the sequences of these CLL-related C mu- and C alpha-expressing cDNA were compared with those of the IgG+ CLL clones, it was clear that they were derived from the same ancestral gene as the IgG-expressing CLL B cell, thus documenting their common origin. Finally, nucleotide point mutations were observed in the mu- and alpha-expressing cDNA of certain patients, indicating divergence with the CLL. These data suggest that IgM+ B cells, which are precursors of the leukemic B cells, exist in increased numbers in the blood of most patients with IgG+ B-CELL and that these cells may differentiate, accumulate V genes mutations, and undergo isotype switching in vivo. In addition, the data are consistent with a sequential-hit model for the evolution of CLL.

  4. Mouse retinal adaptive response to proton irradiation: Correlation with DNA repair and photoreceptor cell death

    Science.gov (United States)

    Tronov, V. A.; Vinogradova, Yu. V.; Poplinskaya, V. A.; Nekrasova, E. I.; Ostrovsky, M. A.

    2015-01-01

    Emerging body of data indicate protecting effect of low level of stress (preconditioning) on retina. Our previous study revealed non-linear dose-response relationship for cytotoxicity of both ionizing radiation and N-methyl-N-nitrosourea (MNU) on mouse retina. Moreover, non cytotoxic dose of MNU increased tolerance of retina to following challenge dose of MNU. This result displays protection of retina through mechanism of recovery. In present study we used the mouse model for MNU-induced retinal degeneration to evaluate adaptive response of retina to proton irradiation and implication in it of glial Muller cells. The data showed that the recovery of retina after genotoxic agents has been associated with increased efficacy of DNA damage repair and lowered death of retinal photoreceptor cells.

  5. Exercise-Induced Skeletal Muscle Adaptations Alter the Activity of Adipose Progenitor Cells.

    Directory of Open Access Journals (Sweden)

    Daniel Zeve

    Full Text Available Exercise decreases adiposity and improves metabolic health; however, the physiological and molecular underpinnings of these phenomena remain unknown. Here, we investigate the effect of endurance training on adipose progenitor lineage commitment. Using mice with genetically labeled adipose progenitors, we show that these cells react to exercise by decreasing their proliferation and differentiation potential. Analyses of mouse models that mimic the skeletal muscle adaptation to exercise indicate that muscle, in a non-autonomous manner, regulates adipose progenitor homeostasis, highlighting a role for muscle-derived secreted factors. These findings support a humoral link between skeletal muscle and adipose progenitors and indicate that manipulation of adipose stem cell function may help address obesity and diabetes.

  6. DAMPs and autophagy: cellular adaptation to injury and unscheduled cell death.

    Science.gov (United States)

    Zhang, Qiuhong; Kang, Rui; Zeh, Herbert J; Lotze, Michael T; Tang, Daolin

    2013-04-01

    Autophagy is a lysosome-mediated catabolic process involving the degradation of intracellular contents (e.g., proteins and organelles) as well as invading microbes (e.g., parasites, bacteria and viruses). Multiple forms of cellular stress can stimulate this pathway, including nutritional imbalances, oxygen deprivation, immunological response, genetic defects, chromosomal anomalies and cytotoxic stress. Damage-associated molecular pattern molecules (DAMPs) are released by stressed cells undergoing autophagy or injury, and act as endogenous danger signals to regulate the subsequent inflammatory and immune response. A complex relationship exists between DAMPs and autophagy in cellular adaption to injury and unscheduled cell death. Since both autophagy and DAMPs are important for pathogenesis of human disease, it is crucial to understand how they interplay to sustain homeostasis in stressful or dangerous environments. PMID:23388380

  7. Is There a Regulatory Role of Immunoglobulins on Tissue Forming Cells Relevant in Chronic Inflammatory Lung Diseases?

    Directory of Open Access Journals (Sweden)

    Michael Roth

    2011-01-01

    Full Text Available Epithelial cells, fibroblasts and smooth muscle cells together form and give structure to the airway wall. These three tissue forming cell types are structure giving elements and participate in the immune response to inhaled particles including allergens and dust. All three cell types actively contribute to the pathogenesis of chronic inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD. Tissue forming cells respond directly to allergens through activated immunoglobulins which then bind to their corresponding cell surface receptors. It was only recently reported that allergens and particles traffic through epithelial cells without modification and bind to the immunoglobulin receptors on the surface of sub-epithelial mesenchymal cells. In consequence, these cells secrete pro-inflammatory cytokines, thereby extending the local inflammation. Furthermore, activation of the immunoglobulin receptors can induce proliferation and tissue remodeling of the tissue forming cells. New studies using anti-IgE antibody therapy indicate that the inhibition of immunoglobulins reduces the response of tissue forming cells. The unmeasured questions are: (i why do tissue forming cells express immunoglobulin receptors and (ii do tissue forming cells process immunoglobulin receptor bound particles? The focus of this review is to provide an overview of the expression and function of various immunoglobulin receptors.

  8. Modeling of a 5-cell direct methanol fuel cell using adaptive-network-based fuzzy inference systems

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Rongrong; Li, Chunwen [Department of Automation, Tsinghua University, Beijing 100084 (China); Qi, Liang; Xie, Xiaofeng [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing 100084 (China); Ding, Qingqing [Department of Electrical Engineering, Tsinghua University, Beijing 100084 (China); Ma, ChenChi M. [National Tsing Hua University, Hsinchu 300 (China)

    2008-12-01

    The methanol concentrations, temperature and current were considered as inputs, the cell voltage was taken as output, and the performance of a direct methanol fuel cell (DMFC) was modeled by adaptive-network-based fuzzy inference systems (ANFIS). The artificial neural network (ANN) and polynomial-based models were selected to be compared with the ANFIS in respect of quality and accuracy. Based on the ANFIS model obtained, the characteristics of the DMFC were studied. The results show that temperature and methanol concentration greatly affect the performance of the DMFC. Within a restricted current range, the methanol concentration does not greatly affect the stack voltage. In order to obtain higher fuel utilization efficiency, the methanol concentrations and temperatures should be adjusted according to the load on the system. (author)

  9. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells

    OpenAIRE

    Coccia, Margherita; Harrison, Oliver J.; Schiering, Chris; Asquith, Mark J.; Becher, Burkhard; Powrie, Fiona; Maloy, Kevin J.

    2012-01-01

    Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus-triggered intestinal inflammation by augmen...

  10. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    Science.gov (United States)

    Chiappalupi, Sara; Luca, Giovanni; Mancuso, Francesca; Madaro, Luca; Fallarino, Francesca; Nicoletti, Carmine; Calvitti, Mario; Arato, Iva; Falabella, Giulia; Salvadori, Laura; Di Meo, Antonio; Bufalari, Antonello; Giovagnoli, Stefano; Calafiore, Riccardo; Donato, Rosario; Sorci, Guglielmo

    2015-01-01

    We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1]. PMID:26759818

  11. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    Directory of Open Access Journals (Sweden)

    Sara Chiappalupi

    2015-12-01

    Full Text Available We report data about the effects of intraperitoneal (i.p. injection of specific pathogen-free (SPF porcine Sertoli cells (SeC encapsulated into clinical grade alginate-based microcapsules (SeC-MC on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD, an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1].

  12. Sickle cell disease: a neglected chronic disease of increasing global health importance.

    Science.gov (United States)

    Chakravorty, Subarna; Williams, Thomas N

    2015-01-01

    Sickle cell disease (SCD) is a single gene disorder causing a debilitating systemic syndrome characterised by chronic anaemia, acute painful episodes, organ infarction and chronic organ damage and by a significant reduction in life expectancy. The origin of SCD lies in the malarial regions of the tropics where carriers are protected against death from malaria and hence enjoy an evolutionary advantage. More recently, population migration has meant that SCD now has a worldwide distribution and that a substantial number of children are born with the condition in higher-income areas, including large parts of Europe and North and South America. Newborn screening, systematic clinical follow-up and prevention of sepsis and organ damage have led to an increased life expectancy among people with SCD in many such countries; however, in resource-limited settings where the majority continue to be born, most affected children continue to die in early childhood, usually undiagnosed, due to the lack of effective programmes for its early detection and treatment. As new therapies emerge, potentially leading to disease amelioration or cure, it is of paramount importance that the significant burden of SCD in resource-poor countries is properly recognised. PMID:25239949

  13. Dendritic Cells in Innate and Adaptive Immune Responses against Influenza Virus

    Directory of Open Access Journals (Sweden)

    Artur Summerfield

    2009-11-01

    Full Text Available Dendritic cells (DC are major players in both innate and adaptive immune responses against influenza virus. These immune responses, as well as the important interface between the innate and adaptive systems, are orchestrated by specialized subsets of DC, including conventional steady-state DC, migratory DC and plasmacytoid DC. The characteristics and efficacy of the responses are dependent on the relative activity of these DC subsets, rendering DC crucial for the development of both naïve and memory immune responses. However, due to their critical role, DC also contribute to the immunopathological processes observed during acute influenza, such as that caused by the pathogenic H5N1 viruses. Therein, the role of different DC subsets in the induction of interferon type I, proinflammatory cytokine and chemokine responses is important for the outcome of interaction between the virus and host immune defences. The present review will present current knowledge on this area, relating to the importance of DC activity for the induction of efficacious humoral and cell-mediated immune responses. This will include the main viral elements associated with the triggering or inhibition of DC activation. Finally, the current knowledge on understanding how differences in various vaccines influence the manner of immune defence induction will be presented.

  14. Adaptive Second Order Sliding Mode Control of a Fuel Cell Hybrid System for Electric Vehicle Applications

    Directory of Open Access Journals (Sweden)

    Jianxing Liu

    2015-01-01

    Full Text Available We present an adaptive-gain second order sliding mode (SOSM control applied to a hybrid power system for electric vehicle applications. The main advantage of the adaptive SOSM is that it does not require the upper bound of the uncertainty. The proposed hybrid system consists of a polymer electrolyte membrane fuel cell (PEMFC with a unidirectional DC/DC converter and a Li-ion battery stack with a bidirectional DC/DC converter, where the PEMFC is employed as the primary energy source and the battery is employed as the second energy source. One of the main limitations of the FC is its slow dynamics mainly due to the air-feed system and fuel-delivery system. Fuel starvation phenomenon will occur during fast load demand. Therefore, the second energy source is required to assist the main source to improve system perofrmance. The proposed energy management system contains two cascade control structures, which are used to regulate the fuel cell and battery currents to track the given reference currents and stabilize the DC bus voltage while satisfying the physical limitations. The proposed control strategy is evaluated for two real driving cycles, that is, Urban Dynamometer Driving Schedule (UDDS and Highway Fuel Economy Driving Schedule (HWFET.

  15. Adaptation of cardiac structure by mechanical feedback in the environment of the cell: a model study.

    Science.gov (United States)

    Arts, T; Prinzen, F W; Snoeckx, L H; Rijcken, J M; Reneman, R S

    1994-01-01

    In the cardiac left ventricle during systole mechanical load of the myocardial fibers is distributed uniformly. A mechanism is proposed by which control of mechanical load is distributed over many individual control units acting in the environment of the cell. The mechanics of the equatorial region of the left ventricle was modeled by a thick-walled cylinder composed of 6-1500 shells of myocardial fiber material. In each shell a separate control unit was simulated. The direction of the cells was varied so that systolic fiber shortening approached a given optimum of 15%. End-diastolic sarcomere length was maintained at 2.1 microns. Regional early-systolic stretch and global contractility stimulated growth of cellular mass. If systolic shortening was more than normal the passive extracellular matrix stretched. The design of the load-controlling mechanism was derived from biological experiments showing that cellular processes are sensitive to mechanical deformation. After simulating a few hundred adaptation cycles, the macroscopic anatomical arrangement of helical pathways of the myocardial fibers formed automatically. If pump load of the ventricle was changed, wall thickness and cavity volume adapted physiologically. We propose that the cardiac anatomy may be defined and maintained by a multitude of control units for mechanical load, each acting in the cellular environment. Interestingly, feedback through fiber stress is not a compelling condition for such control. PMID:8038399

  16. Output-Adaptive Tetrahedral Cut-Cell Validation for Sonic Boom Prediction

    Science.gov (United States)

    Park, Michael A.; Darmofal, David L.

    2008-01-01

    A cut-cell approach to Computational Fluid Dynamics (CFD) that utilizes the median dual of a tetrahedral background grid is described. The discrete adjoint is also calculated, which permits adaptation based on improving the calculation of a specified output (off-body pressure signature) in supersonic inviscid flow. These predicted signatures are compared to wind tunnel measurements on and off the configuration centerline 10 body lengths below the model to validate the method for sonic boom prediction. Accurate mid-field sonic boom pressure signatures are calculated with the Euler equations without the use of hybrid grid or signature propagation methods. Highly-refined, shock-aligned anisotropic grids were produced by this method from coarse isotropic grids created without prior knowledge of shock locations. A heuristic reconstruction limiter provided stable flow and adjoint solution schemes while producing similar signatures to Barth-Jespersen and Venkatakrishnan limiters. The use of cut-cells with an output-based adaptive scheme completely automated this accurate prediction capability after a triangular mesh is generated for the cut surface. This automation drastically reduces the manual intervention required by existing methods.

  17. Cell invasion in the spheroid sprouting assay: a spatial organisation analysis adaptable to cell behaviour.

    Directory of Open Access Journals (Sweden)

    Silvia Blacher

    Full Text Available The endothelial cell spheroid assay provides a suitable in vitro model to study (lymph angiogenesis and test pro- and anti-(lymph angiogenic factors or drugs. Usually, the extent of cell invasion, observed through optical microscopy, is measured. The present study proposes the spatial distribution of migrated cells as a new descriptor of the (lymph angiogenic response. The utility of this novel method rests with its capacity to locally characterise spheroid structure, allowing not only the investigation of single and collective cell invasion but also the evolution of the spheroid core itself. Moreover, the proposed method can be applied to 2D-projected spheroid images obtained by optical microscopy, as well as to 3D images acquired by confocal microscopy. To validate the proposed methodology, endothelial cell invasion was evaluated under different experimental conditions. The results were compared with widely used global parameters. The comparison shows that our method prevents local spheroid modifications from being overlooked and leading to the possible misinterpretation of results.

  18. Revealing stiffening and brittling of chronic myelogenous leukemia hematopoietic primary cells through their temporal response to shear stress

    Science.gov (United States)

    Laperrousaz, B.; Berguiga, L.; Nicolini, F. E.; Martinez-Torres, C.; Arneodo, A.; Maguer Satta, V.; Argoul, F.

    2016-06-01

    Cancer cell transformation is often accompanied by a modification of their viscoelastic properties. When capturing the stress-to-strain response of primary chronic myelogenous leukemia (CML) cells, from two data sets of CD34+ hematopoietic cells isolated from healthy and leukemic bone marrows, we show that the mean shear relaxation modulus increases upon cancer transformation. This stiffening of the cells comes along with local rupture events, detected as reinforced sharp local maxima of this modulus, suggesting that these cancer cells respond to a local mechanical stress by a cascade of local brittle failure events.

  19. Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

    Science.gov (United States)

    Morvaridi, Susan; Dhall, Deepti; Greene, Mark I; Pandol, Stephen J; Wang, Qiang

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis. PMID:26567630

  20. Advantages of a single-cycle production assay to study cell culture-adaptive mutations of hepatitis C virus

    DEFF Research Database (Denmark)

    Russell, Rodney S; Meunier, Jean-Christophe; Takikawa, Shingo;

    2008-01-01

    mutations that were selected during serial passage in Huh-7.5 cells were studied. Recombinant genomes containing all five mutations produced 3-4 logs more infectious virions than did wild type. Neither a coding mutation in NS5A nor a silent mutation in E2 was adaptive, whereas coding mutations in E2, p7......, and NS2 all increased virus production. A single-cycle replication assay in CD81-deficient cells was developed to study more precisely the effect of the adaptive mutations. The E2 mutation had minimal effect on the amount of infectious virus released but probably enhanced entry into cells. In contrast...

  1. Characterization of the specific CD4+ T cell response against the F protein during chronic hepatitis C virus infection.

    Directory of Open Access Journals (Sweden)

    De-Yong Gao

    Full Text Available BACKGROUND: The hepatitis C virus (HCV Alternate Reading Frame Protein (ARFP or F protein presents a double-frame shift product of the HCV core gene. We and others have previously reported that the specific antibodies against the F protein could be raised in the sera of HCV chronically infected patients. However, the specific CD4(+ T cell responses against the F protein during HCV infection and the pathological implications remained unclear. In the current study, we screened the MHC class II-presenting epitopes of the F protein through HLA-transgenic mouse models and eventually validated the specific CD4(+ T cell responses in HCV chronically infected patients. METHODOLOGY: DNA vaccination in HLA-DR1 and-DP4 transgenic mouse models, proliferation assay to test the F protein specific T cell response, genotyping of Chronic HCV patients and testing the F-peptide stimulated T cell response in the peripheral blood mononuclear cell (PBMC by in vitro expansion and interferon (IFN- γ intracellular staining. PRINCIPAL FINDINGS: At least three peptides within HCV F protein were identified as HLA-DR or HLA-DP4 presenting epitopes by the proliferation assays in mouse models. Further study with human PBMCs evidenced the specific CD4(+ T cell responses against HCV F protein as well in patients chronically infected with HCV. CONCLUSION: The current study provided the evidence for the first time that HCV F protein could elicit specific CD4(+ T cell response, which may provide an insight into the immunopathogenesis during HCV chronic infection.

  2. Breaking the Blood-Brain Barrier With Mannitol to Aid Stem Cell Therapeutics in the Chronic Stroke Brain.

    Science.gov (United States)

    Tajiri, Naoki; Lee, Jea Young; Acosta, Sandra; Sanberg, Paul R; Borlongan, Cesar V

    2016-01-01

    Blood-brain barrier (BBB) permeabilizers, such as mannitol, can facilitate peripherally delivered stem cells to exert therapeutic benefits on the stroke brain. Although this BBB permeation-aided stem cell therapy has been demonstrated in the acute stage of stroke, such BBB permeation in the chronic stage of the disease remains to be examined. Adult Sprague-Dawley rats initially received sham surgery or experimental stroke via the 1-h middle cerebral artery occlusion (MCAo) model. At 1 month after the MCAo surgery, stroke animals were randomly assigned to receive human umbilical cord stem cells only (2 million viable cells), mannitol only (1.1 mol/L mannitol at 4°C), combined human umbilical cord stem cells (200,000 viable cells) and mannitol (1.1 mol/L mannitol at 4°C), and vehicle (phosphate-buffered saline) only. Stroke animals that received human umbilical cord blood cells alone or combined human umbilical cord stem cells and mannitol exhibited significantly improved motor performance and significantly better brain cell survival in the peri-infarct area compared to stroke animals that received vehicle or mannitol alone, with mannitol treatment reducing the stem cell dose necessary to afford functional outcomes. Enhanced neurogenesis in the subventricular zone accompanied the combined treatment of human umbilical cord stem cells and mannitol. We showed that BBB permeation facilitates the therapeutic effects of a low dose of peripherally transplanted stem cells to effectively cause functional improvement and increase neurogenesis in chronic stroke.

  3. Method for contact resistivity measurements on photovoltaic cells and cell adapted for such measurement

    Science.gov (United States)

    Burger, Dale R. (Inventor)

    1986-01-01

    A method is disclosed for scribing at least three grid contacts of a photovoltaic cell to electrically isolate them from the grid contact pattern used to collect solar current generated by the cell, and using the scribed segments for determining parameters of the cell by a combination of contact end resistance (CER) measurements using a minimum of three equally or unequally spaced lines, and transmission line modal (TLM) measurements using a minimum of four unequally spaced lines. TLM measurements may be used to determine sheet resistance under the contact, R.sub.sk, while CER measurements are used to determine contact resistivity, .rho..sub.c, from a nomograph of contact resistivity as a function of contact end resistance and sheet resistivity under the contact. In some cases, such as the case of silicon photovoltaic cells, sheet resistivity under the contact may be assumed to be equal to the known sheet resistance, R.sub.s, of the semiconductor material, thereby obviating the need for TLM measurements to determine R.sub.sk.

  4. Managing inter-cell interference with advanced receivers and rank adaptation in 5G small cells

    DEFF Research Database (Denmark)

    Tavares, Fernando Menezes Leitão; Berardinelli, Gilberto; Catania, Davide;

    2015-01-01

    The use of receivers with interference suppression capabilities is expected to be a significant performance booster in 5th Generation (5G) ultra-dense small cell networks. In this respect, they could represent an alternative to traditional frequency reuse techniques, facilitating the inter...

  5. Fibre-specific responses to endurance and low volume high intensity interval training: striking similarities in acute and chronic adaptation.

    Directory of Open Access Journals (Sweden)

    Trisha D Scribbans

    ; correspondingly, training-induced adaptations resulting for these protocols, and other HIT and END protocols are strikingly similar.

  6. Induction of IgA and sustained deficiency of cell proliferative response in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Yalena Amador-Ca(n)izares; Liz Alvarez-Lajonchere; Ivis Guerra; Ingrid Rodnguez-Alonso; Gillian Martínez-Donato; Julián Triana; Eddy E González-Horta; Angel Pérez; Santiago Due(n)as-Carrera

    2008-01-01

    AIM: In the present study, antibody and peripheral blood mononuclear cells (PBMC) proliferative responses against hepatitis C virus (HCV) antigens were evaluated in HCV chronically infected patients. METHODS: Paired serum and PBMC samples were taken six months apart from 34 individuals, either treated or not, and tested by enzyme-linked immunosorbent assay (ELISA) and carboxyfluorescein succinimidyl ester staining.RESULTS: Over 70% of the patients showed specific IgG and IgM against capsid, E1 and NS3, while HVR-1 was recognized by half of the patients. An increase in the levels of the anti-capsid IgM (P = 0.027) and IgG (P=0.0006) was observed in six-month samples, compared to baseline. Similarly, a significantly higher percent of patients had detectable IgA reactivity to capsid (P=0.017) and NS3 (P=0.005) after six months, compared to baseline. Particularly, IgA against structural antigens positively correlated with hepatic damage (P=0.036). IgG subclasses evaluation against capsid and NS3 revealed a positive recognition mediated by IgG1 in more than 80% of the individuals. On the contrary, less than 30% of the patients showed a positive proliferative response either of CD4+ or CD8+ T cells, being the capsid poorly recognized. CONCLUSION: These results confirm that while the cellular immune response is narrow and weak, a broad and vigorous humoral response occurs in HCV chronic infection. The observed correlation between IgA and hepatic damage may have diagnostic significance, although it warrants further confirmation.

  7. Accessible bioprinting: adaptation of a low-cost 3D-printer for precise cell placement and stem cell differentiation.

    Science.gov (United States)

    Reid, John A; Mollica, Peter A; Johnson, Garett D; Ogle, Roy C; Bruno, Robert D; Sachs, Patrick C

    2016-06-01

    The precision and repeatability offered by computer-aided design and computer-numerically controlled techniques in biofabrication processes is quickly becoming an industry standard. However, many hurdles still exist before these techniques can be used in research laboratories for cellular and molecular biology applications. Extrusion-based bioprinting systems have been characterized by high development costs, injector clogging, difficulty achieving small cell number deposits, decreased cell viability, and altered cell function post-printing. To circumvent the high-price barrier to entry of conventional bioprinters, we designed and 3D printed components for the adaptation of an inexpensive 'off-the-shelf' commercially available 3D printer. We also demonstrate via goal based computer simulations that the needle geometries of conventional commercially standardized, 'luer-lock' syringe-needle systems cause many of the issues plaguing conventional bioprinters. To address these performance limitations we optimized flow within several microneedle geometries, which revealed a short tapered injector design with minimal cylindrical needle length was ideal to minimize cell strain and accretion. We then experimentally quantified these geometries using pulled glass microcapillary pipettes and our modified, low-cost 3D printer. This systems performance validated our models exhibiting: reduced clogging, single cell print resolution, and maintenance of cell viability without the use of a sacrificial vehicle. Using this system we show the successful printing of human induced pluripotent stem cells (hiPSCs) into Geltrex and note their retention of a pluripotent state 7 d post printing. We also show embryoid body differentiation of hiPSC by injection into differentiation conducive environments, wherein we observed continuous growth, emergence of various evaginations, and post-printing gene expression indicative of the presence of all three germ layers. These data demonstrate an

  8. [MORPHOFUNCTIONAL STATE OF BLOOD CELLS AFTER CHRONIC EXPOSURE OF THE PROTEIN KINASES INHIBITOR MALEIMIDE DERIVATIVE].

    Science.gov (United States)

    Byelinska, I V; Lynchak, O V; Tsyvinska, S M; Rybalchenko, V K

    2015-01-01

    The effect of the protein kinases inhibitor maleimide derivative (MI-1, 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione), inhibitor of VEGF-R1,2,3, FGF-R1, EGF-R(h), PDK1, Src(h), Syk(h), YES, ZAP70 et al. with antineoplastic activity, on blood cells parameters of rats after chronic exposure has been studied. Administration of MI-1 at doses 0.027 and 2.7 mg/kg (suppress colon carcinogenesis) for 20 and 26 weeks does not affect the morphofunctional state of red blood cells in healthy rats. This is confirmed by the lack of differences in the concentration of hemoglobin in blood, red blood cells count, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, hematocrit and mean corpuscular volume, and the number of reticulocytes in blood after 20 and 26 weeks of exposure compared with the control group. MI-1 at indicated doses does not influence total leukocytes count and content (eosinophilic and neutrophilic granulocytes, lymphocytes, monocytes) and does not inhibit thrombocytopoiesis (platelet count remains unchanged). No negative effect of MI-1 on hematopoiesis is not limited (by the hemopoietic system) use of this compound as a potential antitumor drug PMID:26552308

  9. Minimal residual disease surveillance in chronic lymphocytic leukemia by fluorescence-activated cell sorting.

    Science.gov (United States)

    Ringelstein-Harlev, Shimrit; Fineman, Riva

    2014-10-01

    Achievement of complete response (CR) to therapy in chronic lymphocytic leukemia (CLL) has become a feasible goal, directly correlating with prolonged survival. It has been established that the classic definition of CR actually encompasses a variety of disease loads, and more sensitive multiparameter flow cytometry and polymerase chain reaction methods can detect the disease burden with a much higher sensitivity. Detection of malignant cells with a sensitivity of 1 tumor cell in 10,000 cells (10(-4)), using the abovementioned sophisticated techniques, is the current cutoff for minimal residual disease (MRD). Tumor burdens lower than 10(-4) are defined as MRD-negative. Several studies in CLL have determined the achievement of MRD negativity as an independent favorable prognostic factor, leading to prolonged disease-free and overall survival, regardless of the treatment protocol or the presence of other pre-existing prognostic indicators. Minimal residual disease evaluation using flow cytometry is a sensitive and applicable approach which is expected to become an integral part of future prospective trials in CLL designed to assess the role of MRD surveillance in treatment tailoring.

  10. Minimal Residual Disease Surveillance in Chronic Lymphocytic Leukemia by Fluorescence-Activated Cell Sorting

    Directory of Open Access Journals (Sweden)

    Shimrit Ringelstein-Harlev

    2014-10-01

    Full Text Available Achievement of complete response (CR to therapy in chronic lymphocytic leukemia (CLL has become a feasible goal, directly correlating with prolonged survival. It has been established that the classic definition of CR actually encompasses a variety of disease loads, and more sensitive multiparameter flow cytometry and polymerase chain reaction methods can detect the disease burden with a much higher sensitivity. Detection of malignant cells with a sensitivity of 1 tumor cell in 10,000 cells (10–4, using the abovementioned sophisticated techniques, is the current cutoff for minimal residual disease (MRD. Tumor burdens lower than 10–4 are defined as MRD-negative. Several studies in CLL have determined the achievement of MRD negativity as an independent favorable prognostic factor, leading to prolonged disease-free and overall survival, regardless of the treatment protocol or the presence of other pre-existing prognostic indicators. Minimal residual disease evaluation using flow cytometry is a sensitive and applicable approach which is expected to become an integral part of future prospective trials in CLL designed to assess the role of MRD surveillance in treatment tailoring.

  11. Harnessing memory adaptive regulatory T cells to control autoimmunity in type 1 diabetes

    Institute of Scientific and Technical Information of China (English)

    Cheng-Rui Li; Bas J.G. Baaten; Linda M. Bradley

    2012-01-01

    Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β-cells in the pancreatic islets.There is an immediate need to restore both β-cell function and immune tolerance to control disease progression and ultimately cure T1D.Currently,there is no effective treatment strategy to restore glucose regulation in patients with T1D.FoxP3-expressing CD4+ regulatory T cells (Tregs) are potential candidates to control autoimmunity because they play a central role in maintaining self-tolerance.However,deficiencies in either naturally occurring Tregs (nTregs) themselves and/or their ability to control pathogenic effector T cells have been associated with T1D.Here,we hypothesize that nTregs can be replaced by FoxP3+ adaptive Tregs (aTregs),which are uniquely equipped to combat autoreactivity in T1D.Unlike nTregs,aTregs are stable and provide long-lived protection.In this review,we summarize the current understanding of aTregs and their potential for use as an immunological intervention to treat T1D.

  12. Load-adaptive frequency reuse scheme for inter-cell interference coordination in relay networks

    Institute of Scientific and Technical Information of China (English)

    CHEN Mu-qiong; JI Hong; LI Xi

    2010-01-01

    Cellular relay networks adopting orthogonal frequency division multiple(OFDM)technology has been widely accepted for next generation wireless communication due to its advantage in enlarging coverage scale as well as improving data rate.In order to improve the performance of user equipments(UEs)near the cell edge,especially to avoid the interference from inter-cell and intra cell,an enhanced soft frequency reuse scheme is adopted in this paper to assure inter-cell interference coordination(ICIC).Compared with traditional frequency allocation work,the proposed scheme is interference-aware and load-adaptive,which dynamically assigns available frequency among UES under certain schedule method in variable traffic load condition and mitigates interference using information provided by interference indicator.It can improve signal-to-interference plus noise ratio(SINR)of the UE in each sub channel thus enable the system achieve better throughput and blocking probability performance.Simulation results prove that the proposed scheme may achieve desirable performance on throughput,blocking probability and spectral utilization in the sector under different traffic load compared with other schemes.

  13. Adipose- and muscle-derived Wnts trigger pancreatic β-cell adaptation to systemic insulin resistance.

    Science.gov (United States)

    Kozinski, Kamil; Jazurek, Magdalena; Dobrzyn, Pawel; Janikiewicz, Justyna; Kolczynska, Katarzyna; Gajda, Anna; Dobrzyn, Agnieszka

    2016-01-01

    Wnt signaling molecules are associated with obesity, hyperlipidemia, and type 2 diabetes (T2D). Here, we show that two Wnt proteins, WNT3a and WNT4, are specifically secreted by skeletal muscle and adipose tissue during the development of insulin resistance and play an important role in cross-talk between insulin-resistant tissues and pancreatic beta cells. The activation of Frizzled receptor and Wnt signaling in pancreatic islets via circulating WNT3a in blood resulted in higher insulin secretion and an increase in beta cell proliferation, thus leading to islet adaptation in a pre-diabetic state. Interestingly, in fully developed T2D, the expression profiles of Wnt3a and Wnt4 in adipose tissue and muscle cells and blood plasma levels of these proteins were opposite to the pre-diabetic state, thus favoring the downregulation of Wnt signaling in beta cells and resulting in dysfunctional pancreatic islets. These results demonstrate that alterations in the secretion profile of a canonical Wnt activator (WNT3a) and inhibitor (WNT4) from insulin-resistant tissues during the development of T2D are responsible for triggering progression from a pre-diabetic to a diabetic state. We also show here that WNT3a and WNT4 are potent myokines, and their expression and secretion are regulated in response to nutritional and metabolic changes. PMID:27527335

  14. Chronic low-dose UVA irradiation induces local suppression of contact hypersensitivity, Langerhans cell depletion and suppressor cell activation in C3H/HeJ mice

    International Nuclear Information System (INIS)

    It has previously been demonstrated that chronic low-dose solar-simulated UV radiation could induce both local and systemic immunosuppression as well as tolerance to a topically applied hapten. In this study, we have used a chronic low-dose UV-irradiation protocol to investigate the effects of UVA on the skin immune system of C3H/HeJ mice. Irradiation with UVA+B significantly suppressed the local and systemic primary contact hypersensitivity (CHS) response to the hapten 2,4,6-trinitrochlorobenzene. Furthermore, UVA+B reduced Langerhans cell (LC) and dendritic epidermal T cell (DETC) densities in chronically UV-irradiated mice. Ultraviolet A irradiation induced local, but not systemic, immunosuppression and reduced LC (32%) but not DETC from the epidermis compared to the shaved control animals. Treatment of mice with both UVA+B and UVA radiation also induced an impaired secondary CHS response, and this tolerance was transferable with spleen cells. (Author)

  15. Recognition of antigen-specific B-cell receptors from chronic lymphocytic leukemia patients by synthetic antigen surrogates.

    Science.gov (United States)

    Sarkar, Mohosin; Liu, Yun; Morimoto, Jumpei; Peng, Haiyong; Aquino, Claudio; Rader, Christoph; Chiorazzi, Nicholas; Kodadek, Thomas

    2014-12-18

    In patients with chronic lymphocytic leukemia (CLL), a single neoplastic antigen-specific B cell accumulates and overgrows other B cells, leading to immune deficiency. CLL is often treated with drugs that ablate all B cells, leading to further weakening of humoral immunity, and a more focused therapeutic strategy capable of targeting only the pathogenic B cells would represent a significant advance. One approach to this would be to develop synthetic surrogates of the CLL antigens allowing differentiation of the CLL cells and healthy B cells in a patient. Here, we describe nonpeptidic molecules capable of targeting antigen-specific B cell receptors with good affinity and selectivity using a combinatorial library screen. We demonstrate that our hit compounds act as synthetic antigen surrogates and recognize CLL cells and not healthy B cells. Additionally, we argue that the technology we developed can be used to identify other classes of antigen surrogates.

  16. The association of mast cells and serotonin in children with chronic abdominal pain of unknown etiology

    Directory of Open Access Journals (Sweden)

    Shankar Ravi

    2010-10-01

    Full Text Available Abstract Background Abdominal pain of unknown origin affects up to 20% of school-aged children. Evaluation of children is symptom-based without clear guidelines to investigate molecular mechanisms of abdominal pain. Aberrant molecular mechanisms may increase intestinal permeability leading to interactions between the immune and nervous systems, subclinical inflammation, and visceral pain. This study evaluated the association between interleukin-6 (IL-6, mast cell infiltrates, and serotonin (5-HT levels in gastrointestinal (GI biopsies, with perceived abdominal pain in a pediatric cohort. Methods Clinical data and biopsy samples from pediatric patients (n = 48 with chronic abdominal pain, with and without inflammation were included. Formalin-fixed paraffin-embedded GI biopsies were sectioned and immunohistochemistry performed for IL-6 and 5-HT; mast cells were identified with toluidine blue stain. Histological findings were compared to self-reported abdominal pain between groups. Results There was significantly greater IL-6 immunoreactivity in biopsies with confirmed histologic inflammation (p = 0.004. There was a greater number of mast cells per HPF in non-inflammatory biopsies (3.5 ± 2.9 compared to the inflammatory biopsies (2.6 ± 1.8 p = 0.049. The non-inflammatory biopsy group was significantly less likely to respond to standard treatment as evidenced by higher pain reports (p = .018. Mast cells (p = .022 and 5-HT (p = .02 were significantly related to abdominal pain scores. Conclusions A potential association between self-reported abdominal pain, number of mast cells, and 5-HT levels, which may contribute to perceived GI pain in pediatric patients may exist.

  17. Gene expression profile of human lung epithelial cells chronically exposed to single-walled carbon nanotubes

    Science.gov (United States)

    Chen, Dongquan; Stueckle, Todd A.; Luanpitpong, Sudjit; Rojanasakul, Yon; Lu, Yongju; Wang, Liying

    2015-01-01

    A rapid increase in utility of engineered nanomaterials, including carbon nanotubes (CNTs), has raised a concern over their safety. Based on recent evidence from animal studies, pulmonary exposure of CNTs may lead to nanoparticle accumulation in the deep lung without effective clearance which could interact with local lung cells for a long period of time. Physicochemical similarities of CNTs to asbestos fibers may contribute to their asbestos-like carcinogenic potential after long-term exposure, which has not been well addressed. More studies are needed to identify and predict the carcinogenic potential and mechanisms for promoting their safe use. Our previous study reported a long-term in vitro exposure model for CNT carcinogenicity and showed that 6-month sub-chronic exposure of single-walled carbon nanotubes (SWCNT) causes malignant transformation of human lung epithelial cells. In addition, the transformed cells induced tumor formation in mice and exhibited an apoptosis resistant phenotype, a key characteristic of cancer cells. Although the potential role of p53 in the transformation process was identified, the underlying mechanisms of oncogenesis remain largely undefined. Here, we further examined the gene expression profile by using genome microarrays to profile molecular mechanisms of SWCNT oncogenesis. Based on differentially expressed genes, possible mechanisms of SWCNT-associated apoptosis resistance and oncogenesis were identified, which included activation of pAkt/p53/Bcl-2 signaling axis, increased gene expression of Ras family for cell cycle control, Dsh-mediated Notch 1, and downregulation of apoptotic genes BAX and Noxa. Activated immune responses were among the major changes of biological function. Our findings shed light on potential molecular mechanisms and signaling pathways involved in SWCNT oncogenic potential.

  18. Adaptive responses to osmotic stress in kidney-derived cell lines from Scatophagus argus, a euryhaline fish.

    Science.gov (United States)

    Gui, Lang; Zhang, Peipei; Liang, Xuemei; Su, Maoliang; Wu, Di; Zhang, Junbin

    2016-06-01

    The euryhaline fish, the spotted scat (Scatophagus argus), is exceptional for its ability to tolerate rapid fluctuations in salinity. To better understand fish osmoregulation and enable more precise analyses of specific features of adaptive responses to the osmotic stress in fish, a S. argus kidney-derived cell line (SK) was developed and subcultured for more than 70 passages. The cells were mostly fibroblast-like, with a normal diploid karyotype (2n=48). A low-osmolarity-adapted SK cell line (SK-la) was induced by growth in a hypotonic solution (150 mOsm). Effects of different osmotic stresses (150, 300 and 450 mOsm) on cell growth, cell morphology, cell volume changes and cell damage in SK, SK-la and CIK (a kidney-derived cell line from freshwater grass carp) cells were studied. These were compared by use of microscopic observation, flow cytometry and a Na-K-ATPase (NKA) assay. SK cells became smaller and grew rapidly in response to hypotonic stress (150 mOsm), and exhibited no visible morphological changes in response to hypertonic stress (450 mOsm). SK-la grew well by moderate hypertonicity (300 mOsm) but depressed in severe hypertonicity (450 mOsm), the number of unhealthy SK-la cells rose as osmolarity increased. In contrast, CIK cells became unhealthy with anisotonic challenge. The NKA activities of SK and CIK cells were assayed after exposure to anisotonic conditions, and rapid decreases were detected immediately except SK cells which were not affected in hypotonicity. Unlike in SK and CIK, an increase following a down-regulation of NKA activity was observed in SK-la cells upon moderate hypertonic stress. These results suggested that SK and SK-la cells had stronger osmoregulatory capacity than CIK cells, and provided new insights on the osmosensing and osmotic adaption in euryhaline fish kidney. PMID:26911257

  19. Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties.

    Directory of Open Access Journals (Sweden)

    Lenora Ann Pluchino

    Full Text Available Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK and benzo[a]pyrene (B[a]P, and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.

  20. Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells

    DEFF Research Database (Denmark)

    Klitgaard, Josephine L; Koefoed, Klaus; Geisler, Christian;

    2013-01-01

    The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage ...

  1. Inhibition of protease-resistant prion protein formation in a transformed deer cell line infected with chronic wasting disease

    NARCIS (Netherlands)

    Raymond, G.J.; Olsen, E.A.; Lee, K.S.; Raymond, L.D.; Bryant, P.K.; Baron, G.S.; Caughey, W.S.; Kocisko, D.A.; McHolland, L.E.; Favara, C.; Langeveld, J.P.M.; Zijderveld, van F.G.; Mayer, R.T.; Miller, M.W.; Williams, E.S.; Caughey, B.

    2006-01-01

    Chronic wasting disease (CWD) is an emerging transmissible spongiform encephalopathy (prion disease) of North American cervids, i.e., mule deer, white-tailed deer, and elk (wapiti). To facilitate in vitro studies of CWD, we have developed a transformed deer cell line that is persistently infected wi

  2. Acute and chronic wound fluids inversely influence adipose-derived stem cell function: molecular insights into impaired wound healing.

    Science.gov (United States)

    Koenen, Paola; Spanholtz, Timo A; Maegele, Marc; Stürmer, Ewa; Brockamp, Thomas; Neugebauer, Edmund; Thamm, Oliver C

    2015-02-01

    Wound healing is a complex biological process that requires a well-orchestrated interaction of mediators as well as resident and infiltrating cells. In this context, mesenchymal stem cells play a crucial role as they are attracted to the wound site and influence tissue regeneration by various mechanisms. In chronic wounds, these processes are disturbed. In a comparative approach, adipose-derived stem cells (ASC) were treated with acute and chronic wound fluids (AWF and CWF, respectively). Proliferation and migration were investigated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and transwell migration assay. Gene expression changes were analysed using quantitative real time-polymerase chain reaction. AWF had a significantly stronger chemotactic impact on ASC than CWF (77·5% versus 59·8% migrated cells). While proliferation was stimulated by AWF up to 136·3%, CWF had a negative effect on proliferation over time (80·3%). Expression of b-FGF, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was strongly induced by CWF compared with a mild induction by AWF. These results give an insight into impaired ASC function in chronic wounds. The detected effect of CWF on proliferation and migration of ASC might be one reason for an insufficient healing process in chronic wounds.

  3. Effect of up-regulated expression of tumor suppressor gene p14ARF on apoptosis of chronic myeloid leukemia cells

    Institute of Scientific and Technical Information of China (English)

    白元松

    2013-01-01

    Objective To investigate the effect of up-regulated expression of tumor suppressor gene p14ARFon apoptosis of chronic myeloid leukemia (CML) cells and its interaction with imatinib.Methods Tumor suppressor gene p14ARFwas transduced into K562 (K562-p14ARF) and 4blast crisis primary CML cells (CML-BC 1-4) using vesicular stomatitis virus glycoprotein (VSV-G)

  4. Th17 Responses in Chronic Allergic Airway Inflammation Abrogate Regulatory T cell-mediated Tolerance and Contribute to Airway Remodeling

    OpenAIRE

    Zhao, Jingyue; Lloyd, Clare M.; Noble, Alistair

    2012-01-01

    The role of Th17 responses in airway remodeling in asthma is currently unknown. We demonstrate that both parenteral and mucosal allergen sensitization followed by allergen inhalation leads to Th17-biased lung immune responses. Unlike Th17 cells generated in vitro, lung Th17 cells did not produce TNF-α or IL-22. Eosinophilia predominated in acute inflammation while neutrophilia and IL-17 increased in chronic disease. Allergen-induced tolerance involved Foxp3, Helios and GARP expressing regulat...

  5. Robustness and adaptation reveal plausible cell cycle controlling subnetwork in Saccharomyces cerevisiae.

    Science.gov (United States)

    Huang, Jiun-Yan; Huang, Chi-Wei; Kao, Kuo-Ching; Lai, Pik-Yin

    2013-04-10

    Biological systems are often organized spatially and temporally by multi-scale functional subsystems (modules). A specific subcellular process often corresponds to a subsystem composed of some of these interconnected modules. Accurate identification of system-level modularity organization from the large scale networks can provide valuable information on subsystem models of subcellular processes or physiological phenomena. Computational identification of functional modules from the large scale network is the key approach to solve the complexity of modularity in the past decade, but the overlapping and multi-scale nature of modules often renders unsatisfactory results in these methods. Most current methods for modularity detection are optimization-based and suffered from the drawback of size resolution limit. It is difficult to trace the origin of the unsatisfactory results, which may be due to poor data, inappropriate objective function selection or simply resulted from natural evolution, and hence no system-level accurate modular models for subcellular processes can be offered. Motivated by the idea of evolution with robustness and adaption as guiding principles, we propose a novel approach that can identify significant multi-scale overlapping modules that are sufficiently accurate at the system and subsystem levels, giving biological insights for subcellular processes. The success of our evolution strategy method is demonstrated by applying to the yeast protein-protein interaction network. Functional subsystems of important physiological phenomena can be revealed. In particular, the cell cycle controlling network is selected for detailed discussion. The cell cycle subcellular processes in yeast can be successfully dissected into functional modules of cell cycle control, cell size check point, spindle assembly checkpoint, and DNA damage check point in G2/M and S phases. The interconnections between check points and cell cycle control modules provide clues on the

  6. Robustness and adaptation reveal plausible cell cycle controlling subnetwork in Saccharomyces cerevisiae.

    Science.gov (United States)

    Huang, Jiun-Yan; Huang, Chi-Wei; Kao, Kuo-Ching; Lai, Pik-Yin

    2013-04-10

    Biological systems are often organized spatially and temporally by multi-scale functional subsystems (modules). A specific subcellular process often corresponds to a subsystem composed of some of these interconnected modules. Accurate identification of system-level modularity organization from the large scale networks can provide valuable information on subsystem models of subcellular processes or physiological phenomena. Computational identification of functional modules from the large scale network is the key approach to solve the complexity of modularity in the past decade, but the overlapping and multi-scale nature of modules often renders unsatisfactory results in these methods. Most current methods for modularity detection are optimization-based and suffered from the drawback of size resolution limit. It is difficult to trace the origin of the unsatisfactory results, which may be due to poor data, inappropriate objective function selection or simply resulted from natural evolution, and hence no system-level accurate modular models for subcellular processes can be offered. Motivated by the idea of evolution with robustness and adaption as guiding principles, we propose a novel approach that can identify significant multi-scale overlapping modules that are sufficiently accurate at the system and subsystem levels, giving biological insights for subcellular processes. The success of our evolution strategy method is demonstrated by applying to the yeast protein-protein interaction network. Functional subsystems of important physiological phenomena can be revealed. In particular, the cell cycle controlling network is selected for detailed discussion. The cell cycle subcellular processes in yeast can be successfully dissected into functional modules of cell cycle control, cell size check point, spindle assembly checkpoint, and DNA damage check point in G2/M and S phases. The interconnections between check points and cell cycle control modules provide clues on the

  7. Embryonic Stem Cells-loaded Gelatin Microcryogels Slow Progression of Chronic Kidney Disease

    Institute of Scientific and Technical Information of China (English)

    Xiao-Dong Geng; Wei Zheng; Cong-Mei Wu; Shu-Qiang Wang; Quan Hong; Guang-Yan Cai; Xiang-Mei Chen

    2016-01-01

    Background: Chronic kidney disease (CKD) has become a public health problem.New interventions to slow or prevent disease progression are urgently needed.In this setting, cell therapies associated with regenerative effects are attracting increasing interest.We evaluated the effect of embryonic stem cells (ESCs) on the progression of CKD.Methods: Adult male Sprague-Dawley rats were subjected to 5/6 nephrectomy.We used pedicled greater omentum flaps packing ESC-loaded gelatin microcryogets (GMs) on the 5/6 nephrectomized kidney.The viability of ESCs within the GMs was detected using in vio two-photon fluorescence confocal imaging.Rats were sacrificed after 12 weeks.Renal injury was evaluated using serum creatinine, urea nitrogen, 24 h protein, renal pathology, and tubular injury score results.Structural damage was evaluated by periodic acid-Schiff and Masson trichrome staining.Results: In vitro, ESCs could be automatically loaded into the GMs.Uniform cell distribution, good cell attachment, and viability were achieved from day 1 to 7 in vitro.After 12 weeks, in the pedicled greater omentum flaps packing ESC-loaded GMs on 5/6 nephrectomized rats group, the plasma urea nitrogen levels were 26% lower than in the right nephrectomy group, glomerulosclerosis index was 62% lower and tubular injury index was 40% lower than in the 5/6 nephrectomized rats group without GMs.Conclusions: In a rat model of established CKD, we demonstrated that the pedicled greater omentum flaps packing ESC-loaded GMs on the 5/6 nephrectomized kidney have a long-lasting therapeutic rescue function, as shown by the decreased progression of CKD and reduced glomerular injury.

  8. Adaptive Optics: Arroyo Simulation Tool and Deformable Mirror Actuation Using Golay Cells

    Science.gov (United States)

    Lint, Adam S.

    2005-01-01

    The Arroyo C++ libraries, written by Caltech post-doc student Matthew Britton, have the ability to simulate optical systems and atmospheric signal interference. This program was chosen for use in an end-to-end simulation model of a laser communication system because it is freely distributed and has the ability to be controlled by a remote system or "smart agent." Proposed operation of this program by a smart agent has been demonstrated, and the results show it to be a suitable simulation tool. Deformable mirrors, as a part of modern adaptive optics systems, may contain thousands of tiny, independently controlled actuators used to modify the shape of the mirror. Each actuator is connected to two wires, creating a cumbersome and expensive device. Recently, an alternative actuation method that uses gas-filled tubes known as Golay cells has been explored. Golay cells, operated by infrared lasers instead of electricity, would replace the actuator system thereby creating a more compact deformable mirror. The operation of Golay cells and their ability to move a deformable mirror in excess of the required 20 microns has been demonstrated. Experimentation has shown them to be extremely sensitive to pressure and temperature, making them ideal for use in a controlled environment.

  9. GPU accelerated cell-based adaptive mesh refinement on unstructured quadrilateral grid

    Science.gov (United States)

    Luo, Xisheng; Wang, Luying; Ran, Wei; Qin, Fenghua

    2016-10-01

    A GPU accelerated inviscid flow solver is developed on an unstructured quadrilateral grid in the present work. For the first time, the cell-based adaptive mesh refinement (AMR) is fully implemented on GPU for the unstructured quadrilateral grid, which greatly reduces the frequency of data exchange between GPU and CPU. Specifically, the AMR is processed with atomic operations to parallelize list operations, and null memory recycling is realized to improve the efficiency of memory utilization. It is found that results obtained by GPUs agree very well with the exact or experimental results in literature. An acceleration ratio of 4 is obtained between the parallel code running on the old GPU GT9800 and the serial code running on E3-1230 V2. With the optimization of configuring a larger L1 cache and adopting Shared Memory based atomic operations on the newer GPU C2050, an acceleration ratio of 20 is achieved. The parallelized cell-based AMR processes have achieved 2x speedup on GT9800 and 18x on Tesla C2050, which demonstrates that parallel running of the cell-based AMR method on GPU is feasible and efficient. Our results also indicate that the new development of GPU architecture benefits the fluid dynamics computing significantly.

  10. Plant adaptation to fluctuating environment and biomass production are strongly dependent on guard cell potassium channels

    Science.gov (United States)

    Lebaudy, Anne; Vavasseur, Alain; Hosy, Eric; Dreyer, Ingo; Leonhardt, Nathalie; Thibaud, Jean-Baptiste; Véry, Anne-Aliénor; Simonneau, Thierry; Sentenac, Hervé

    2008-01-01

    At least four genes encoding plasma membrane inward K+ channels (Kin channels) are expressed in Arabidopsis guard cells. A double mutant plant was engineered by disruption of a major Kin channel gene and expression of a dominant negative channel construct. Using the patch-clamp technique revealed that this mutant was totally deprived of guard cell Kin channel (GCKin) activity, providing a model to investigate the roles of this activity in the plant. GCKin activity was found to be an essential effector of stomatal opening triggered by membrane hyperpolarization and thereby of blue light-induced stomatal opening at dawn. It improved stomatal reactivity to external or internal signals (light, CO2 availability, and evaporative demand). It protected stomatal function against detrimental effects of Na+ when plants were grown in the presence of physiological concentrations of this cation, probably by enabling guard cells to selectively and rapidly take up K+ instead of Na+ during stomatal opening, thereby preventing deleterious effects of Na+ on stomatal closure. It was also shown to be a key component of the mechanisms that underlie the circadian rhythm of stomatal opening, which is known to gate stomatal responses to extracellular and intracellular signals. Finally, in a meteorological scenario with higher light intensity during the first hours of the photophase, GCKin activity was found to allow a strong increase (35%) in plant biomass production. Thus, a large diversity of approaches indicates that GCKin activity plays pleiotropic roles that crucially contribute to plant adaptation to fluctuating and stressing natural environments. PMID:18367672