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Sample records for programmed death type-1

  1. Programmed cell death-1, PD-1, is dysregulated in T cells from children with new onset type 1 diabetes.

    PubMed

    Granados, Hector M; Draghi, Andrew; Tsurutani, Naomi; Wright, Kyle; Fernandez, Marina L; Sylvester, Francisco A; Vella, Anthony T

    2017-01-01

    Programmed death cell 1 (PD-1) is an inhibitor of T cell activation and is also functionally linked to glycolysis. We hypothesized that PD-1 expression is defective in activated T cells from children with type 1 diabetes (T1D), resulting in abnormal T cell glucose metabolism. In this pilot study, we enrolled children with new onset T1D within 2 weeks of diagnosis (T1D), unaffected siblings of T1D (SIBS), unaffected, unrelated children (CTRL), children with new onset, and untreated Crohn disease (CD). We repeated the assays 4-6 months post-diagnosis in T1D (T1D follow up). We analyzed anti-CD3/-CD28-stimulated peripheral blood mononuclear cells (PBMC) subsets for PD-1 expression by flow cytometry at baseline and after 24 h in culture. We measured cytokines in the culture medium by multiplex ELISA and glycolytic capacity with a flux analyzer. We enrolled 37 children. T cells derived from subjects with T1D had decreased PD-1 expression compared to the other study groups. However, in T1D follow-up T cells expressed PD-1 similarly to controls, but had no differences in PBMC cytokine production. Nonetheless, T1D follow up PBMCs had enhanced glycolytic capacity compared to T1D. Activated T cells from T1D fail to upregulate PD-1 upon T-cell receptor stimulation, which may contribute to the pathogenesis of T1D. T1D follow up PBMC expression of PD-1 normalizes, together with a significant increase in glycolysis compared to T1D. Thus, insulin therapy in T1D children is associated with normal PD1 expression and heightened glycolytic capacity in PBMC.

  2. Programmed cell death

    SciTech Connect

    1995-12-31

    The purpose of this conference to provide a multidisciplinary forum for exchange of state-of-the-art information on the role programmed cell death plays in normal development and homeostasis of many organisms. This volume contains abstracts of papers in the following areas: invertebrate development; immunology/neurology; bcl-2 family; biochemistry; programmed cell death in viruses; oncogenesis; vertebrate development; and diseases.

  3. Programmed cell death.

    PubMed

    Samuilov, V D; Oleskin, A V; Lagunova, E M

    2000-08-01

    This paper reviews data on programmed cell death (apoptosis) in animals and plants. Necrosis is a pathological scenario of cell death, which entails an inflammatory response in animal tissues. Apoptosis results in the disintegration of animal/plant cells into membrane vesicles enclosing the intracellular content, which are thereupon engulfed by adjacent or specialized cells (phagocytes) in animals. Plants lack such specialized cells, and plant cell walls prevent phagocytosis. The paper considers the main molecular mechanisms of apoptosis in animals and the pathways of activation of caspases, evolutionarily conserved cysteine proteases. A self-contained section concerns itself with the process of programmed cell death (PCD) in microorganisms including: 1) cell death in the myxomycete Dictyostelium discoideum and the parasitic flagellate Trypanosoma cruzi; 2) PCD in genetically manipulated yeast expressing the proapoptotic Bax and Bak proteins; 3) the death of a part of a prokaryotic cell population upon the depletion of nutrient resources or under stress; 4) the elimination of cells after a loss of a plasmid encoding a stable cytotoxic agent in combination with an unstable antidote; and 5) PCD in phage-infected bacterial cells.

  4. Competing-risk analysis of ESRD and death among patients with type 1 diabetes and macroalbuminuria.

    PubMed

    Forsblom, Carol; Harjutsalo, Valma; Thorn, Lena M; Wadén, Johan; Tolonen, Nina; Saraheimo, Markku; Gordin, Daniel; Moran, John L; Thomas, Merlin C; Groop, Per-Henrik

    2011-03-01

    Patients with both type 1 diabetes and CKD have an increased risk of adverse outcomes. The competing risks of death and ESRD may confound the estimates of risk for each outcome. Here, we sought to determine the major predictors of the cumulative incidence of ESRD and pre-ESRD mortality in patients with type 1 diabetes and macroalbuminuria while incorporating the competing risk for the alternate outcome into a Fine-Gray competing-risks analysis. We followed 592 patients with macroalbuminuria for a median of 9.9 years. During this time, 56 (9.5%) patients died and 210 (35.5%) patients developed ESRD. Predictors of incident ESRD, taking baseline renal function and the competing risk for death into account, included an elevated HbA(1c), elevated LDL cholesterol, male sex, weight-adjusted insulin dose, and a shorter duration of diabetes. By contrast, predictors of pre-ESRD death, taking baseline renal function and the competing risk for ESRD into account, included only age, the presence of established macrovascular disease, and elevated cholesterol levels. This competing-risks approach has potential to highlight the appropriate targets and strategies for preventing premature mortality in patients with type 1 diabetes.

  5. Characterizing sudden death and dead-in-bed syndrome in Type 1 diabetes: analysis from two childhood-onset Type 1 diabetes registries.

    PubMed

    Secrest, A M; Becker, D J; Kelsey, S F; Laporte, R E; Orchard, T J

    2011-03-01

    Type 1 diabetes mellitus increases the risk for sudden unexplained death, generating concern that diabetes processes and/or treatments underlie these deaths. Young (< 50 years) and otherwise healthy patients who are found dead in bed have been classified as experiencing 'dead-in-bed' syndrome. We thus identified all unwitnessed deaths in two related registries (the Children's Hospital of Pittsburgh and Allegheny County) yielding 1319 persons with childhood-onset (age < 18 years) Type 1 diabetes diagnosed between 1965 and 1979. Cause of death was determined by a Mortality Classification Committee (MCC) of at least two physician epidemiologists, based on the death certificate and additional records surrounding the death. Of the 329 participants who had died, the Mortality Classification Committee has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were sudden unexplained deaths (13 male) and seven met dead-in-bed criteria. The Mortality Classification Committee adjudicated cause of death in the seven dead-in-bed persons as: diabetic coma (n =4), unknown (n=2) and cardiomyopathy (n=1, found on autopsy). The three dead-in-bed individuals who participated in a clinical study had higher HbA(1c) , lower BMI and higher daily insulin dose compared with both those dying from other causes and those surviving. Sudden unexplained death in Type 1 diabetes seems to be increased 10-fold and associated with male sex, while dead-in-bed individuals have a high HbA(1c) and insulin dose and low BMI. Although sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to sudden unexplained death and dead-in-bed death. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

  6. [Educational program to type 1 diabetes mellitus patients: basic topics].

    PubMed

    Leite, Silmara A Oliveira; Zanim, Ligia Maria; Granzotto, Paula Carolina D; Heupa, Sabrina; Lamounier, Rodrigo N

    2008-03-01

    Type 1 diabetes incidence has been increasing worldwide, however the vast majority of patients do not have a good glycaemic control. This review focuses on diabetes educational programs designed for children, young adults and their families, as well as regular pump users educational tips, collected from papers published between 2000 and 2007. A comprehensive review of the literature has identified 40 articles describing the methods and the evaluation of diabetes self-management education interventions. Three research questions are posed. First: what are the recommendations and standards for diabetes self-management education from the different diabetes institutions/associations? Second: is there sufficient evidence to recommend any adaptation of any particular program? And third: Are the educational programs effective in lowering glycated haemoglobin (HbA1c)? The patient and his family should be instructed and trained to take appropriate decisions for diabetes management regarding their daily care. Diabetes self-management education improves glicaemic control (both in an individual basis as well as in groups) in such a way that the longer the education training in diabetes the better is the effect on glycaemic control is.

  7. Sudden death in type 1 diabetes: the mystery of the 'dead in bed' syndrome.

    PubMed

    Tu, Emily; Twigg, Stephen M; Semsarian, Christopher

    2010-01-07

    Sudden cardiac death is an unpredictable and devastating event, particularly in the young. A significant proportion of sudden deaths in the young are unexplained-no cause is identified either during life or at post-mortem. This is seen in a subgroup of young patients with type 1 diabetes who have dead in bed syndrome, where these victims are in good health, retire to bed, only to be found dead the following morning in a bed which is undisturbed, suggesting no terminal struggle or seizure. The underlying cause of dead in bed syndrome remains unknown, but is likely to be due to a terminal malignant arrhythmia. A plausible hypothesis is that it may be secondary to QT interval prolongation (followed by a degenerate ventricular tachycardia), caused by a number of factors including acute hypoglycaemia, on a background of cardiac autonomic neuropathy, and possible genetic influences. It is envisaged that understanding the causes and triggers of dead in bed syndrome will allow appropriate therapeutic interventions to be initiated in high-risk patients with type 1 diabetes, with the ultimate goal to prevent sudden death.

  8. Programmed cell death: Superman meets Dr Death.

    PubMed

    Meier, Pascal; Silke, John

    2003-12-01

    This year's Cold Spring Harbor meeting on programmed cell death (September 17-21, 2003), organised by Craig Thompson and Junying Yuan, was proof that the 'golden age' of research in this field is far from over. There was a flurry of fascinating insights into the regulation of diverse apoptotic pathways and unexpected non-apoptotic roles for some of the key apoptotic regulators and effectors. In addition to their role in cell death, components of the apoptotic molecular machinery are now known to also function in a variety of essential cellular processes, such as regulating glucose homeostasis, lipid metabolism, cell proliferation and differentiation.

  9. Mortality associated with neurofibromatosis type 1: A study based on Italian death certificates (1995-2006)

    PubMed Central

    2011-01-01

    Background Persons affected by neurofibromatosis type 1 (NF1) have a decreased survival, yet information on NF1-associated mortality is limited. Methods/Aim The National Mortality Database and individual Multiple-Causes-of-Death records were used to estimate NF1-associated mortality in Italy in the period 1995-2006, to compare the distribution of age at death (as a proxy of survival) to that of the general population and to evaluate the relation between NF1 and other medical conditions by determining whether the distribution of underlying causes of NF1-associated deaths differs from that of general population. Results Of the nearly 6.75 million deaths in the study period, 632 had a diagnosis of NF1, yet for nearly three-fourths of them the underlying cause was not coded as neurofibromatosis. The age distribution showed that NF1-associated deaths also occurred among the elderly, though mortality in early ages was high. The mean age for NF1-associated death was approximately 20 years lower than that for the general population. The gender differential may suggest that women are affected by more severe NF1-related complications, or they may simply reflect a greater tendency for NF1 to be reported on the death certificates of young women. Regarding the relation with other medical conditions, we found an excess, as the underlying cause of death, for malignant neoplasm of connective and other soft tissue and brain, but not for other sites. We also found an excess for obstructive chronic bronchitis and musculoskeletal system diseases among elderly persons. Conclusion This is the first nationally representative population-based study on NF1-associated mortality in Italy. It stresses the importance of the Multiple-Causes-of-Death Database in providing a more complete picture of mortality for conditions that are frequently not recorded as the underlying cause of death, or to study complex chronic diseases or diseases that have no specific International Classification of

  10. Characterising sudden death and dead-in-bed syndrome in Type 1 diabetes: Analysis from 2 childhood-onset Type 1 diabetes registries

    PubMed Central

    Secrest, A. M.; Becker, D. J.; Kelsey, S. F.; LaPorte, R. E.; Orchard, T. J.

    2011-01-01

    Aims Type 1 diabetes mellitus increases the risk for sudden unexplained death (SUD), generating concern that diabetes processes and/or treatments underlie these deaths. Young (<50 yrs) and otherwise healthy patients who are found dead in bed have been classified as experiencing “dead in bed” (DIB) syndrome. Methods We thus identified all un-witnessed deaths in two related registries (Children’s Hospital of Pittsburgh and Allegheny County) yielding 1,319 persons with childhood-onset (age<18 yrs) Type 1 DM diagnosed between 1965 and 1979. Cause of death was determined by a mortality classification committee (MCC) of at least 2 physician epidemiologists, based on the death certificate and additional records surrounding the death. Results Of the 329 participants who had died, the MCC has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were SUDs (13 male), and 7 met DIB criteria. The MCC adjudicated cause of death in the 7 DIB persons as: diabetic coma (n=4), unknown (n=2), and cardiomyopathy (n=1, found on autopsy). The 3 DIB individuals who participated in a clinical study had higher HbA1c, lower BMI, and higher daily insulin dose compared to both those dying from other causes and those surviving. Conclusions SUD in Type 1 DM seems to be increased 10-fold and associated with male sex, while DIB individuals have a high HbA1c and insulin dose, and low BMI. Though sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to SUD and DIB. PMID:21309837

  11. Causes of Death and Prognostic Factors in Multiple Endocrine Neoplasia Type 1: A Prospective Study

    PubMed Central

    Ito, Tetsuhide; Igarashi, Hisato; Uehara, Hirotsugu; Berna, Marc J.; Jensen, Robert T.

    2013-01-01

    Abstract Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking. To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%–14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled

  12. Sudden unexpected nocturnal death in Chiari type 1 malformation and potential role of opioid analgesics

    PubMed Central

    Roohi, Fereydoon; Gropen, Toby; Kula, Roger W.

    2014-01-01

    Background: Chiari malformation type 1 (CM1) is a common congenital anomaly of the craniocervical junction. CM1 is reported to run a usually benign course and patients typically experience no symptoms or chronic, slowly progressive symptoms. However, recent reports indicate that a subset of patients with CM1 may present with acute deterioration and sudden unexpected death (SUD). We report a case of SUD during sleep in a young man with CM1, which we believe was related to the administration of common and therapeutic doses of narcotic analgesics for the management of pain. We will clarify the pathophysiology of acute deterioration and SUD in CM1 and the possibility that the adverse effects of opiate analgesics likely were the leading cause of death in our patient. Case Description: In this review, we present a 29-year-old male with worsening headache secondary to previously diagnosed CM1. The patient died suddenly and unexpectedly after administration of common and therapeutic doses of narcotic analgesics for the management of pain. Conclusion: The mechanism(s) of acute neurological deterioration and sudden death in patients with CM1 remains poorly understood. We believe the rapid fatal deterioration in our patient following administration of opioids suggests that this category of medication may cause sudden unexpected “neurogenic” cardiac death in CM1 patients by inducing sleep-related breathing difficulties and associated hypercapnia. Hypercapnia by further increasing intracranial pressure can result in a sudden pressure-induced decompensation of the cardiopulmonary control centers in the brain stem and cause instantaneous cardiorespiratory arrest. PMID:24778905

  13. The vicious cycle of apoptotic beta-cell death in type 1 diabetes.

    PubMed

    Kaminitz, Ayelet; Stein, Jerry; Yaniv, Isaac; Askenasy, Nadir

    2007-01-01

    Autoimmune insulitis, the cause of type 1 diabetes, evolves through several discrete stages that culminate in beta-cell death. In the first stage, antigenic epitopes of B-cell-specific peptides are processed by antigen presenting cells in local lymph nodes, and auto-reactive lymphocyte clones are propagated. Subsequently, cell-mediated and direct cytokine-mediated reactions are generated against the beta-cells, and the beta-cells are sensitized to apoptosis. Ironically, the beta-cells themselves contribute some of the cytokines and chemokines that provoke the immune reaction within the islets. Once this vicious cycle of autoimmunity is fully developed, the fate of the beta-cells in the islets is sealed, and clinical diabetes inevitably ensues. Differences in various aspects of these concurrent events appear to underlie the significant discrepancies in experimental data observed in experimental models that simulate autoimmune insulitis.

  14. Monte Carlo Study Elucidates the Type 1/Type 2 Choice in Apoptotic Death Signaling in Healthy and Cancer Cells

    PubMed Central

    Raychaudhuri, Subhadip; Raychaudhuri, Somkanya C

    2013-01-01

    Apoptotic cell death is coordinated through two distinct (type 1 and type 2) intracellular signaling pathways. How the type 1/type 2 choice is made remains a central problem in the biology of apoptosis and has implications for apoptosis related diseases and therapy. We study the problem of type 1/type 2 choice in silico utilizing a kinetic Monte Carlo model of cell death signaling. Our results show that the type 1/type 2 choice is linked to deterministic versus stochastic cell death activation, elucidating a unique regulatory control of the apoptotic pathways. Consistent with previous findings, our results indicate that caspase 8 activation level is a key regulator of the choice between deterministic type 1 and stochastic type 2 pathways, irrespective of cell types. Expression levels of signaling molecules downstream also regulate the type 1/type 2 choice. A simplified model of DISC clustering elucidates the mechanism of increased active caspase 8 generation and type 1 activation in cancer cells having increased sensitivity to death receptor activation. We demonstrate that rapid deterministic activation of the type 1 pathway can selectively target such cancer cells, especially if XIAP is also inhibited; while inherent cell-to-cell variability would allow normal cells stay protected. PMID:24709706

  15. [Pathophysiologic programming of cell death].

    PubMed

    Dobryszycka, W

    1998-01-01

    In multicellular organisms homeostasis depends on a balance between cell proliferation and cell death. In this review principles of the physiology of programmed cell death (apoptosis), i.e. biochemical features, involved genes and proteolytic enzymes, are described. Alterations in apoptosis contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, inflammation, hematopoietic and immunological system defects (e.g. AIDS), neurodegenerative disorders. Specific effect on regulation of apoptosis might lead to new possibilities for treatment. Methods of quantitative determinations of apoptosis are discussed.

  16. Programmed cell death in Giardia.

    PubMed

    Bagchi, Susmita; Oniku, Abraham E; Topping, Kate; Mamhoud, Zahra N; Paget, Timothy A

    2012-06-01

    Programmed cell death (PCD) has been observed in many unicellular eukaryotes; however, in very few cases have the pathways been described. Recently the early divergent amitochondrial eukaryote Giardia has been included in this group. In this paper we investigate the processes of PCD in Giardia. We performed a bioinformatics survey of Giardia genomes to identify genes associated with PCD alongside traditional methods for studying apoptosis and autophagy. Analysis of Giardia genomes failed to highlight any genes involved in apoptotic-like PCD; however, we were able to induce apoptotic-like morphological changes in response to oxidative stress (H2O2) and drugs (metronidazole). In addition we did not detect caspase activity in induced cells. Interestingly, we did observe changes resembling autophagy when cells were starved (staining with MDC) and genome analysis revealed some key genes associated with autophagy such as TOR, ATG1 and ATG 16. In organisms such as Trichomonas vaginalis, Entamoeba histolytica and Blastocystis similar observations have been made but no genes have been identified. We propose that Giardia possess a pathway of autophagy and a form of apoptosis very different from the classical known mechanism; this may represent an early form of programmed cell death.

  17. Effects of Antiretroviral Drugs on Human Immunodeficiency Virus Type 1-Induced CD4+ T-Cell Death

    PubMed Central

    Estaquier, Jérôme; Lelièvre, Jean-Daniel; Petit, Frédéric; Brunner, Thomas; Moutouh-de Parseval, Laure; Richman, Douglas D.; Ameisen, Jean Claude; Corbeil, Jacques

    2002-01-01

    Apoptosis of peripheral blood T cells plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 (HIV-1) primes CD4+ T cells from healthy donors for apoptosis, which occurs after CD95 ligation or CD3-T-cell receptor (TCR) stimulation. CD95-mediated death did not depend on CD4 T-cell infection, since it occurred in the presence of the reverse transcriptase inhibitor didanosine (ddI). In contrast, apoptosis induced by productive infection (CD3-TCR stimulation) is prevented by both CD95 decoy receptor and ddI. Our data suggest that HIV-1 triggers at least two distinct death pathways: a CD95-dependent pathway that does not require viral replication and a viral replication-mediated cell death independent of the CD95 pathway. Further experiments indicated that saquinavir, a protease inhibitor, at a 0.2 μM concentration, decreased HIV-mediated CD95 expression and thus cell death, which is independent of its role in inhibiting viral replication. However, treatment of peripheral blood mononuclear cells from healthy donors with a higher concentration (10 μM) of an HIV protease inhibitor, saquinavir or indinavir, induced both a loss in mitochondrial membrane potential (ΔΨm) and cell death. Thus, protease inhibitors have the potential for both beneficial and detrimental effects on CD4+ T cells independent of their antiretroviral effects. PMID:12021329

  18. Bovine herpesvirus type 1 induces cell death by a cell-type-dependent fashion.

    PubMed

    Geiser, Vicki; Rose, Suzanne; Jones, Clinton

    2008-06-01

    Bovine herpesvirus 1 (BHV-1), a member of the alpha-herpesvirinae sub-family, causes significant losses to the cattle industry. BHV-1 establishes latency in trigeminal ganglionic sensory neurons, but periodically reactivates from latency. Previous studies suggested that infection with BHV-1-induced novel morphological changes in rabbit skin (RS) cells versus bovine kidney cells (MDBK). Consequently, we hypothesized that viral infection led to a novel form of cell death in RS cells compared to MDBK cells. To test this hypothesis, we examined the levels of apoptosis in these cell types following infection with BHV-1. Infection of RS, but not MDBK, cells leads to high levels of apoptosis compared to mock-infected cells. Previous studies indicated that a BHV-1 recombinant virus that does not express the bICP0 protein grows poorly in permissive cells and induces a persistent-like infection. This suggested that bICP0 played an important role in regulating cell death following infection. To test this hypothesis, we compared the levels of apoptosis in cells infected with the bICP0 null mutant versus viral strains that expressed bICP0. The bICP0 null mutant induces low levels of apoptosis in RS or MDBK cells. When MDBK cells are treated with UV light prior to infection, bICP0 expressing viral strains, but not the bICP0 null mutant, inhibited UV-induced apoptosis. Infection of MDBK cells with the bICP0 null mutant, leads to an accumulation of autophagosomes that are not detected following infection with bICP0 expressing viruses. These studies suggest that the bICP0 null mutant induces autophagy in MDBK cells, and bICP0 protein expression mediates cell-type specific cytotoxicity.

  19. A Comparison of Two Internet Programs for Adolescents with Type 1 Diabetes: Design and Methods

    PubMed Central

    Grey, Margaret; Whittemore, Robin; Liberti, Lauren; Delamater, Alan; Murphy, Kathryn; Faulkner, Melissa S.

    2012-01-01

    Implementing psycho-educational programs for youth with type 1 diabetes in clinical care and reaching diverse youth with type 1 diabetes is challenging due to youth, provider, and organizational barriers. This study was designed to compare the effectiveness of an internet coping skills training program with a control condition of internet diabetes education. Each program consists of 5 weekly interactive lessons; the coping skills training program also provides the ability for youth to interact with each other as well as a health coach. Approximately 300 youth with type 1 diabetes will be recruited to participate in this multi-site clinical trial. The primary outcomes are metabolic control, quality of life, and family conflict. Secondary outcomes include stress, coping, self-efficacy, and social competence. Usage, satisfaction, and cost will also be evaluated. In addition, mediators and moderators to intervention effects will be explored. An internet based psycho-educational program for youth with type 1 diabetes may be a promising approach that can be easily be integrated into clinical care. PMID:22484337

  20. A comparison of two internet programs for adolescents with type 1 diabetes: design and methods.

    PubMed

    Grey, Margaret; Whittemore, Robin; Liberti, Lauren; Delamater, Alan; Murphy, Kathryn; Faulkner, Melissa S

    2012-07-01

    Implementing psycho-educational programs for youth with type 1 diabetes in clinical care and reaching diverse youth with type 1 diabetes is challenging due to youth, provider, and organizational barriers. This study was designed to compare the effectiveness of an internet coping skills training program with a control condition of internet diabetes education. Each program consists of 5 weekly interactive lessons; the coping skills training program also provides the ability for youth to interact with each other as well as a health coach. Approximately 300 youths with type 1 diabetes will be recruited to participate in this multi-site clinical trial. The primary outcomes are metabolic control, quality of life, and family conflict. Secondary outcomes include stress, coping, self-efficacy, and social competence. Usage, satisfaction, and cost will also be evaluated. In addition, mediators and moderators to intervention effects will be explored. An internet based psycho-educational program for youth with type 1 diabetes may be a promising approach that can be easily be integrated into clinical care.

  1. Programmed cell death in aging.

    PubMed

    Tower, John

    2015-09-01

    Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis. Mis-regulation of PCD is increasingly implicated in aging and aging-related disease. During aging the cell turnover rate declines for several highly-mitotic tissues. Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types. Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease. In contrast, cancer cells and senescent cells are resistant to PCD, enabling them to increase in abundance during aging. PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear. PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.

  2. Programmed Cell Death in Breast Cancer

    DTIC Science & Technology

    1998-10-01

    Programmed cell death , or apoptosis, is a genetically regulated process through which a cell is active in bringing about its own death for the sake...delays and inhibits the cell death response, so that the breast cancer cell lines are much less susceptible to thapsigargin-induced apoptosis than...lymphoid cell lines, an observation that parallels the differential susceptibility of breast cancer and lymphomas to chemotherapy-induced cell death in

  3. Development of an Internet coping skills training program for teenagers with type 1 diabetes.

    PubMed

    Whittemore, Robin; Grey, Margaret; Lindemann, Evie; Ambrosino, Jodie; Jaser, Sarah

    2010-01-01

    The purpose of this study was to develop an Internet coping skills training program and to evaluate its feasibility and acceptability compared with an Internet education intervention for teenagers with type 1 diabetes. A multiphase mixed-methods design with focus groups, a randomized pilot study, and a program evaluation was used. Teenagers with type 1 diabetes, parents, and health professionals were included in the development and evaluative phases along with the research and information technology team. The pilot study included 12 teenagers with type 1 diabetes (mean [SD] age, 14.4 [.90] years; 58% female; mean [SD] duration of diabetes, 5.9 [3.0] years). Psychosocial data and HbA1c levels were collected at baseline and at 3 and 6 months. Results indicate that the development of a psychosocial Internet intervention was complex and required multiple iterations of development and evaluation. Results of this study also indicate the feasibility and acceptability of translating a group-based intervention for teenagers with type 1 diabetes to the Internet. Thus, this study demonstrates a systematic approach to Internet intervention development. Including teenagers with type 1 diabetes and a multidisciplinary professional team into the intervention design was critical to the success of this project.

  4. Development of an Internet Coping Skills Training Program for Teenagers With Type 1 Diabetes

    PubMed Central

    WHITTEMORE, ROBIN; GREY, MARGARET; LINDEMANN, EVIE; AMBROSINO, JODIE; JASER, SARAH

    2010-01-01

    The purpose of this study was to develop an Internet coping skills training program and to evaluate its feasibility and acceptability compared with an Internet education intervention for teenagers with type 1 diabetes. A multiphase mixed-methods design with focus groups, a randomized pilot study, and a program evaluation was used. Teenagers with type 1 diabetes, parents, and health professionals were included in the development and evaluative phases along with the research and information technology team. The pilot study included 12 teenagers with type 1 diabetes (mean [SD] age, 14.4 [.90] years; 58% female; mean [SD] duration of diabetes, 5.9 [3.0] years). Psychosocial data and HbA1c levels were collected at baseline and at 3 and 6 months. Results indicate that the development of a psychosocial Internet intervention was complex and required multiple iterations of development and evaluation. Results of this study also indicate the feasibility and acceptability of translating a group-based intervention for teenagers with type 1 diabetes to the Internet. Thus, this study demonstrates a systematic approach to Internet intervention development. Including teenagers with type 1 diabetes and a multidisciplinary professional team into the intervention design was critical to the success of this project. PMID:20182161

  5. Programmed Cell Death in Breast Cancer.

    DTIC Science & Technology

    1996-10-01

    TITLE: Programmed Cell Death in Breast Cancer PRINCIPAL INVESTIGATOR: Clark W. Distelhorst, M.D. CONTRACTING ORGANIZATION: Case Western Reserve...Programmed Cell Death in Breast Cancer DAMD17-94-J-4451 6. AUTHOR(S) Clark W. Distelhorst, M.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8...cell death , apoptosis, in breast cancer cells has been developed. This model is based on induction of apoptosis by the selective endoplasmic reticulum

  6. Behavioral Programs for Type 1 Diabetes Mellitus: A Systematic Review and Meta-analysis.

    PubMed

    Pillay, Jennifer; Armstrong, Marni J; Butalia, Sonia; Donovan, Lois E; Sigal, Ronald J; Chordiya, Pritam; Dhakal, Sanjaya; Vandermeer, Ben; Hartling, Lisa; Nuspl, Megan; Featherstone, Robin; Dryden, Donna M

    2015-12-01

    Whether behavioral approaches for self-management programs benefit individuals with type 1 diabetes mellitus is unclear. To determine the effects of behavioral programs for patients with type 1 diabetes on behavioral, clinical, and health outcomes and to investigate factors that might moderate effect. 6 electronic databases (1993 to June 2015), trial registries and conference proceedings (2011 to 2014), and reference lists. 36 prospective, controlled studies involving participants of any age group that compared behavioral programs with usual care, active controls, or other programs. One reviewer extracted and another verified data. Two reviewers assessed quality and strength of evidence (SOE). Moderate SOE showed reduction in glycated hemoglobin (HbA1c) at 6 months after the intervention compared with usual care (mean difference, -0.29 [95% CI, -0.45 to -0.13] percentage points) and compared with active controls (-0.44 [CI, -0.69 to -0.19] percentage points). At the end of the intervention and 12-month follow-up or longer, there were no statistically significant differences in HbA1c (low SOE) for comparisons with usual care or active control. Compared with usual care, generic quality of life at program completion did not differ (moderate SOE). Other outcomes had low or insufficient SOE. Adults appeared to benefit more for glycemic control at program completion (-0.28 [CI, -0.57 to 0.01] percentage points) than did youth (-0.12 [CI, -0.43 to 0.19] percentage points). Program intensity appeared not to influence effectiveness; some individual delivery appears beneficial. All studies had medium or high risk of bias. There was scarce evidence for many outcomes. Behavioral programs for type 1 diabetes offer some benefit for glycemic control, at least at short-term follow-up, but improvement for other outcomes has not been shown. (PROSPERO registration number: CRD42014010515). Agency for Healthcare Research and Quality. (PROSPERD registration number: CRD42014010515).

  7. Unusual cause of aborted sudden cardiac death in a teen athlete: homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene.

    PubMed

    Phillips, Susie B; Batlivala, Sarosh; Knudson, Jarrod D

    2015-10-01

    Common aetiologies of sudden cardiac death in children include coronary anomalies, channelopathies, and cardiomyopathies. Less frequently, hypercoagulable states cause sudden arrest. We report an unusual case of aborted sudden cardiac death in a teenager, ultimately found to have homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene.

  8. Feasibility of the SMART Project: A Text Message Program for Adolescents With Type 1 Diabetes.

    PubMed

    Herbert, Linda Jones; Mehta, Priya; Monaghan, Maureen; Cogen, Fran; Streisand, Randi

    2014-11-01

    This study investigated response rates to the Self-Management and Research Technology Project, a 6-week text message program for adolescents with type 1 diabetes designed to provide diabetes self-management reminders and education. The rate of response to texts was high, with 78% of texts responded to during the 6-week period. Girls and participants who self-reported sending a large number of personal daily texts had higher response rates; other demographic and medical variables were unrelated to text response rates. Inclusion of mobile health technologies such as text messages in clinical care may be a unique, relevant method of intervention for youths with type 1 diabetes, regardless of age, socioeconomic status, or glycemic control.

  9. Role of programmed cell death in development.

    PubMed

    Ranganath, R M; Nagashree, N R

    2001-01-01

    Programmed cell death (PCD) is an integral part of both animal and plant development. In animals, model systems such as Caenorhabditis elegans, Drosophila melanogaster, and mice have shown a general cell death profile of induction, caspase mediation, cell death, and phagocytosis. Tremendous strides have been made in cell death research in animals in the past decade. The ordering of the C. elegans genes Ced-3, 4 and 9, identification of caspase-activated DNase that degrades nuclear DNA during PCD, identification of signal transduction modules involving caspases as well as the caspase-independent pathway, and the involvement of mitochondria are some of the findings of immense value in understanding animal PCDs. Similarly, the caspase inactivation mechanisms of infecting viruses to stall host cell death give a new dimension to the viral infection process. However, plant cell death profiles provide an entirely different scenario. The presence of a cell wall that cannot be phagocytosed, absence of the hallmarks of animal PCDs such as DNA laddering, formation of apoptotic bodies, a cell-death-specific nuclease, a biochemical machinery of killer enzymes such as caspases all point to novel ways of cell elimination. Large gaps in our understanding of plant cell death have prompted speculative inferences and comparisons with animal cell death mechanisms. This paper deals with both animals and plants for a holistic view on cell death in eukaryotes.

  10. Internet Psycho-Education Programs Improve Outcomes in Youth With Type 1 Diabetes

    PubMed Central

    Grey, Margaret; Whittemore, Robin; Jeon, Sangchoon; Murphy, Kathryn; Faulkner, Melissa S.; Delamater, Alan

    2013-01-01

    OBJECTIVE The purpose of this study was to determine the efficacy of two Internet-based psycho-educational programs designed to improve outcomes for youth with type 1 diabetes transitioning to adolescence. RESEARCH DESIGN AND METHODS The study was a multisite clinical trial of 320 youth (aged 11–14 years; 37% minority; 55% female) randomized to one of two Internet-based interventions: TeenCope or Managing Diabetes. Primary outcomes were HbA1c and quality of life (QOL). Secondary outcomes included coping, self-efficacy, social competence, self-management, and family conflict. Data were collected at baseline and after 3, 6, and 12 months online. Youth were invited to cross over to the other program after 12 months, and follow-up data were collected at 18 months. Analyses were based on mixed models using intent-to-treat and per-protocol procedures. RESULTS Youth in both groups had stable QOL and minimal increases in HbA1c levels over 12 months, but there were no significant differences between the groups in primary outcomes. After 18 months, youth who completed both programs had lower HbA1c (P = 0.04); higher QOL (P = 0.02), social acceptance (P = 0.01), and self-efficacy (P = 0.03) and lower perceived stress (P = 0.02) and diabetes family conflict (P = 0.02) compared with those who completed only one program. CONCLUSIONS Internet interventions for youth with type 1 diabetes transitioning to adolescence result in improved outcomes, but completion of both programs was better than only one, suggesting that these youth need both diabetes management education and behavioral interventions. Delivering these programs via the Internet represents an efficient way to reach youth and improve outcomes. PMID:23579179

  11. Costs of Development and Maintenance of an Internet Program for Teens with Type 1 Diabetes

    PubMed Central

    Grey, Margaret; Liberti, Lauren; Whittemore, Robin

    2015-01-01

    Many adolescents with type 1 diabetes (T1D) have difficulty completing self-management tasks within the context of their social environments. Group-based approaches to psycho-educational support have been shown to prevent declines in glucose control, but are challenging to implement due to youths’ many activities and costs. A novel solution is providing psycho-educational support via the internet. The purpose of this study is to describe the cost of developing and maintaining two internet psycho-educational programs, both of which have been shown to improve health outcomes in adolescents with T1D. We calculated actual costs of personnel and programming in the development of TEENCOPE™ and Managing Diabetes, two highly interactive programs that were evaluated in a multi-site clinical trial (n=320). Cost calculations were set at U.S. dollars and converted to value for 2013 as expenses were incurred over 6 years. Development costs over 1.5 years totaled $324,609, with the majority of costs being for personnel to develop and write content in a creative and engaging format, to get feedback from teens on content and a prototype, and IT programming. Maintenance of the program, including IT support, a part-time moderator to assure safety of the discussion board (0.5–1 hour/week), and yearly update of content was $43,845/year, or $137.00 per youth over 4.5 years. Overall, program and site development were relatively expensive, but the program reach was high, including non-white youth from 4 geographically distinct regions. Once developed, maintenance was minimal. With greater dissemination, cost-per-youth would decrease markedly, beginning to offset the high development expense. PMID:26213677

  12. Effectiveness of a Death-Education Program in Reducing Death Anxiety of Nursing Students.

    ERIC Educational Resources Information Center

    Johansson, Noreen; Lally, Terry

    1991-01-01

    Evaluated effectiveness of death education program in reducing death anxiety experienced by 22 junior and senior nursing students. Subjects were pre- and posttested with State Form of State-Trait Anxiety Inventory and viewed film of death experience. Posttest analysis indicated that death education program was effective in decreasing death anxiety…

  13. Programmed cell death in plant reproduction.

    PubMed

    Wu, H M; Cheun, A Y

    2000-10-01

    Reproductive development is a rich arena to showcase programmed cell death in plants. After floral induction, the first act of reproductive development in some plants is the selective killing of cells destined to differentiate into an unwanted sexual organ. Production of functional pollen grains relies significantly on deterioration and death of the anther tapetum, a tissue whose main function appears to nurture and decorate the pollen grains with critical surface molecules. Degeneration and death in a number of anther tissues result ultimately in anther rupture and dispersal of pollen grains. Female sporogenesis frequently begins with the death of all but one of the meiotic derivatives, with surrounding nucellar cells degenerating in concert with embryo sac expansion. Female tissues that interact with pollen undergo dramatic degeneration, including death, to ensure the encounter of compatible male and female gametes. Pollen and pistil interact to kill invading pollen from an incompatible source. Most observations on cell death in reproductive tissues have been on the histological and cytological levels. We discuss various cell death phenomena in reproductive development with a view towards understanding the biochemical and molecular mechanisms that underlie these processes.

  14. Research Program on Type 1 Diabetes and Youth Depression in Puerto Rico

    PubMed Central

    Cumba-Avilés, Eduardo; Sáez-Santiago, Emily

    2016-01-01

    This work reviews the progress and current state of a research program on Diabetes and youth depression in Puerto Rico. Given the high depression rate, its impact in youth with Type 1 Diabetes (T1D), and the lack of interventions to target this link in an integrative way, the manual titled Cognitive-Behavioral Treatment for Depression in Adolescents with T1D was developed. After its first use in an Open Trial, we currently assess the initial efficacy of its revised version to reduce depression and improve glycemic control, self-care, and quality of life. We present its approach, and initial data on its feasibility, acceptability and potential to reduce emotional problems in T1D youth. We discuss implications of this line of research for health psychology, and its utility to model the development of interventions alike focused on other chronic illnesses. PMID:27818725

  15. Research Program on Type 1 Diabetes and Youth Depression in Puerto Rico.

    PubMed

    Cumba-Avilés, Eduardo; Sáez-Santiago, Emily

    2016-01-01

    This work reviews the progress and current state of a research program on Diabetes and youth depression in Puerto Rico. Given the high depression rate, its impact in youth with Type 1 Diabetes (T1D), and the lack of interventions to target this link in an integrative way, the manual titled Cognitive-Behavioral Treatment for Depression in Adolescents with T1D was developed. After its first use in an Open Trial, we currently assess the initial efficacy of its revised version to reduce depression and improve glycemic control, self-care, and quality of life. We present its approach, and initial data on its feasibility, acceptability and potential to reduce emotional problems in T1D youth. We discuss implications of this line of research for health psychology, and its utility to model the development of interventions alike focused on other chronic illnesses.

  16. Programmed cell death in seeds of angiosperms.

    PubMed

    López-Fernández, María Paula; Maldonado, Sara

    2015-12-01

    During the diversification of angiosperms, seeds have evolved structural, chemical, molecular and physiologically developing changes that specially affect the nucellus and endosperm. All through seed evolution, programmed cell death (PCD) has played a fundamental role. However, examples of PCD during seed development are limited. The present review examines PCD in integuments, nucellus, suspensor and endosperm in those representative examples of seeds studied to date.

  17. Efficacy and implementation of an Internet psychoeducational program for teens with type 1 diabetes.

    PubMed

    Whittemore, Robin; Liberti, Lauren S; Jeon, Sangchoon; Chao, Ariana; Minges, Karl E; Murphy, Kathryn; Grey, Margaret

    2016-12-01

    The purpose of the study was to evaluate the participation and preliminary efficacy of an Internet psychoeducational program (Teens.Connect) shown to be efficacious under controlled conditions compared with an open-access diabetes website for youth (Planet D) on the primary outcomes of A1C and quality of life (QoL), and secondary outcomes of psychosocial and behavioral factors. Teens with type 1 diabetes (n = 124, 11-14 yr) from two clinical sites were randomly prescribed one of the programs and completed baseline, 3-month and 6-month data. A1C was obtained from clinic records. Participation data included number of log ins, posts to the discussion board, and lessons completed (Teens.Connect only). Descriptive and mixed model analyses were used. Eighty-five percent (85%) of consented teens registered for their prescribed program. Satisfaction and log ins were similar between groups (satisfaction ranged 3.3-3.5/5; mean log ins = 14/teen). Posts to the discussion forum were higher in Planet D (mean = 28 vs. 19). Participation in the Teens.Connect lessons was low, with only 69% of teens completing any lesson. After 6 months there were no significant differences in A1C, QoL or secondary outcomes between groups. Teens in the Teens.Connect group reported lower perceived stress over time (p < 0.01). Teens do not actively participate in an Internet psychoeducational program when they do not have frequent reminders, which may have contributed to a lack of treatment effect. Teens have many competing demands. Strategic implementation that includes targeted reminders and family support may be necessary to assure participation and improvement in health outcomes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Programmed cell death 50 (and beyond)

    PubMed Central

    Lockshin, R A

    2016-01-01

    In the 50 years since we described cell death as ‘programmed,' we have come far, thanks to the efforts of many brilliant researchers, and we now understand the mechanics, the biochemistry, and the genetics of many of the ways in which cells can die. This knowledge gives us the resources to alter the fates of many cells. However, not all cells respond similarly to the same stimulus, in either sensitivity to the stimulus or timing of the response. Cells prevented from dying through one pathway may survive, survive in a crippled state, or die following a different pathway. To fully capitalize on our knowledge of cell death, we need to understand much more about how cells are targeted to die and what aspects of the history, metabolism, or resources available to individual cells determine how each cell reaches and crosses the threshold at which it commits to death. PMID:26564398

  19. Programmed death phenomena: from organelle to organism.

    PubMed

    Skulachev, Vladimir P

    2002-04-01

    Programmed death phenomena appear to be inherent not only in living cells (apoptosis), but also in subcellular organelles (e.g., self-elimination of mitochondria, called mitoptosis), organs (organoptosis), and even whole organisms (phenoptosis). In all these cases, the "Samurai law of biology"--it is better to die than to be wrong--seems to be operative. The operation of this law helps complicated living systems avoid the risk of ruin when a system of lower hierarchic position makes a significant mistake. Thus, mitoptosis purifies a cell from damaged and hence unwanted mitochondria; apoptosis purifies a tissue from unwanted cells; and phenoptosis purifies a community from unwanted individuals. Defense against reactive oxygen species (ROS) is probably one of the primary evolutionary functions of programmed death mechanisms. So far, it seems that ROS play a key role in the mito-, apo-, organo-, and phenoptoses, which is consistent with Harman's theory of aging. Here a concept is described that tries to unite Weismann's hypothesis of aging as an adaptive programmed death mechanism and the generally accepted alternative point of view that considers aging as an inevitable result of accumulation in an organism of occasional injuries. It is suggested that injury accumulation is monitored by a system(s) actuating a phenoptotic death program when the number of injuries reaches some critical level. The system(s) in question are organized in such a way that the lethal case appears to be a result of phenoptosis long before the occasional injuries make impossible the functioning of the organism. It is stressed that for humans these cruel regulations look like an atavism that, if overcome, might dramatically prolong the human life span.

  20. Impact of disease-management programs on metabolic control in patients with type 1 diabetes mellitus

    PubMed Central

    Lin, Kun; Yang, Xiaoping; Wu, Yixi; Chen, Shuru; Yin, Guoshu; Zhan, Jianjun; Lin, Chujia; Xu, Wencan; Chen, Yongsong; Lin, Dan; Xie, Peiwen; Fang, Yishan; Lin, Qiuqiang; Lin, Shaoda

    2016-01-01

    Abstract The aim of this study is to evaluate the effect of diabetes disease management program (DMP) on glycemic control in type 1 diabetes mellitus (T1DM) patients in Shantou China. A sample of 240 participants recruited from 3C study Shantou subgroup was followed up in DMP for 3 years. The DMP provided self-management education, individualized therapy plan, diabetes complications screening, and laboratory examination periodical according to clinical practice guidelines. Primary outcomes were changes in hemoglobin A1C (HbA1c). Two hundred one of the participants completed the follow-up. There was a significant decrease in the HbA1c levels after DMP implemented. The mean (± SD) pre- and post-intervention HbA1c levels were 10.26% ± 3.30% and 8.57% ± 1.57% respectively with a P value <0.001. General linear mixed model analyse demonstrated that changes in glycemic control were associated with insulin treatment regimen, frequency of Self-Monitoring of Blood Glucose (SMBG), diabetes diet adherence, physical activity, and duration of diabetes. DMP helped to improve glycemic control and should be general implemented in China's T1DM. Individuals with basal-bolus regimen (multiple daily injections or pump therapy), more frequency of SMBG, following a diabetes diet, more physical activity, shorter diabetes duration may derive greater benefits from DMP. PMID:28033258

  1. Programmed cell death during quinoa perisperm development.

    PubMed

    López-Fernández, María Paula; Maldonado, Sara

    2013-08-01

    At seed maturity, quinoa (Chenopodium quinoa Willd.) perisperm consists of uniform, non-living, thin-walled cells full of starch grains. The objective of the present study was to study quinoa perisperm development and describe the programme of cell death that affects the entire tissue. A number of parameters typically measured during programmed cell death (PCD), such as cellular morphological changes in nuclei and cytoplasm, endoreduplication, DNA fragmentation, and the participation of nucleases and caspase-like proteases in nucleus dismantling, were evaluated; morphological changes in cytoplasm included subcellular aspects related to starch accumulation. This study proved that, following fertilization, the perisperm of quinoa simultaneously accumulates storage reserves and degenerates, both processes mediated by a programme of developmentally controlled cell death. The novel findings regarding perisperm development provide a starting point for further research in the Amaranthaceae genera, such as comparing seeds with and without perisperm, and specifying phylogeny and evolution within this taxon. Wherever possible and appropriate, differences between quinoa perisperm and grass starchy endosperm--a morphologically and functionally similar, although genetically different tissue--were highlighted and discussed.

  2. Programmed cell death during quinoa perisperm development

    PubMed Central

    Maldonado, Sara

    2013-01-01

    At seed maturity, quinoa (Chenopodium quinoa Willd.) perisperm consists of uniform, non-living, thin-walled cells full of starch grains. The objective of the present study was to study quinoa perisperm development and describe the programme of cell death that affects the entire tissue. A number of parameters typically measured during programmed cell death (PCD), such as cellular morphological changes in nuclei and cytoplasm, endoreduplication, DNA fragmentation, and the participation of nucleases and caspase-like proteases in nucleus dismantling, were evaluated; morphological changes in cytoplasm included subcellular aspects related to starch accumulation. This study proved that, following fertilization, the perisperm of quinoa simultaneously accumulates storage reserves and degenerates, both processes mediated by a programme of developmentally controlled cell death. The novel findings regarding perisperm development provide a starting point for further research in the Amaranthaceae genera, such as comparing seeds with and without perisperm, and specifying phylogeny and evolution within this taxon. Wherever possible and appropriate, differences between quinoa perisperm and grass starchy endosperm—a morphologically and functionally similar, although genetically different tissue—were highlighted and discussed. PMID:23833197

  3. Hemoglobins, programmed cell death and somatic embryogenesis.

    PubMed

    Hill, Robert D; Huang, Shuanglong; Stasolla, Claudio

    2013-10-01

    Programmed cell death (PCD) is a universal process in all multicellular organisms. It is a critical component in a diverse number of processes ranging from growth and differentiation to response to stress. Somatic embryogenesis is one such process where PCD is significantly involved. Nitric oxide is increasingly being recognized as playing a significant role in regulating PCD in both mammalian and plant systems. Plant hemoglobins scavenge NO, and evidence is accumulating that events that modify NO levels in plants also affect hemoglobin expression. Here, we review the process of PCD, describing the involvement of NO and plant hemoglobins in the process. NO is an effector of cell death in both plants and vertebrates, triggering the cascade of events leading to targeted cell death that is a part of an organism's response to stress or to tissue differentiation and development. Expression of specific hemoglobins can alter this response in plants by scavenging the NO, thus, interrupting the death process. Somatic embryogenesis is used as a model system to demonstrate how cell-specific expression of different classes of hemoglobins can alter the embryogenic process, affecting hormone synthesis, cell metabolite levels and genes associated with PCD and embryogenic competence. We propose that plant hemoglobins influence somatic embryogenesis and PCD through cell-specific expression of a distinct plant hemoglobin. It is based on the premise that both embryogenic competence and PCD are strongly influenced by cellular NO levels. Increases in cellular NO levels result in elevated Zn(2+) and reactive-oxygen species associated with PCD, but they also result in decreased expression of MYC2, a transcription factor that is a negative effector of indoleacetic acid synthesis, a hormone that positively influences embryogenic competence. Cell-specific hemoglobin expression reduces NO levels as a result of NO scavenging, resulting in cell survival. Copyright © 2013 Elsevier Ireland Ltd

  4. Causes of death due to hematological and non-hematological cancers in 57 US patients with type 1 Gaucher Disease who were never treated with enzyme replacement therapy.

    PubMed

    Weinreb, Neal J; Lee, Robert E

    2013-01-01

    Patients with type 1 Gaucher disease (GD1) have increased risk of developing myeloma, other hematological cancers, hepatocellular carcinoma, and other solid tumors. Patient awareness of the GD1-cancer association causes anxiety and fear. Little is known about cancer as a cause of death in GD1, especially in patients never treated with GD1-specific therapies. Consequently, the effect of treatment on cancer mortality in GD1 patients is difficult to evaluate. In this review, starting with a population of 184 GD1 cases never treated, we annotate and analyze the causes of death of 57 GD1 patients who died of cancer. The proportional mortality ratio (PMR) for all malignancies in patients with GD1 is 1.57 (p = 0.0002), but it is much higher for myeloma (PMR = 9.66) and other hematological cancers, hepatocellular carcinoma, and kidney cancer (PMR = ≍4). However, deaths from colorectal and pancreatic cancers were not more frequent than expected, and deaths from lung, breast, gynecological, and prostate cancer occurred less than anticipated. Herein, we discuss whether GD1 is truly a hereditary cancer syndrome and the problem of comorbidities and cancer risk assessment, and we speculate as to whether the variability in death by cancer type might be attributable to biochemical sequelae of tumor cell and macrophage/stromal cell GBA1 mutation affecting signals for metastasis, the process most closely associated with cancer mortality.

  5. Development of a Quantitative Methylation-Specific Polymerase Chain Reaction Method for Monitoring Beta Cell Death in Type 1 Diabetes

    PubMed Central

    Husseiny, Mohamed I.; Kuroda, Akio; Kaye, Alexander N.; Nair, Indu; Kandeel, Fouad; Ferreri, Kevin

    2012-01-01

    DNA methylation is a mechanism by which cells control gene expression, and cell-specific genes often exhibit unique patterns of DNA methylation. We previously reported that the mouse insulin-2 gene (Ins2) promoter has three potential methylation (CpG) sites, all of which are unmethylated in insulin-producing cells but methylated in other tissues. In this study we examined Ins2 exon 2 and found a similar tissue-specific methylation pattern. These methylation patterns can differentiate between DNA from insulin-producing beta cells and other tissues. We hypothesized that damaged beta cells release their DNA into circulation at the onset of type 1 diabetes mellitus (T1DM) and sought to develop a quantitative methylation-specific polymerase chain reaction (qMSP) assay for circulating beta cell DNA to monitor the loss of beta cells. Methylation-specific primers were designed to interrogate two or more CpG in the same assay. The cloned mouse Ins2 gene was methylated in vitro and used for development of the qMSP assay. We found the qMSP method to be sensitive and specific to differentiate between insulin-producing cells and other tissues with a detection limit of 10 copies in the presence of non-specific genomic DNA background. We also compared different methods for data analysis and found that the Relative Expression Ratio method is the most robust method since it incorporates both a reference value to normalize day-to-day variability as well as PCR reaction efficiencies to normalize between the methylation-specific and bisulfite-specific components of the calculations. The assay was applied in the streptozotocin-treated diabetic mouse model and detected a significant increase in circulating beta cell DNA before the rise in blood glucose level. These results demonstrate that this qMSP assay can be used for monitoring circulating DNA from insulin-producing cells, which will provide the basis for development of assays to detect beta cell destruction in early T1DM. PMID

  6. The type 1 Interleukin 1 receptor is not required for the death of murine hippocampal dentate granule cells and microglia activation

    PubMed Central

    Harry, G. Jean; Funk, Jason; Lefebvre d’Hellencourt, Christian; Aoyama, Mineyoshi

    2008-01-01

    Alterations in the inflammatory process, neuronal death, and glia response have been observed under manipulation of the interleukin-1 (IL-1) cytokine and subsequent signaling through the type 1 IL-1 receptor (IL-1R1). To investigate the influence of IL-1R1 activation in the pathophysiology of a chemical-induced injury to the murine hippocampus, we examined the level and pattern of neuronal death and neuroinflammation in 25-day-old male mice exposed to trimethyltin hydroxide (2.0 mg/kg, i.p.). In IL-1R1 null (IL-1R1−/−) mice, the pattern and severity of dentate granule cell death was similar as compared to wild type mice. In both groups of mice, mRNA levels for TNFα and MIP-1α were elevated and the early activation of microglia, including their ability to progress to a phagocytic phenotype, was maintained. Compared to WT mice, IL-1R1−/− mice displayed a limited glial fibrillary acidic protein (GFAP) astrocytic response, as well as a preferential induction in mRNA levels of Fas signaling components. Cumulatively, these results indicate that IL-1R1 activation is not necessary for TMT-induced death of dentate granule neurons or local activation of microglia; however, IL-1R1 signaling is involved in mediating the structural response of astrocytes to injury and may also regulate apoptotic mechanisms by influencing Fas signaling components. PMID:18191113

  7. Programmed Cell Death in Unicellular Phytoplankton.

    PubMed

    Bidle, Kay D

    2016-07-11

    Unicellular, planktonic, prokaryotic and eukaryotic photoautotrophs (phytoplankton) have an ancient evolutionary history on Earth during which time they have played key roles in the regulation of marine food webs, biogeochemical cycles, and Earth's climate. Since they represent the basis of aquatic ecosystems, the manner in which phytoplankton die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining nutrient flow. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of abiotic (nutrient, light, osmotic) and biotic (virus infection, allelopathy) environmental stresses, have an integral grip on cell fate, and have shaped the ecological success and evolutionary trajectory of diverse phytoplankton lineages. A combination of physiological, biochemical, and genetic techniques in model algal systems has demonstrated a conserved molecular and mechanistic framework of stress surveillance, signaling, and death activation pathways, involving collective and coordinated participation of organelles, redox enzymes, metabolites, and caspase-like proteases. This mechanistic understanding has provided insight into the integration of sensing and transduction of stress signals into cellular responses, and the mechanistic interfaces between PCD, cell stress and virus infection pathways. It has also provided insight into the evolution of PCD in unicellular photoautotrophs, the impact of PCD on the fate of natural phytoplankton assemblages and its role in aquatic biogeochemical cycles.

  8. Normal development, oncogenesis and programmed cell death.

    PubMed

    Liebermann, D A

    1998-09-10

    Meeting's Report -- June 2, 1998, Sugarload Estate Conference Center, Philadelphia, Pennsylvania, USA. A symposium on Normal Development, Oncogenesis and Programmed Cell Death, was held at the Sugarload Estate Conference Center, Philadelphia, Pennsylvania, USA sponsored by the Fels Cancer Institute, Temple University School of Medicine, with the support of the Alliance Pharmaceutical Corporation. The symposium was organized by Drs Dan A Liebermann and Barbara Hoffman at the Fels. Invited speakers included: Dr Andrei V Gudkov (University of Illinois) who started the symposium talking about 'New cellular factors modulating the tumor suppressor function of p53'; Dr Yuri Lazebnik (Cold Spring Harbor Laboratories) spoke about 'Caspases considered as enemies within'; Dr E Premkumar Reddy (Fels Institute, Temple University) talked about recent exciting findings in his laboratory regarding 'JAK-STATs dedicated signaling pathways'; Dr Michael Greenberg (Harvard University) spoke about 'Signal transduction pathways that regulate differentiation and survival in the developing nervous system'; Dr Richard Kolesnick's (Memorial Sloan-Kettering Cancer Center) talk has been focused at 'Stress signals for apoptosis, including Ceramide and c-Jun Kinase/Stress-activated Protein Kinase'; Dr Barbara Hoffman (Fels Institute, Temple University) described research, conducted in collaboration with Dr Dan A Liebermann, aimed at deciphering the roles of 'myc, myb, and E2F as negative regulators of terminal differentiation', using hematopoietic cells as model system. Dr Daniel G Tenen (Harvard Medical School), described studies aimed at understanding the 'Regulation of hematopoietic cell development by lineage specific transcription regulators'. Dr George C Prendergast (The Wistar Institute) talked about the 'Myc-Bin1 signaling pathway in cell death and differentiation. Dr Ruth J Muschel (University of Pennsylvania) spoke about work, conducted in collaboration with Dr WG McKenna, aimed at

  9. The Fas death pathway controls coordinated expansions of type 1 CD8 and type 2 CD4 T cells in Trypanosoma cruzi infection.

    PubMed

    Guillermo, Landi V Costilla; Silva, Elisabeth M; Ribeiro-Gomes, Flávia L; De Meis, Juliana; Pereira, Wânia F; Yagita, Hideo; DosReis, George A; Lopes, Marcela F

    2007-04-01

    We investigated the role of the Fas ligand (FasL)/Fas death pathway on apoptosis and cytokine production by T cells in Trypanosoma cruzi infection. Anti-FasL, but not anti-TNF-alpha or anti-TRAIL, blocked activation-induced cell death of CD8 T cells and increased secretion of IL-10 and IL-4 by CD4 T cells from T. cruzi-infected mice. CD4 and CD8 T cells up-regulated Fas/FasL expression during T. cruzi infection. However, Fas expression increased earlier in CD8 T cells, and a higher proportion of CD8 T cells was activated and expressed IFN-gamma compared with CD4 T cells. Injection of anti-FasL in infected mice reduced parasitemia and CD8 T cell apoptosis and increased the ratio of CD8:CD4 T cells recovered from spleen and peritoneum. FasL blockade increased the number of activated T cells, enhanced NO production, and reduced parasite loads in peritoneal macrophages. Injection of anti-FasL increased IFN-gamma secretion by splenocytes responding to T. cruzi antigens but also exacerbated production of type 2 cytokines IL-10 and IL-4 at a late stage of acute infection. These results indicate that the FasL/Fas death pathway regulates apoptosis and coordinated cytokine responses by type 1 CD8 and type 2 CD4 T cells in T. cruzi infection.

  10. Predictive Efficacy Biomarkers of Programmed Cell Death 1/Programmed Cell Death 1 Ligand Blockade Therapy.

    PubMed

    Fang, Xiao-Na; Fu, Li-Wu

    2016-01-01

    Inhibitors of immune check-point molecule, programmed cell death 1 (PD-1) and its ligand, programmed cell death ligand 1 (PD-L1) have attracted much attention in cancer immunotherapy recently due to their durable antitumor effects in various malignances, especially the advanced ones. Unfortunately, only a fraction of patients with advanced tumors could benefit from anti-PD-1/PD-L1 therapy, while others still worsened. The key to this point is that there are no efficient biomarkers for screening anti-PD-1/PD-L1-sensitive patients. In this review, we aim at summarizing the latest advances of anti-PD-1/PDL1 immunotherapy and the potential predictive efficacy biomarkers to provide evidences for identifying anti-PD-1/PDL1- sensitive patients. The present article also includes the patent review coverage on this topic.

  11. Programming of adiposity in offspring of mothers with type 1 diabetes at age 7 years.

    PubMed

    Lindsay, Robert S; Nelson, Scott M; Walker, James D; Greene, Stephen A; Milne, Gillian; Sattar, Naveed; Pearson, Donald W

    2010-05-01

    The goals of this study were to examine the influence of maternal type 1 diabetes during pregnancy on offspring adiposity and glucose tolerance at age 7 years and to assess whether metabolic factors at birth (neonatal leptin and insulin) predict adverse outcomes. We examined 100 offspring of mothers with type 1 diabetes (OT1DM) and 45 offspring of control mothers. Mothers had previously been recruited during pregnancy, and, where possible, birth weight, umbilical cord insulin, and leptin were measured. Children were classed as overweight and obese using age-specific reference ranges. OT1DM had similar height (control, 1.25 +/- 0. 06 m; OT1DM, 1.24 +/- 0.06 m; P = 0.81) but were heavier (control, 25.5 +/- 3.8 kg; OT1DM, 27.1 +/- 5.7 kg; P = 0.048) and had an increased BMI (control, 16.4 kg/m(2); OT1DM, 17.4 +/- 2.6 kg/m(2), P = 0.005). Waist circumference (control, 56.0 +/- 3.7 cm; OT1DM, 58 +/- 6.8 cm; P = 0.02) and sum of skinfolds were increased (control, 37.5 +/- 17.0 mm [n = 42]; OT1DM, 46.1 +/- 24.2 mm [n = 91]; P = 0.02), and there was a marked increase in the prevalence of overweight and obese children (OT1DM, 22% overweight and 12% obese; control, 0% overweight and 7% obese; chi(2) P = 0.001). Glucose tolerance was not different compared with that in control subjects. BMI at age 7 years correlated with cord leptin (OT1DM, r = 0.25; n = 61, P = 0.047), weakly with adjusted birth weight (r = 0.19; P = 0.06) and hematocrit (r = 0.25; n = 50, P = 0.07), but not cord insulin (OT1DM, r = -0.08; P = 0.54). OT1DM are at increased risk of overweight and obesity in childhood. This risk appears to relate, in part, to fetal leptin and hematocrit but not insulin.

  12. Redox regulation in plant programmed cell death.

    PubMed

    De Pinto, M C; Locato, V; De Gara, L

    2012-02-01

    Programmed cell death (PCD) is a genetically controlled process described both in eukaryotic and prokaryotic organisms. Even if it is clear that PCD occurs in plants, in response to various developmental and environmental stimuli, the signalling pathways involved in the triggering of this cell suicide remain to be characterized. In this review, the main similarities and differences in the players involved in plant and animal PCD are outlined. Particular attention is paid to the role of reactive oxygen species (ROS) as key inducers of PCD in plants. The involvement of different kinds of ROS, different sites of ROS production, as well as their interaction with other molecules, is crucial in activating PCD in response to specific stimuli. Moreover, the importance is stressed on the balance between ROS production and scavenging, in various cell compartments, for the activation of specific steps in the signalling pathways triggering this cell suicide process. The review focuses on the complexity of the interplay between ROS and antioxidant molecules and enzymes in determining the most suitable redox environment required for the occurrence of different forms of PCD. © 2011 Blackwell Publishing Ltd.

  13. Programmed death 1 immune checkpoint inhibitors.

    PubMed

    Trivedi, Meghna S; Hoffner, Brianna; Winkelmann, Jennifer L; Abbott, Maura E; Hamid, Omid; Carvajal, Richard D

    2015-12-01

    Programmed death 1 (PD-1) is an immune checkpoint that provides inhibitory signals to the immune system in order to modulate the activity of T cells in peripheral tissues and maintain self-tolerance in the setting of infection and inflammation. In cancer, the immune checkpoints are exploited so that the tumor cells are able to evade the immune system. Immune checkpoint inhibitors are a type of cancer immunotherapy that targets pathways such as PD-1 in order to reinvigorate and enhance the immune response against tumor cells. The US Food and Drug Administration (FDA) has approved 2 PD-1 inhibitors, nivolumab and pembrolizumab, and several others are under investigation. Although PD-1 inhibitors have demonstrated activity in many different types of malignancies, FDA approval has been granted only in melanoma and in non-small cell lung cancer (NSCLC). Identifying biomarkers that can predict response to PD-1 inhibitors is critical to maximizing the benefit of these agents. Future directions for PD-1 inhibitors include investigation of combination therapies, use in malignancies other than melanoma and NSCLC, and refinement of biomarkers.

  14. Programmed Cell Death-1/Programmed Death-ligand 1 Pathway: A New Target for Sepsis.

    PubMed

    Liu, Qiang; Li, Chun-Sheng

    2017-04-20

    Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment. Studies of the association between PD-1/PD-L1 and sepsis published up to January 31, 2017, were obtained by searching the PubMed database. English language studies, including those based on animal models, clinical research, and reviews, with data related to PD-1/PD-L1 and sepsis, were evaluated. Immunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of the PD-1/PD-L1 pathway could reduce the exhaustion of T-cells and enhance the proliferation and activation of T-cells. The anti-PD-1/PD-L1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and future studies aimed at revaluating the efficacy and safety of this targeted approach.

  15. Programmed cell death in the plant immune system.

    PubMed

    Coll, N S; Epple, P; Dangl, J L

    2011-08-01

    Cell death has a central role in innate immune responses in both plants and animals. Besides sharing striking convergences and similarities in the overall evolutionary organization of their innate immune systems, both plants and animals can respond to infection and pathogen recognition with programmed cell death. The fact that plant and animal pathogens have evolved strategies to subvert specific cell death modalities emphasizes the essential role of cell death during immune responses. The hypersensitive response (HR) cell death in plants displays morphological features, molecular architectures and mechanisms reminiscent of different inflammatory cell death types in animals (pyroptosis and necroptosis). In this review, we describe the molecular pathways leading to cell death during innate immune responses. Additionally, we present recently discovered caspase and caspase-like networks regulating cell death that have revealed fascinating analogies between cell death control across both kingdoms.

  16. New Areas for Preventive Programing: Sudden Infant Death Syndrome.

    ERIC Educational Resources Information Center

    Lowman, Joseph

    Crisis intervention programs for persons experiencing the sudden death of family members or surviving natural disasters have been advocated as methods of primary prevention, although few have actually been implemented. A program utilizing nurses to deliver grief intervention to parents losing a baby to Sudden Infant Death Syndrome (SIDS) was…

  17. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1.

    PubMed

    Wahbi, Karim; Babuty, Dominique; Probst, Vincent; Wissocque, Ludivine; Labombarda, Fabien; Porcher, Raphaël; Bécane, Henri Marc; Lazarus, Arnaud; Béhin, Anthony; Laforêt, Pascal; Stojkovic, Tanya; Clementy, Nicolas; Dussauge, Aurélie Pattier; Gourraud, Jean Baptiste; Pereon, Yann; Lacour, Arnaud; Chapon, Françoise; Milliez, Paul; Klug, Didier; Eymard, Bruno; Duboc, Denis

    2017-03-07

    To describe the incidence and identify predictors of sudden death (SD), major conduction defects and sustained ventricular tachyarrhythmias (VTA) in myotonic dystrophy type 1 (DM1). We retrospectively enrolled 1388 adults with DM1 referred to six French medical centres between January 2000 and October 2013. We confirmed their vital status, classified all deaths, and determined the incidence of major conduction defects requiring permanent pacing and sustained VTA. We searched for predictors of overall survival, SD, major conduction defects, and sustained VTA by Cox regression analysis. Over a median 10-year follow-up, 253 (18.2%) patients died, 39 (3.6%) suddenly. Analysis of the cardiac rhythm at the time of the 39 SD revealed sustained VTA in 9, asystole in 5, complete atrioventricular block in 1 and electromechanical dissociation in two patients. Non-cardiac causes were identified in the five patients with SD who underwent autopsies. Major conduction defects developed in 143 (19.3%) and sustained VTA in 26 (2.3%) patients. By Cox regression analysis, age, family history of SD and left bundle branch block were independent predictors of SD, while age, male sex, electrocardiographic conduction abnormalities, syncope, and atrial fibrillation were independent predictors of major conduction defects; non-sustained VTA was the only predictor of sustained VTA. SD was a frequent mode of death in DM1, with multiple mechanisms involved. Major conduction defects were by far more frequent than sustained VTA, whose only independent predictor was a personal history of non-sustained VTA. ClinicalTrials.gov no: NCT01136330.

  18. Self-management problem solving for adolescents with type 1 diabetes: intervention processes associated with an Internet program.

    PubMed

    Mulvaney, Shelagh A; Rothman, Russell L; Osborn, Chandra Y; Lybarger, Cindy; Dietrich, Mary S; Wallston, Kenneth A

    2011-11-01

    Describe intervention processes associated with an Internet self-management problem solving program for adolescents with type 1 diabetes, and relate participant characteristics to program use. Forty-one adolescents with type 1 diabetes, aged 13-17, participated in an Internet intervention. Participants reported psychosocial self-management barriers related to social issues (45%), time pressures (22%), and emotions (25%). Most adolescents (76%) completed the two guided problem solving cycles, and most (97%) problems were appropriate and specific to diabetes. Of the 61 diabetes problems reported, 92% were mostly or completely solved. Baseline hemoglobin A1c, diabetes duration, and age were not related to online activities, however females posted more often to the forum (U=130.0, Z=2.13, p=.033). The majority of parents (87%) interacted with their child about the website. Adolescents experience psychosocial barriers to self-management that can be addressed by teaching problem solving via the Internet. An Internet self-management problem solving program with minimal external support provides a viable option for diabetes clinics to improve pediatric diabetes outcomes. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  19. Regulation of Neuroinflammation through Programed Death-1/Programed Death Ligand Signaling in Neurological Disorders

    PubMed Central

    Zhao, Shangfeng; Li, Fengwu; Leak, Rehana K.; Chen, Jun; Hu, Xiaoming

    2014-01-01

    Immune responses in the central nervous system (CNS), which involve both resident glial cells and infiltrating peripheral immune cells, play critical roles in the progress of brain injuries and neurodegeneration. To avoid inflammatory damage to the compromised brain, the immune cell activities in the CNS are controlled by a plethora of chemical mediators and signal transduction cascades, such as inhibitory signaling through programed death-1 (PD-1) and programed death ligand (PD-L) interactions. An increasing number of recent studies have highlighted the importance of PD-1/PD-L pathway in immune regulation in CNS disorders such as ischemic stroke, multiple sclerosis, and Alzheimer’s disease. Here, we review the current knowledge of the impact of PD-1/PD-L signaling on brain injury and neurodegeneration. An improved understanding of the function of PD-1/PD-L in the cross-talk between peripheral immune cells, CNS glial cells, and non-immune CNS cells is expected to shed further light on immunomodulation and help develop effective and safe immunotherapies for CNS disorders. PMID:25232304

  20. Programmed cell death for defense against anomaly and tumor formation

    SciTech Connect

    Kondo, Sohei; Norimura, Toshiyuki; Nomura, Taisei

    1995-12-31

    Cell death after exposure to low-level radiation is often considered evidence that radiation is poisonous, however small the dose. Evidence has been accumulating to support the notion that cell death after low-level exposure to radiation results from activation of suicidal genes {open_quote}programmed cell death{close_quote} or {open_quote}apoptosis{close_quote} - for the health of the whole body. This paper gives experimental evidence that embryos of fruit flies and mouse fetuses have potent defense mechanisms against teratogenic or tumorigenic injury caused by radiation and carcinogens, which function through programmed cell death.

  1. Centenarian Rates and Life Expectancy Related to the Death Rates of Multiple Sclerosis, Asthma, and Rheumatoid Arthritis and the Incidence of Type 1 Diabetes in Children.

    PubMed

    Lens-Pechakova, Lilia S

    2016-02-01

    The autoimmune diseases are among the 10 leading causes of death for women and the number two cause of chronic illness in America as well as a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter life span and are a model of accelerated immunosenescence. Conversely, centenarians are used as a model of successful aging and have shown several immune parameters that are better preserved and lower levels of autoantibodies. The study reported here focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed Organisation for Economic Co-operation and Development (OECD) countries, because multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relationship pattern, help to identify common factors, and determine new important factors that contribute to longevity and healthy aging. The relationships between the mortality rates data of multiple sclerosis (MS), rheumatoid arthritis (RA), asthma, the incidence of type 1 diabetes (T1D) from one side and centenarian rates (two sets) as well as life expectancy data from the other side were assessed using regression models and Pearson correlation coefficients. The data obtained correspond to an inverse linear correlation with different degrees of linearity. This is the first observation of a clear tendency of diminishing centenarian rates or life expectancy in countries having higher death rates of asthma, MS, and RA and a higher incidence of T1D in children. The conclusion is that most probably there are common mechanistic pathways and factors affecting the above diseases and at the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways, and other factors connected to autoimmune diseases with those of longevity could clarify the processes involved, so as to promote longevity and limit the expansion of those

  2. Programming stress-induced altruistic death in engineered bacteria

    PubMed Central

    Tanouchi, Yu; Pai, Anand; Buchler, Nicolas E; You, Lingchong

    2012-01-01

    Programmed death is often associated with a bacterial stress response. This behavior appears paradoxical, as it offers no benefit to the individual. This paradox can be explained if the death is ‘altruistic': the killing of some cells can benefit the survivors through release of ‘public goods'. However, the conditions where bacterial programmed death becomes advantageous have not been unambiguously demonstrated experimentally. Here, we determined such conditions by engineering tunable, stress-induced altruistic death in the bacterium Escherichia coli. Using a mathematical model, we predicted the existence of an optimal programmed death rate that maximizes population growth under stress. We further predicted that altruistic death could generate the ‘Eagle effect', a counter-intuitive phenomenon where bacteria appear to grow better when treated with higher antibiotic concentrations. In support of these modeling insights, we experimentally demonstrated both the optimality in programmed death rate and the Eagle effect using our engineered system. Our findings fill a critical conceptual gap in the analysis of the evolution of bacterial programmed death, and have implications for a design of antibiotic treatment. PMID:23169002

  3. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy.

    PubMed

    Naidoo, Jarushka; Wang, Xuan; Woo, Kaitlin M; Iyriboz, Tunc; Halpenny, Darragh; Cunningham, Jane; Chaft, Jamie E; Segal, Neil H; Callahan, Margaret K; Lesokhin, Alexander M; Rosenberg, Jonathan; Voss, Martin H; Rudin, Charles M; Rizvi, Hira; Hou, Xue; Rodriguez, Katherine; Albano, Melanie; Gordon, Ruth-Ann; Leduc, Charles; Rekhtman, Natasha; Harris, Bianca; Menzies, Alexander M; Guminski, Alexander D; Carlino, Matteo S; Kong, Benjamin Y; Wolchok, Jedd D; Postow, Michael A; Long, Georgina V; Hellmann, Matthew D

    2017-03-01

    Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion

  4. Nitric Oxide-induced Activation of the Type 1 Ryanodine Receptor Is Critical for Epileptic Seizure-induced Neuronal Cell Death.

    PubMed

    Mikami, Yoshinori; Kanemaru, Kazunori; Okubo, Yohei; Nakaune, Takuya; Suzuki, Junji; Shibata, Kazuki; Sugiyama, Hiroki; Koyama, Ryuta; Murayama, Takashi; Ito, Akihiro; Yamazawa, Toshiko; Ikegaya, Yuji; Sakurai, Takashi; Saito, Nobuhito; Kakizawa, Sho; Iino, Masamitsu

    2016-09-01

    Status epilepticus (SE) is a life-threatening emergency that can cause neurodegeneration with debilitating neurological disorders. However, the mechanism by which convulsive SE results in neurodegeneration is not fully understood. It has been shown that epileptic seizures produce markedly increased levels of nitric oxide (NO) in the brain, and that NO induces Ca(2+) release from the endoplasmic reticulum via the type 1 ryanodine receptor (RyR1), which occurs through S-nitrosylation of the intracellular Ca(2+) release channel. Here, we show that through genetic silencing of NO-induced activation of the RyR1 intracellular Ca(2+) release channel, neurons were rescued from seizure-dependent cell death. Furthermore, dantrolene, an inhibitor of RyR1, was protective against neurodegeneration caused by SE. These results demonstrate that NO-induced Ca(2+) release via RyR is involved in SE-induced neurodegeneration, and provide a rationale for the use of RyR1 inhibitors for the prevention of brain damage following SE.

  5. A focused preconceptional and early pregnancy program in women with type 1 diabetes reduces perinatal mortality and malformation rates to general population levels.

    PubMed

    McElvy, S S; Miodovnik, M; Rosenn, B; Khoury, J C; Siddiqi, T; Dignan, P S; Tsang, R C

    2000-01-01

    To evaluate the impact of a focused preconceptional and early pregnancy program specializing in the care of women with Type 1 diabetes on perinatal mortality and congenital malformations. This clinical study included women with Type 1 diabetes in an interdisciplinary Diabetes in Pregnancy Program Project Grant (PPG) funded by the NIH (1978-1993); these women were enrolled preconceptionally or during the first trimester (up to 14 weeks) and had pregnancies continuing beyond 20 weeks gestation. Strict glucose control was implemented and adherence assessed. Antepartum fetal surveillance was started at 32 weeks gestation. All live-born infants and stillbirths were examined. A retrospective comparison analysis of the period before PPG I (1973-1978) and after cessation of funding (1993-1999) was performed, specifically evaluating perinatal mortality and congenital malformation rates. Data were analyzed using analysis of variance, chi2, and Fisher's exact test. Three hundred and six women were enrolled in three 5-year periods: PPG I (1978-1983) n = 111, PPG II (1983-1988) n = 103, and PPG III (1988-1993) n = 92. Entry and interval glycohemoglobin A1 concentrations obtained decreased with each consecutive PPG. An emphasis on preconception care began in 1984, with preconception enrollment reaching 23% for PPG II and increasing in PPG III to 37%. As preconception enrollment increased, perinatal mortality rate decreased from 3% for PPG I and 2% for PPG II, to 0% in PPG III, and the congenital malformation rate decreased to a low 2.2% by PPG III. Comparison data collected for the period before PPG 1 (1973-1978) n = 79 revealed a perinatal mortality rate of 7% and a congenital malformation rate of 14%. Also, a postprogram retrospective analysis of the period 1993-1999 (n = 82) revealed an increase in perinatal mortality, with one death compared to none in PPG III, and a congenital malformation rate of 3.65% compared to 2.2% during PPG III. The preconception enrollment for this

  6. Death Education in Paramedic Programs: A Nationwide Assessment.

    ERIC Educational Resources Information Center

    Smith, Tracy L.; Walz, Bruce J.

    1995-01-01

    A self-administered survey was sent to all U.S. paramedic programs (n=537) concerning aspects of death education, including method of instruction, educational supplements, assessment techniques, and integration into general course work. Of the 51% that responded, 95% offered death education, with the most common subjects being legal and ethical…

  7. Anti program death-1/anti program death-ligand 1 in digestive cancers

    PubMed Central

    de Guillebon, Eléonore; Roussille, Pauline; Frouin, Eric; Tougeron, David

    2015-01-01

    Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program death-1 (PD-1) and program death-ligand 1 (PD-L1) will lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs), called immune checkpoint inhibitors (ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L1 mAbs (MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase II will start soon. In metastatic colorectal cancer (CRC), a phase III trial of MPDL3280A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration (i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection of patients likely to benefit from ICIs. PMID:26306141

  8. Anti program death-1/anti program death-ligand 1 in digestive cancers.

    PubMed

    de Guillebon, Eléonore; Roussille, Pauline; Frouin, Eric; Tougeron, David

    2015-08-15

    Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program death-1 (PD-1) and program death-ligand 1 (PD-L1) will lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs), called immune checkpoint inhibitors (ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L1 mAbs (MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase II will start soon. In metastatic colorectal cancer (CRC), a phase III trial of MPDL3280A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration (i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection of patients likely to benefit from ICIs.

  9. Programmed cell death as a defence against infection.

    PubMed

    Jorgensen, Ine; Rayamajhi, Manira; Miao, Edward A

    2017-03-01

    Eukaryotic cells can die from physical trauma, which results in necrosis. Alternatively, they can die through programmed cell death upon the stimulation of specific signalling pathways. In this Review, we discuss the role of different cell death pathways in innate immune defence against bacterial and viral infection: apoptosis, necroptosis, pyroptosis and NETosis. We describe the interactions that interweave different programmed cell death pathways, which create complex signalling networks that cross-guard each other in the evolutionary 'arms race' with pathogens. Finally, we describe how the resulting cell corpses - apoptotic bodies, pore-induced intracellular traps (PITs) and neutrophil extracellular traps (NETs) - promote the clearance of infection.

  10. A Randomized Controlled Trial of an Internet-Based Mentoring Program for Type 1 Diabetes Patients with Inadequate Glycemic Control

    PubMed Central

    Suh, Sunghwan; Jean, Cheol; Koo, Mihyun; Lee, Sun Young; Cho, Min Ja; Sim, Kang-Hee; Jin, Sang-Man; Bae, Ji Cheol

    2014-01-01

    Background To determine whether an internet-based mentoring program can improve glycemic control in subjects with type 1 diabetes mellitus (T1DM). Methods Subjects with T1DM on intensive insulin therapy and with hemoglobin A1c (HbA1c) ≥8.0% were randomized to mentored (glucometer transmission with feedback from mentors) or control (glucometer transmission without feedback) groups and were examined for 12 weeks. Five mentors were interviewed and selected, of which two were T1DM patients themselves and three were parents with at least one child diagnosed with T1DM since more than 5 years ago. Results A total of 57 T1DM adult subjects with a mean duration after being diagnosed with diabetes of 7.4 years were recruited from Samsung Medical Center. Unfortunately, the mentored group failed to show significant improvements in HbA1c levels or other outcomes, including the quality of life, after completion of the study. However, the mentored group monitored their blood glucose (1.41 vs. 0.30) and logged into our website (http://ubisens.co.kr/) more frequently (20.59 times vs. 5.07 times) than the control group. Conclusion A 12-week internet-based mentoring program for T1DM patients with inadequate glycemic control did not prove to be superior to the usual follow-up. However, the noted increase in the subjects' frequency of blood glucose monitoring may lead to clinical benefits. PMID:24851207

  11. Reliable Method for Detection of Programmed Cell Death in Yeast

    PubMed Central

    Teng, Xinchen; Hardwick, J. Marie

    2011-01-01

    Summary Accumulating evidence suggests that yeasts are capable of undergoing programmed cell death (PCD) to benefit long-term survival of the species, and that yeast and mammals may share at least partially conserved PCD pathways. In our experience, mammalian apoptosis assays have not been readily applicable to yeast. Therefore, to take advantage of yeast as a genetic tool to study PCD, we developed a yeast cell death assay that can reliably reveal viability differences between wild-type strains and strains lacking the mitochondrial fission genes DNM1/Drp1 and FIS1, orthologs of mammalian cell death regulators. Cell viability following treatment with acetic acid is quantified by colony formation and vital dye (FUN1) staining to reproducibly detect dose-dependent, genetically programmed yeast cell death. PMID:19609767

  12. Programmed Cell Death of Dendritic Cells in Immune Regulation

    PubMed Central

    Chen, Min; Wang, Jin

    2010-01-01

    Summary Programmed cell death is essential for the maintenance of lymphocyte homeostasis and immune tolerance. Dendritic cells (DCs), the most efficient antigen presenting cells, represent a small cell population in the immune system. However, DCs play major roles in the regulation of both innate and adaptive immune responses. Programmed cell death in DCs is essential for regulating DC homeostasis and consequently, the scope of immune responses. Interestingly, different DC subsets show varied turnover rates in vivo. The conventional DCs are relatively short-lived in most lymphoid organs, while plasmacytoid DCs are long-lived cells. Mitochondrion-dependent programmed cell death plays an important role in regulating spontaneous DC turnover. Antigen-specific T cells are also capable of killing DCs, thereby providing a mechanism for negative feedback regulation of immune responses. It has been shown that a surplus of DCs due to defects in programmed cell death leads to overactivation of lymphocytes and the onset of autoimmunity. Studying programmed cell death in DCs will shed light on the roles for DC turnover in the regulation of the duration and magnitude of immune responses in vivo, and in the maintenance of immune tolerance. PMID:20636805

  13. Programmed Cell Death and Complexity in Microbial Systems.

    PubMed

    Durand, Pierre M; Sym, Stuart; Michod, Richard E

    2016-07-11

    Programmed cell death (PCD) is central to organism development and for a long time was considered a hallmark of multicellularity. Its discovery, therefore, in unicellular organisms presents compelling questions. Why did PCD evolve? What is its ecological effect on communities? To answer these questions, one is compelled to consider the impacts of PCD beyond the cell, for death obviously lowers the fitness of the cell. Here, we examine the ecological effects of PCD in different microbial scenarios and conclude that PCD can increase biological complexity. In mixed microbial communities, the mode of death affects the microenvironment, impacting the interactions between taxa. Where the population comprises groups of relatives, death has a more explicit effect. Death by lysis or other means can be harmful, while PCD can evolve by providing advantages to relatives. The synchronization of death between individuals suggests a group level property is being maintained and the mode of death also appears to have had an impact during the origin of multicellularity. PCD can result in the export of fitness from the cell to the group level via re-usable resources and PCD may also provide a mechanism for how groups beget new groups comprising kin. Furthermore, PCD is a means for solving a central problem of group living - the toxic effects of death - by making resources in dying cells beneficial to others. What emerges from the data reviewed here is that while PCD carries an obvious cost to the cell, it can be a driver of complexity in microbial communities.

  14. CD40L induces functional tunneling nanotube networks exclusively in dendritic cells programmed by mediators of type-1 immunity

    PubMed Central

    Zaccard, Colleen R.; Watkins, Simon C.; Kalinski, Pawel; Fecek, Ronald J.; Yates, Aarika L.; Salter, Russell D.; Ayyavoo, Velpandi; Rinaldo, Charles R.; Mailliard, Robbie B.

    2014-01-01

    The ability of dendritic cells (DC) to mediate CD4+ T cell help for cellular immunity is guided by instructive signals received during DC maturation, and the resulting pattern of DC responsiveness to the Th signal, CD40L. Furthermore, the professional transfer of antigenic information from migratory DC to lymph node-residing DC is critical for the effective induction of cellular immune responses. Here we report that, in addition to their enhanced IL-12p70 producing capacity, human DC matured in the presence of inflammatory mediators of type-1 immunity (DC1) are uniquely programmed to form networks of tunneling nanotube-like structures in response to CD40L-expressing Th cells or recombinant CD40L. This immunologic process of DC ‘reticulation’ facilitates intercellular trafficking of endosome-associated vesicles and Ag, but also pathogens such HIV-1, and is regulated by the opposing roles of IFN-γ and IL-4. The initiation of DC reticulation represents a novel helper function of CD40L and a superior mechanism of intercellular communication possessed by DC1, as well as a target for exploitation by pathogens to enhance direct cell-to-cell spread. PMID:25548234

  15. Winter wheat cells subjected to freezing temperature undergo death process with features of programmed cell death.

    PubMed

    Lyubushkina, Irina V; Grabelnych, Olga I; Pobezhimova, Tamara P; Stepanov, Aleksey V; Fedyaeva, Anna V; Fedoseeva, Irina V; Voinikov, Victor K

    2014-05-01

    Programmed cell death is a process defined as genetically regulated self-destruction or cell suicide. It can be activated by different internal and external factors, but few studies have investigated whether this process occurs under cold and freezing temperatures. In this study, a freezing treatment (-8 °C for 6 h) induced cell death with features of programmed cell death in suspension cultures of winter wheat (Triticum aestivum L.). This process occurred for 10 days after cold exposure. The death of cells in culture was slow and prolonged, and was accompanied by protoplast shrinkage, DNA fragmentation, and an increase in the level of reactive oxygen species. Other changes observed after the freezing treatment included an increase in the respiration rate, changes in mitochondrial transmembrane potential (∆Ψ m ), and the release of cytochrome c from mitochondria into the cytosol. These findings indicated that mitochondria are involved in the cell death process that occurs after a freezing treatment in cells of winter wheat.

  16. Biochemical evidence for programmed cell death in rabbit uterine epithelium.

    PubMed Central

    Rotello, R. J.; Hocker, M. B.; Gerschenson, L. E.

    1989-01-01

    Uterine epithelial cell proliferation, differentiation, and death are known to be regulated by estrogen and progesterone. The authors investigated a specific pattern of cell death called apoptosis, or programmed cell death, which is biochemically characterized by a specific pattern of DNA degradation. DNA isolated from endometrium of ovariectomized pseudopregnant rabbits showed a pattern of DNA cleavage at internucleosomal locations. In comparison, DNA from the endometrium of non-ovariectomized animals, as well as several other organs, did not exhibit that pattern. This biochemical evidence supports previous and present morphologic data and correlates with it. Under the experimental conditions used, only the uterine epithelial compartment of the endometrium shows apoptotic cell death, which is absent in the stromal compartment. Images Figure 1 Figure 2 PMID:2923180

  17. Programed Death is Favored by Natural Selection in Spatial Systems

    NASA Astrophysics Data System (ADS)

    Werfel, Justin; Ingber, Donald E.; Bar-Yam, Yaneer

    2015-06-01

    Standard evolutionary theories of aging and mortality, implicitly based on mean-field assumptions, hold that programed mortality is untenable, as it opposes direct individual benefit. We show that in spatial models with local reproduction, programed deaths instead robustly result in long-term benefit to a lineage, by reducing local environmental resource depletion via spatiotemporal patterns causing feedback over many generations. Results are robust to model variations, implying that direct selection for shorter life span may be quite widespread in nature.

  18. Ceramide mediates caspase-independent programmed cell death.

    PubMed

    Thon, Lutz; Möhlig, Heike; Mathieu, Sabine; Lange, Arne; Bulanova, Elena; Winoto-Morbach, Supandi; Schütze, Stefan; Bulfone-Paus, Silvia; Adam, Dieter

    2005-12-01

    Although numerous studies have implicated the sphingolipid ceramide in the induction of cell death, a causative function of ceramide in caspase-dependent apoptosis remains a highly debated issue. Here, we show that ceramide is a key mediator of a distinct route to programmed cell death (PCD), i.e., caspase-independent PCD. Under conditions where apoptosis is either not initiated or actively inhibited, TNF induces caspase-independent PCD in L929 fibrosarcoma cells, NIH3T3 fibroblasts, human leukemic Jurkat T cells, and lung fibroblasts by increasing intracellular ceramide levels prior to the onset of cell death. Survival is significantly enhanced when ceramide accumulation is prevented, as demonstrated in fibroblasts genetically deficient for acid sphingomyelinase, in L929 cells overexpressing acid ceramidase, by pharmacological intervention, or by RNA interference. Jurkat cells deficient for receptor-interacting protein 1 (RIP1) do not accumulate ceramide and therefore are fully resistant to caspase-independent PCD whereas Jurkat cells overexpressing the mitochondrial protein Bcl-2 are partially protected, implicating RIP1 and mitochondria as components of the ceramide death pathway. Our data point to a role of caspases (but not cathepsins) in suppressing the ceramide death pathway under physiological conditions. Moreover, clonogenic survival of tumor cells is clearly reduced by induction of the ceramide death pathway, promising additional options for the development of novel tumor therapies.

  19. Multiple cell death programs: Charon's lifts to Hades.

    PubMed

    Bursch, Wilfried

    2004-11-01

    Cells use different pathways for active self-destruction as reflected by different morphology: while in apoptosis (or "type I") nuclear fragmentation associated with cytoplasmic condensation but preservation of organelles is predominant, autophagic degradation of cytoplasmic structures preceding nuclear collapse is a characteristic of a second type of programmed cell death (PCD). The diverse morphologies can be attributed--at least to some extent--to distinct biochemical and molecular events (e.g. caspase-dependent and -independent death programs; DAP-kinase activity, Ras-expression). However, apoptosis and autophagic PCD are not mutually exclusive phenomena. Rather, diverse PCD programs emerged during evolution, the conservation of which apparently allows cells a flexible response to environmental changes, either physiological or pathological.

  20. Ceramide Synthase-dependent Ceramide Generation and Programmed Cell Death

    PubMed Central

    Mullen, Thomas D.; Jenkins, Russell W.; Clarke, Christopher J.; Bielawski, Jacek; Hannun, Yusuf A.; Obeid, Lina M.

    2011-01-01

    The sphingolipid ceramide has been widely implicated in the regulation of programmed cell death or apoptosis. The accumulation of ceramide has been demonstrated in a wide variety of experimental models of apoptosis and in response to a myriad of stimuli and cellular stresses. However, the detailed mechanisms of its generation and regulatory role during apoptosis are poorly understood. We sought to determine the regulation and roles of ceramide production in a model of ultraviolet light-C (UV-C)-induced programmed cell death. We found that UV-C irradiation induces the accumulation of multiple sphingolipid species including ceramide, dihydroceramide, sphingomyelin, and hexosylceramide. Late ceramide generation was also found to be regulated by Bcl-xL, Bak, and caspases. Surprisingly, inhibition of de novo synthesis using myriocin or fumonisin B1 resulted in decreased overall cellular ceramide levels basally and in response to UV-C, but only fumonisin B1 inhibited cell death, suggesting the presence of a ceramide synthase (CerS)-dependent, sphingosine-derived pool of ceramide in regulating programmed cell death. We found that this pool did not regulate the mitochondrial pathway, but it did partially regulate activation of caspase-7 and, more importantly, was necessary for late plasma membrane permeabilization. Attempting to identify the CerS responsible for this effect, we found that combined knockdown of CerS5 and CerS6 was able to decrease long-chain ceramide accumulation and plasma membrane permeabilization. These data identify a novel role for CerS and the sphingosine salvage pathway in regulating membrane permeability in the execution phase of programmed cell death. PMID:21388949

  1. Oxidative Stress and Programmed Cell Death in Yeast

    PubMed Central

    Farrugia, Gianluca; Balzan, Rena

    2012-01-01

    Yeasts, such as Saccharomyces cerevisiae, have long served as useful models for the study of oxidative stress, an event associated with cell death and severe human pathologies. This review will discuss oxidative stress in yeast, in terms of sources of reactive oxygen species (ROS), their molecular targets, and the metabolic responses elicited by cellular ROS accumulation. Responses of yeast to accumulated ROS include upregulation of antioxidants mediated by complex transcriptional changes, activation of pro-survival pathways such as mitophagy, and programmed cell death (PCD) which, apart from apoptosis, includes pathways such as autophagy and necrosis, a form of cell death long considered accidental and uncoordinated. The role of ROS in yeast aging will also be discussed. PMID:22737670

  2. Nitric oxide: promoter or suppressor of programmed cell death?

    PubMed

    Wang, Yiqin; Chen, Chen; Loake, Gary J; Chu, Chengcai

    2010-02-01

    Nitric oxide (NO) is a short-lived gaseous free radical that predominantly functions as a messenger and effector molecule. It affects a variety of physiological processes, including programmed cell death (PCD) through cyclic guanosine monophosphate (cGMP)-dependent and - independent pathways. In this field, dominant discoveries are the diverse apoptosis networks in mammalian cells, which involve signals primarily via death receptors (extrinsic pathway) or the mitochondria (intrinsic pathway) that recruit caspases as effector molecules. In plants, PCD shares some similarities with animal cells, but NO is involved in PCD induction via interacting with pathways of phytohormones. NO has both promoting and suppressing effects on cell death, depending on a variety of factors, such as cell type, cellular redox status, and the flux and dose of local NO. In this article, we focus on how NO regulates the apoptotic signal cascade through protein S-nitrosylation and review the recent progress on mechanisms of PCD in both mammalian and plant cells.

  3. Apoptotic-like programmed cell death in plants.

    PubMed

    Reape, Theresa J; McCabe, Paul F

    2008-01-01

    Programmed cell death (PCD) is now accepted as a fundamental cellular process in plants. It is involved in defence, development and response to stress, and our understanding of these processes would be greatly improved through a greater knowledge of the regulation of plant PCD. However, there may be several types of PCD that operate in plants, and PCD research findings can be confusing if they are not assigned to a specific type of PCD. The various cell-death mechanisms need therefore to be carefully described and defined. This review describes one of these plant cell death processes, namely the apoptotic-like PCD (AL-PCD). We begin by examining the hallmark 'apoptotic-like' features (protoplast condensation, DNA degradation) of the cell's destruction that are characteristic of AL-PCD, and include examples of AL-PCD during the plant life cycle. The review explores the possible cellular 'executioners' (caspase-like molecules; mitochondria; de novo protein synthesis) that are responsible for the hallmark features of the cellular destruction. Finally, senescence is used as a case study to show that a rigorous definition of cell-death processes in plant cells can help to resolve arguments that occur in the scientific literature regarding the timing and control of plant cell death.

  4. Necroptosis: an alternative cell death program defending against cancer

    PubMed Central

    Chen, Dongshi; Yu, Jian; Zhang, Lin

    2016-01-01

    One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. PMID:26968619

  5. Interdigital cell death function and regulation: new insights on an old programmed cell death model.

    PubMed

    Hernández-Martínez, Rocío; Covarrubias, Luis

    2011-02-01

    Interdigital cell death (ICD) is the oldest and best-studied model of programmed cell death (PCD) in vertebrates. The classical view of ICD function is the separation of digits by promotion of tissue regression. However, in addition, ICD can contribute to digit individualization by restricting interdigital tissue growth. Depending on the species, the relative contribution of either regression or growth-restricting functions of ICD to limb morphogenesis may differ. Under normal conditions, most cells appear to die by apoptosis during ICD. Accordingly, components of the apoptotic machinery are found in the interdigits, though their role in the initiation and execution of cell death is yet to be defined. Fgf8 has been identified as a survival factor for the distal mesenchymal cells of the limb such that ICD can initiate following specific downregulation of Fgf8 expression in the ectoderm overlying the interdigital tissue. On the other hand, Bmps may promote cell death directly by acting on the interdigital tissue, or indirectly by downregulating Fgf8 expression in the ectoderm. In addition, retinoic acid can activate ICD directly or through a Bmp-mediated mechanism. Interactions at different levels between these factors establish the spatiotemporal patterning of ICD activation. Defining the regulatory network behind ICD activation will greatly advance our understanding of the mechanisms controlling PCD in general.

  6. Death of mitochondria during programmed cell death of leaf mesophyll cells.

    PubMed

    Selga, Tūrs; Selga, Maija; Pāvila, Vineta

    2005-12-01

    The role of plant mitochondria in the programmed cell death (PCD) is widely discussed. However, spectrum and sequence of mitochondrial structural changes during different types of PCD in leaves are poorly described. Pea, cucumber and rye plants were grown under controlled growing conditions. A part of them were sprinkled with ethylene releaser to accelerate cell death. During yellowing the palisade parenchyma mitochondria were attracted to nuclear envelope. Mitochondrial matrix became electron translucent. Mitochondria entered vacuole by invagination of tonoplast and formed multivesicular bodies. Ethephon treatment increased the frequency of sticking of mitochondria to the nuclear envelope or chloroplasts and peroxisomes. Mitochondria divided by different mechanisms and became enclosed in Golgi and ER derived authopagic vacuoles or in the central vacuole. Several fold increase of the diameter of cristae became typical. In all cases mitochondria were attached to nuclear envelope. It can be considered as structural mechanism of promoting of PCD.

  7. Sudden infant death syndrome prevention: a model program for NICUs.

    PubMed

    McMullen, Sherri L; Lipke, Bethann; LeMura, Catherine

    2009-01-01

    Health care providers' opinions can influence how parents place their infant to sleep. Neonatal nurses can improve how they teach and model safe infant sleep practices to parents. To increase neonatal nurses' knowledge, a sudden infant death syndrome (SIDS) prevention program was implemented. Program components included a computerized teaching tool, a crib card, sleep sacks, and discharge instructions. Initial program evaluation showed that 98 percent of infants slept supine and 93 percent slept in sleep sacks in open cribs. However, nurses continued to swaddle some infants with blankets to improve thermoregulation. To increase nursing compliance in modeling safe infant sleep practices, Halo SleepSack Swaddles were provided for nurses to use in place of a blanket to regulate infant temperature. Recent data show that 100 percent of infants in open cribs are now sleeping supine wearing a Halo Swaddle or a traditional Halo SleepSack. This model program can easily be replicated to enhance neonatal nurses' knowledge about SIDS prevention.

  8. Sulfur dioxide induced programmed cell death in Vicia guard cells.

    PubMed

    Yi, Huilan; Yin, Jingjing; Liu, Xin; Jing, Xiuqing; Fan, Sanhong; Zhang, Hufang

    2012-04-01

    Sulfur dioxide (SO(2)) induced nuclear condensation and nuclear fragmentation and rapid loss of guard cell viability in detached epidermis of Vicia leaves at concentrations of 1 mM and higher (3 h exposure). Caspase inhibitors Z-Asp-CH(2)-DCB (0.1 mM) and TLCK (0.1 mM) markedly suppressed SO(2)-induced cell death. The typical nuclear morphological changes and the inhibition effects of caspase inhibitors suggest the activation of a programmed cell death (PCD) pathway. SO(2)-induced cell death can be blocked by either antioxidants (0.1 mM AsA or 200 U/mL CAT) or Ca(2+) antagonists (0.1mM EGTA or LaCl(3)). AsA and CAT also blocked SO(2)-induced ROS production and [Ca(2+)](cyt) increase. However, EGTA and LaCl(3) can inhibit SO(2)-induced [Ca(2+)](cyt) increase, but cannot suppress SO(2)-induced ROS production. Our results indicate that high concentrations of SO(2) induce guard cell death via a PCD pathway through ROS mediating [Ca(2+)](cyt) elevation, which causes harmful effects to plants.

  9. Mechanisms of programmed cell death during oogenesis in Drosophila virilis.

    PubMed

    Velentzas, Athanassios D; Nezis, Ioannis P; Stravopodis, Dimitrios J; Papassideri, Issidora S; Margaritis, Lukas H

    2007-02-01

    We describe the features of programmed cell death occurring in the egg chambers of Drosophila virilis during mid-oogenesis and late oogenesis. During mid-oogenesis, the spontaneously degenerating egg chambers exhibit typical characteristics of apoptotic cell death. As revealed by propidium iodide, rhodamine-conjugated phalloidin staining, and the TUNEL assay, respectively, the nurse cells contain condensed chromatin, altered actin cytoskeleton, and fragmented DNA. In vitro caspase activity assays and immunostaining procedures demonstrate that the atretic egg chambers possess high levels of caspase activity. Features of autophagic cell death are also observed during D. virilis mid-oogenesis, as shown by monodansylcadaverine staining, together with an ultrastructural examination by transmission electron microscopy. During the late stages of oogenesis in D. virilis, once again, the two mechanisms, viz., nurse cell cluster apoptosis and autophagy, operate together, manifesting features of cell death similar to those detailed above. Moreover, an altered form of cytochrome c seems to be released from the mitochondria in the nurse cells proximal to the oocyte. We propose that apoptosis and autophagy function synergistically during oogenesis in D. virilis in order to achieve a more efficient elimination of the degenerated nurse cells and abnormal egg chambers.

  10. Dipeptidyl peptidase-IV inhibition prevents blood-retinal barrier breakdown, inflammation and neuronal cell death in the retina of type 1 diabetic rats.

    PubMed

    Gonçalves, Andreia; Marques, Catarina; Leal, Ermelindo; Ribeiro, Carlos F; Reis, Flávio; Ambrósio, António F; Fernandes, Rosa

    2014-09-01

    Diabetic retinopathy, a leading cause of vision loss in working-age population, is often associated with inflammation and apoptosis. We have previously reported that sitagliptin, a DPP-IV inhibitor, exerts beneficial effects in the retina of type 2 diabetic animals. The present study aimed to evaluate whether sitagliptin can exert protective effects in the retina of type 1 diabetic animals by a mechanism independent of insulin secretion and glycemia normalization. Streptozotocin-induced diabetic rats were treated orally with sitagliptin (5mg/kg/day) for the last two weeks of 4 weeks of diabetes. Sitagliptin treatment did not change the weight and glucose, HbA1c or insulin levels. However, it prevented the diabetes-induced increase in DPP-IV/CD26 activity and levels in serum and retina. Sitagliptin also prevented the increase in blood-retinal barrier (BRB) permeability and inhibited the changes in immunoreactivity and endothelial subcellular distribution of occludin, claudin-5 and ZO-1 proteins induced by diabetes. Furthermore, sitagliptin decreased the retinal inflammatory state and neuronal apoptosis. Sitagliptin inhibited the BRB breakdown in a type 1 diabetic animal model, by a mechanism independent of normalization of glycemia, by preventing changes in tight junctions (TJs) organization. Sitagliptin also exerted protective effects against inflammation and pro-apoptotic state in the retina of diabetic rats. Altogether, these results suggest that sitagliptin might be envisaged to be used to prevent or delay some of the alterations associated with the development of diabetic retinopathy. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Perturbations in the Lipid Profile of Individuals with Newly Diagnosed Type 1 Diabetes Mellitus: Lipidomics Analysis of a Diabetes Antibody Standardization Program Sample Subset

    SciTech Connect

    Sorensen, Christina M.; Ding, Jie; Zhang, Qibin; Alquier, Thierry; Zhao, Rui; Mueller, Patricia W.; Smith, Richard D.; Metz, Thomas O.

    2010-08-01

    Objectives: To characterize the lipid profile of individuals with newly diagnosed type 1 diabetes mellitus using LC-MS-based lipidomics and the accurate mass and time (AMT) tag approach. Design and methods: Lipids were extracted from plasma and sera of 10 subjects from the Diabetes Antibody Standardization Program (years 2000-2005) and 10 non-diabetic subjects and analyzed by capillary liquid chromatography coupled with a hybrid ion-trap-Fourier transform ion cyclotron resonance mass spectrometer. Lipids were identified and quantified using the AMT tag approach. Results: Five hundred sixty lipid features differentiated (q < 0.05) diabetic from healthy individuals in a partial least-squares analysis, characterizing of individuals with recently diagnosed type 1 diabetes mellitus. Conclusions: A lipid profile associated with newly diagnosed type 1 diabetes may aid in further characterization of biochemical pathways involved in lipid regulation or mobilization and lipotoxicity of pancreatic beta-cells.

  12. Death's toolbox: examining the molecular components of bacterial programmed cell death.

    PubMed

    Rice, Kelly C; Bayles, Kenneth W

    2003-11-01

    Programmed cell death (PCD) is a genetically determined process of cellular suicide that is activated in response to cellular stress or damage, as well as in response to the developmental signals in multicellular organisms. Although historically studied in eukaryotes, it has been proposed that PCD also functions in prokaryotes, either during the developmental life cycle of certain bacteria or to remove damaged cells from a population in response to a wide variety of stresses. This review will examine several putative examples of bacterial PCD and summarize what is known about the molecular components of these systems.

  13. Megasporogenesis and programmed cell death in Tillandsia (Bromeliaceae).

    PubMed

    Papini, Alessio; Mosti, Stefano; Milocani, Eva; Tani, Gabriele; Di Falco, Pietro; Brighigna, Luigi

    2011-10-01

    The degeneration of three of four meiotic products is a very common process in the female gender of oogamous eukaryotes. In Tillandsia (and many other angiosperms), the surviving megaspore has a callose-free wall in chalazal position while the other three megaspores are completely embedded in callose. Therefore, nutrients and signals can reach more easily the functional megaspore from the nucellus through the chalazal pole with respect to the other megaspores. The abortion of three of four megaspores was already recognized as the result of a programmed cell death (PCD) process. We investigated the process to understand the modality of this specific type of PCD and its relationship to the asymmetric callose deposition around the tetrad. The decision on which of the four megaspores will be the supernumerary megaspores in angiosperms, and hence destined to undergo programmed cell death, appears to be linked to the callose layer deposition around the tetrad. During supernumerary megaspores degeneration, events leading to the deletion of the cells do not appear to belong to a single type of cell death. The first morphological signs are typical of autophagy, including the formation of autophagosomes. The TUNEL positivity and a change in morphology of mitochondria and chloroplasts indicate the passage to an apoptotic-like PCD phase, while the cellular remnants undergo a final process resembling at least partially (ER swelling) necrotic morphological syndromes, eventually leading to a mainly lipidic cell corpse still separated from the functional megaspore by a callose layer.

  14. Feasibility, Acceptability, and Predictive Validity of a Psychosocial Screening Program for Children and Youth Newly Diagnosed With Type 1 Diabetes

    PubMed Central

    Schwartz, David D.; Cline, Virginia Depp; Axelrad, Marni E.; Anderson, Barbara J.

    2011-01-01

    OBJECTIVE Psychosocial screening has been recommended for pediatric patients with newly diagnosed type 1 diabetes and their families. Our objective was to assess a psychosocial screening protocol in its feasibility, acceptability to families, and ability to predict early emerging complications, nonadherent family behavior, and use of preventive psychology services. RESEARCH DESIGN AND METHODS A total of 125 patients and their caregivers were asked to participate in a standardized screening interview after admission at a large urban children’s hospital with a new diagnosis of type 1 diabetes. Medical records were reviewed for subsequent diabetes-related emergency department (ED) admissions, missed diabetes clinic appointments, and psychology follow-up within 9 months of diagnosis. RESULTS Of 125 families, 121 (96.8%) agreed to participate in the screening, and a subsample of 30 surveyed caregivers indicated high levels of satisfaction. Risk factors at diagnosis predicted subsequent ED admissions with a sensitivity of 100% and a specificity of 98.6%. Children from single-parent households with a history of behavior problems were nearly six times more likely to be seen in the ED after diagnosis. Missed appointments were likeliest among African Americans, 65% of whom missed at least one diabetes-related appointment. Psychology services for preventive intervention were underutilized, despite the high acceptability of the psychosocial screening. CONCLUSIONS Psychosocial screening of newly diagnosed patients with type 1 diabetes is feasible, acceptable to families, and able to identify families at risk for early emerging complications and nonadherence. Challenges remain with regards to reimbursement and fostering follow-up for preventive care. PMID:21216856

  15. The Arabidopsis peptide kiss of death is an inducer of programmed cell death

    PubMed Central

    Blanvillain, Robert; Young, Bennett; Cai, Yao-min; Hecht, Valérie; Varoquaux, Fabrice; Delorme, Valérie; Lancelin, Jean-Marc; Delseny, Michel; Gallois, Patrick

    2011-01-01

    Programmed cell death (PCD) has a key role in defence and development of all multicellular organisms. In plants, there is a large gap in our knowledge of the molecular machinery involved at the various stages of PCD, especially the early steps. Here, we identify kiss of death (KOD) encoding a 25-amino-acid peptide that activates a PCD pathway in Arabidopsis thaliana. Two mutant alleles of KOD exhibited a reduced PCD of the suspensor, a single file of cells that support embryo development, and a reduced PCD of root hairs after a 55°C heat shock. KOD expression was found to be inducible by biotic and abiotic stresses. Furthermore, KOD expression was sufficient to cause death in leaves or seedlings and to activate caspase-like activities. In addition, KOD-induced PCD required light in leaves and was repressed by the PCD-suppressor genes AtBax inhibitor 1 and p35. KOD expression resulted in depolarization of the mitochondrial membrane, placing KOD above mitochondria dysfunction, an early step in plant PCD. A KOD∷GFP fusion, however, localized in the cytosol of cells and not mitochondria. PMID:21326210

  16. Programmed Cell Death of Embryonic Motoneurons Triggered through the FAS Death Receptor

    PubMed Central

    Raoul, Cédric; Henderson, Christopher E.; Pettmann, Brigitte

    1999-01-01

    About 50% of spinal motoneurons undergo programmed cell death (PCD) after target contact, but little is known about how this process is initiated. Embryonic motoneurons coexpress the death receptor Fas and its ligand FasL at the stage at which PCD is about to begin. In the absence of trophic factors, many motoneurons die in culture within 2 d. Most (75%) of these were saved by Fas-Fc receptor body, which blocks interactions between Fas and FasL, or by the caspase-8 inhibitor tetrapeptide IETD. Therefore, activation of Fas by endogenous FasL underlies cell death induced by trophic deprivation. In the presence of neurotrophic factors, exogenous Fas activators such as soluble FasL or anti-Fas antibodies triggered PCD of 40–50% of purified motoneurons over the following 3–5 d; this treatment led to activation of caspase-3, and was blocked by IETD. Sensitivity to Fas activation is regulated: motoneurons cultured for 3 d with neurotrophic factors became completely resistant. Levels of Fas expressed by motoneurons varied little, but FasL was upregulated in the absence of neurotrophic factors. Motoneurons resistant to Fas activation expressed high levels of FLICE-inhibitory protein (FLIP), an endogenous inhibitor of caspase-8 activation. Our results suggest that Fas can act as a driving force for motoneuron PCD, and raise the possibility that active triggering of PCD may contribute to motoneuron loss during normal development and/or in pathological situations. PMID:10579724

  17. A Donation After Circulatory Death Program Has the Potential to Increase the Number of Donors After Brain Death.

    PubMed

    Broderick, Andrew R; Manara, Alex; Bramhall, Simon; Cartmill, Maria; Gardiner, Dale; Neuberger, James

    2016-02-01

    Donation after circulatory death has been responsible for 75% of the increase in the numbers of deceased organ donors in the United Kingdom. There has been concern that the success of the donation after circulatory death program has been at the expense of donation after brain death. The objective of the study was to ascertain the impact of the donation after circulatory death program on donation after brain death in the United Kingdom. Retrospective cohort study. A national organ procurement organization. Patients referred and assessed as donation after circulatory death donors in the United Kingdom between October and December 2013. None. A total of 257 patients were assessed for donation after circulatory death. Of these, 193 were eligible donors. Three patients were deemed medically unsuitable following surgical inspection, 56 patients did not proceed due to asystole, and 134 proceeded to donation. Four donors had insufficient data available for analysis. Therefore, 186 cases were analyzed in total. Organ donation would not have been possible in 79 of the 130 actual donors if donation after circulatory death was not available. Thirty-six donation after circulatory death donors (28% of actual donors) were judged to have the potential to progress to brain death if withdrawal of life-sustaining treatment had been delayed by up to a further 36 hours. A further 15 donation after circulatory death donors had brain death confirmed or had clinical indications of brain death with clear mitigating circumstances in all but three cases. We determined that the maximum potential donation after brain death to donation after circulatory death substitution rate observed was 8%; however due to mitigating circumstances, only three patients (2%) could have undergone brain death testing. The development of a national donation after circulatory death program has had minimal impact on the number of donation after brain death donors. The number of donation after brain death donors

  18. Vacuolar processing enzyme in plant programmed cell death

    PubMed Central

    Hatsugai, Noriyuki; Yamada, Kenji; Goto-Yamada, Shino; Hara-Nishimura, Ikuko

    2015-01-01

    Vacuolar processing enzyme (VPE) is a cysteine proteinase originally identified as the proteinase responsible for the maturation and activation of vacuolar proteins in plants, and it is known to be an ortholog of animal asparaginyl endopeptidase (AEP/VPE/legumain). VPE has been shown to exhibit enzymatic properties similar to that of caspase 1, which is a cysteine protease that mediates the programmed cell death (PCD) pathway in animals. Although there is limited sequence identity between VPE and caspase 1, their predicted three-dimensional structures revealed that the essential amino-acid residues for these enzymes form similar pockets for the substrate peptide YVAD. In contrast to the cytosolic localization of caspases, VPE is localized in vacuoles. VPE provokes vacuolar rupture, initiating the proteolytic cascade leading to PCD in the plant immune response. It has become apparent that the VPE-dependent PCD pathway is involved not only in the immune response, but also in the responses to a variety of stress inducers and in the development of various tissues. This review summarizes the current knowledge on the contribution of VPE to plant PCD and its role in vacuole-mediated cell death, and it also compares VPE with the animal cell death executor caspase 1. PMID:25914711

  19. Chitosan-induced programmed cell death in plants.

    PubMed

    Vasil'ev, L A; Dzyubinskaya, E V; Zinovkin, R A; Kiselevsky, D B; Lobysheva, N V; Samuilov, V D

    2009-09-01

    Chitosan, CN(-), or H(2)O(2) caused the death of epidermal cells (EC) in the epidermis of pea leaves that was detected by monitoring the destruction of cell nuclei; chitosan induced chromatin condensation and marginalization followed by the destruction of EC nuclei and subsequent internucleosomal DNA fragmentation. Chitosan did not affect stoma guard cells (GC). Anaerobic conditions prevented the chitosan-induced destruction of EC nuclei. The antioxidants nitroblue tetrazolium or mannitol suppressed the effects of chitosan, H(2)O(2), or chitosan + H(2)O(2) on EC. H(2)O(2) formation in EC and GC mitochondria that was determined from 2',7'-dichlorofluorescein fluorescence was inhibited by CN(-) and the protonophoric uncoupler carbonyl cyanide m-chlorophenylhydrazone but was stimulated by these agents in GC chloroplasts. The alternative oxidase inhibitors propyl gallate and salicylhydroxamate prevented chitosan- but not CN(-)-induced destruction of EC nuclei; the plasma membrane NADPH oxidase inhibitors diphenylene iodonium and quinacrine abolished chitosan- but not CN(-)-induced destruction of EC nuclei. The mitochondrial protein synthesis inhibitor lincomycin removed the destructive effect of chitosan or H(2)O(2) on EC nuclei. The effect of cycloheximide, an inhibitor of protein synthesis in the cytoplasm, was insignificant; however, it was enhanced if cycloheximide was added in combination with lincomycin. The autophagy inhibitor 3-methyladenine removed the chitosan effect but exerted no influence on the effect of H(2)O(2) as an inducer of EC death. The internucleosome DNA fragmentation in conjunction with the data on the 3-methyladenine effect provides evidence that chitosan induces programmed cell death that follows a combined scenario including apoptosis and autophagy. Based on the results of an inhibitor assay, chitosan-induced EC death involves reactive oxygen species generated by the NADPH oxidase of the plasma membrane.

  20. Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

    PubMed Central

    López-Arencibia, Atteneri; Sifaoui, Ines; Reyes-Batlle, María; Valladares, Basilio; Martínez-Carretero, Enrique; Piñero, José E.; Maciver, Sutherland K.; Lorenzo-Morales, Jacob

    2015-01-01

    Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a life-threatening encephalitis. In order to treat those infections properly, it is necessary to target the treatment not only to the trophozoite but also to the cyst. Furthermore, it may be advantageous to avoid parasite killing by necrosis, which may induce local inflammation. We must also avoid toxicity of host tissue. Many drugs which target eukaryotes are known to induce programmed cell death (PCD), but this process is poorly characterized in Acanthamoeba. Here, we study the processes of programmed cell death in Acanthamoeba, induced by several drugs, such as statins and voriconazole. We tested atorvastatin, fluvastatin, simvastatin, and voriconazole at the 50% inhibitory concentrations (IC50s) and IC90s that we have previously established. In order to evaluate this phenomenon, we investigated the DNA fragmentation, one of the main characteristics of PCD, with quantitative and qualitative techniques. Also, the changes related to phosphatidylserine exposure on the external cell membrane and cell permeability were studied. Finally, because caspases are key to PCD pathways, caspase activity was evaluated in Acanthamoeba. All the drugs assayed in this study induced PCD in Acanthamoeba. To the best of our knowledge, this is the first study where PCD induced by drugs is described quantitatively and qualitatively in Acanthamoeba. PMID:25733513

  1. Arabidopsis ACCELERATED CELL DEATH2 Modulates Programmed Cell DeathW⃞

    PubMed Central

    Yao, Nan; Greenberg, Jean T.

    2006-01-01

    The Arabidopsis thaliana chloroplast protein ACCELERATED CELL DEATH2 (ACD2) modulates the amount of programmed cell death (PCD) triggered by Pseudomonas syringae and protoporphyrin IX (PPIX) treatment. In vitro, ACD2 can reduce red chlorophyll catabolite, a chlorophyll derivative. We find that ACD2 shields root protoplasts that lack chlorophyll from light- and PPIX-induced PCD. Thus, chlorophyll catabolism is not obligatory for ACD2 anti-PCD function. Upon P. syringae infection, ACD2 levels and localization change in cells undergoing PCD and in their close neighbors. Thus, ACD2 shifts from being largely in chloroplasts to partitioning to chloroplasts, mitochondria, and, to a small extent, cytosol. ACD2 protects cells from PCD that requires the early mitochondrial oxidative burst. Later, the chloroplasts of dying cells generate NO, which only slightly affects cell viability. Finally, the mitochondria in dying cells have dramatically altered movements and cellular distribution. Overproduction of both ACD2 (localized to mitochondria and chloroplasts) and ascorbate peroxidase (localized to chloroplasts) greatly reduces P. syringae–induced PCD, suggesting a pro-PCD role for mitochondrial and chloroplast events. During infection, ACD2 may bind to and/or reduce PCD-inducing porphyrin-related molecules in mitochondria and possibly chloroplasts that generate reactive oxygen species, cause altered organelle behavior, and activate a cascade of PCD-inducing events. PMID:16387834

  2. Elevated Expression of Programmed Death-1 and Programmed Death Ligand-1 Negatively Regulates Immune Response against Cervical Cancer Cells

    PubMed Central

    Chen, Zhifang; Pang, Nannan; Du, Rong; Zhu, Yuejie; Fan, Lingling; Cai, Donghui

    2016-01-01

    The present study is to measure the expression of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), as well as its clinical significance in cervical cancer patients. Our results showed that different T cell subsets in patients with cervical cancer had high expression of PD-1, and DCs had high expression of PD-L1. High expression of PD-1 on Treg cells in cervical cancer patients facilitated the production of TGF-β and IL-10 but inhibited the production of IFN-γ. Cervical cancer elevated the expression of PD-1 and PD-L1 in mRNA level. PD-1 expression in peripheral blood of cervical cancer patients was related with tumor differentiation, lymph node metastasis, and invasiveness. PD-1/PD-L1 pathway inhibited lymphocyte proliferation but enhanced the secretion of IL-10 and TGF-β in vitro. In summary, our findings demonstrate that elevated levels of PD-1/PD-L1, TGF-β, and IL-10 in peripheral blood of cervical cancer patients may negatively regulate immune response against cervical cancer cells and contribute to the progression of cervical cancer. Therefore, PD-1/PD-L1 pathway may become an immunotherapy target in the future. PMID:27721577

  3. Impact of a Preconception Counseling Program for Teens With Type 1 Diabetes (READY-Girls) on Patient-Provider Interaction, Resource Utilization, and Cost

    PubMed Central

    Fischl, Andrea F. Rodgers; Herman, William H.; Sereika, Susan M.; Hannan, Margaret; Becker, Dorothy; Mansfield, M. Joan; Freytag, Linda L.; Milaszewski, Kerry; Botscheller, Amanda N.; Charron-Prochownik, Denise

    2010-01-01

    OBJECTIVE To evaluate the impact of a preconception counseling program tailored for teens with type 1 diabetes on cognitive, psychosocial, and behavioral outcomes and to assess its cost-effectiveness. RESEARCH DESIGN AND METHODS A total of 88 teens with type 1 diabetes from two sites were randomized into the READY-Girls (Reproductive-health Education and Awareness of Diabetes in Youth for Girls) intervention (IG) (n = 43) or standard care (SC) (n = 45) groups. During three diabetes clinic visits, IG subjects viewed a two-part CD-ROM, read a book, and met with a nurse. Program effectiveness was measured by knowledge, attitudes, intentions, and behaviors regarding diabetes, pregnancy, sexuality, and preconception counseling. Assessments occurred at baseline, before and after viewing program materials, and at 9 months. Economic analyses included an assessment of resource utilization, direct medical costs, and a break-even cost analysis. RESULTS Age range was 13.2–19.7 years (mean ± SD 16.7 ± 1.7 years); 6% (n = 5) were African American, and 24% (n = 21) were sexually active. Compared with baseline and SC subjects, IG subjects demonstrated a significant group-by-time interaction for benefit and knowledge of preconception counseling and reproductive health: increasing immediately after the first visit (P < 0.001) and being sustained for 9 months (P < 0.05 benefits; P < 0.001 knowledge). For IG subjects, preconception counseling barriers decreased over time (P < 0.001), and intention and initiation of preconception counseling and reproductive health discussions increased (P < 0.001). Costs of adverse reproductive outcomes are high. Direct medical costs of READY-Girls were low. CONCLUSIONS READY-Girls was beneficial and effects were sustained for at least 9 months. This low-cost self-instructional program can potentially empower young women with type 1 diabetes to make well-informed reproductive health choices, adding little time burden or cost to their diabetes

  4. Impact of a preconception counseling program for teens with type 1 diabetes (READY-Girls) on patient-provider interaction, resource utilization, and cost.

    PubMed

    Fischl, Andrea F Rodgers; Herman, William H; Sereika, Susan M; Hannan, Margaret; Becker, Dorothy; Mansfield, M Joan; Freytag, Linda L; Milaszewski, Kerry; Botscheller, Amanda N; Charron-Prochownik, Denise

    2010-04-01

    To evaluate the impact of a preconception counseling program tailored for teens with type 1 diabetes on cognitive, psychosocial, and behavioral outcomes and to assess its cost-effectiveness. A total of 88 teens with type 1 diabetes from two sites were randomized into the READY-Girls (Reproductive-health Education and Awareness of Diabetes in Youth for Girls) intervention (IG) (n = 43) or standard care (SC) (n = 45) groups. During three diabetes clinic visits, IG subjects viewed a two-part CD-ROM, read a book, and met with a nurse. Program effectiveness was measured by knowledge, attitudes, intentions, and behaviors regarding diabetes, pregnancy, sexuality, and preconception counseling. Assessments occurred at baseline, before and after viewing program materials, and at 9 months. Economic analyses included an assessment of resource utilization, direct medical costs, and a break-even cost analysis. Age range was 13.2-19.7 years (mean +/- SD 16.7 +/- 1.7 years); 6% (n = 5) were African American, and 24% (n = 21) were sexually active. Compared with baseline and SC subjects, IG subjects demonstrated a significant group-by-time interaction for benefit and knowledge of preconception counseling and reproductive health: increasing immediately after the first visit (P < 0.001) and being sustained for 9 months (P < 0.05 benefits; P < 0.001 knowledge). For IG subjects, preconception counseling barriers decreased over time (P < 0.001), and intention and initiation of preconception counseling and reproductive health discussions increased (P < 0.001). Costs of adverse reproductive outcomes are high. Direct medical costs of READY-Girls were low. READY-Girls was beneficial and effects were sustained for at least 9 months. This low-cost self-instructional program can potentially empower young women with type 1 diabetes to make well-informed reproductive health choices, adding little time burden or cost to their diabetes management.

  5. Programmed cell death in C. elegans, mammals and plants.

    PubMed

    Lord, Christina E N; Gunawardena, Arunika H L A N

    2012-08-01

    Programmed cell death (PCD) is the regulated removal of cells within an organism and plays a fundamental role in growth and development in nearly all eukaryotes. In animals, the model organism Caenorhabditis elegans (C. elegans) has aided in elucidating many of the pathways involved in the cell death process. Various analogous PCD processes can also be found within mammalian PCD systems, including vertebrate limb development. Plants and animals also appear to share hallmarks of PCD, both on the cellular and molecular level. Cellular events visualized during plant PCD resemble those seen in animals including: nuclear condensation, DNA fragmentation, cytoplasmic condensation, and plasma membrane shrinkage. Recently the molecular mechanisms involved in plant PCD have begun to be elucidated. Although few regulatory proteins have been identified as conserved across all eukaryotes, molecular features such as the participation of caspase-like proteases, Bcl-2-like family members and mitochondrial proteins appear to be conserved between plant and animal systems. Transgenic expression of mammalian and C. elegans pro- and anti-apoptotic genes in plants has been observed to dramatically influence the regulatory pathways of plant PCD. Although these genes often show little to no sequence similarity they can frequently act as functional substitutes for one another, thus suggesting that action may be more important than sequence resemblance. Here we present a summary of these findings, focusing on the similarities, between mammals, C. elegans, and plants. An emphasis will be placed on the mitochondria and its role in the cell death pathway within each organism. Through the comparison of these systems on both a cellular and molecular level we can begin to better understand PCD in plant systems, and perhaps shed light on the pathways, which are controlling the process. This manuscript adds to the field of PCD in plant systems by profiling apoptotic factors, to scale on a protein

  6. The Molecular Ecophysiology of Programmed Cell Death in Marine Phytoplankton

    NASA Astrophysics Data System (ADS)

    Bidle, Kay D.

    2015-01-01

    Planktonic, prokaryotic, and eukaryotic photoautotrophs (phytoplankton) share a diverse and ancient evolutionary history, during which time they have played key roles in regulating marine food webs, biogeochemical cycles, and Earth's climate. Because phytoplankton represent the basis of marine ecosystems, the manner in which they die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining upper-ocean biogeochemistry. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of nutrient stressors and are employed by parasitic viruses, play an integral role in determining the cell fate of diverse photoautotrophs in the modern ocean. Indeed, these multifaceted death pathways continue to shape the success and evolutionary trajectory of diverse phytoplankton lineages at sea. Research over the past two decades has employed physiological, biochemical, and genetic techniques to provide a novel, comprehensive, mechanistic understanding of the factors controlling this key process. Here, I discuss the current understanding of the genetics, activation, and regulation of PCD pathways in marine model systems; how PCD evolved in unicellular photoautotrophs; how it mechanistically interfaces with viral infection pathways; how stress signals are sensed and transduced into cellular responses; and how novel molecular and biochemical tools are revealing the impact of PCD genes on the fate of natural phytoplankton assemblages.

  7. Some new approaches to the detection of programmed cell death

    NASA Astrophysics Data System (ADS)

    Bilyy, Rostyslav O.; Bilyi, Alexander I.; Getman, Vasyl B.; Kit, Yuriy Ya.; Mayor, Christina Ya.; Antonyuk, Volodmyr O.; Stoika, Rostyslav S.

    2006-08-01

    Apoptosis, or programmed cell death, is a form of cell death occurring during normal physiological processes and is used by the multicellular organism for elimination of "old" and impaired cells. Apoptosis is characterized by specific morphological changes such as plasma membrane blebbing, nucleus condensation, and cell wrinkling with further destruction into apoptotic bodies. Apoptosis detection is in focus of instrumental methods used in modern biomedical sciences. The available methods for such purpose are either very expensive, or require time-consuming operations. Their specificity and sensitivity are frequently not sufficient for biomedical diagnostics. We propose to use light scattering analysis for evaluation of apoptosis in cell population, especially for the detection of physical changes of cells, such as cell condensation and degradation into apoptotic bodies. The method proved to be very effective, providing quantitative estimation and high precision, simplicity and low costs of analysis (UA Patent No.64090). Another approach for the detection of apoptosis is based on the recently discovered fact (Bilyy, Stoika 2003; Bilyy et al, 2004; 2005) that apoptotic cells are characterized by increased expression levels of specific glycoproteins in the plasma membrane, which were proved to be selective and specific markers of apoptotic cells. Specific carbohydrate-binding proteins - lectins - were used for identification of mentioned glycoproteins; fluorescent conjugates of lectins were proved to be another novel tool for apoptosis identification using approaches of biophotonics.

  8. The molecular ecophysiology of programmed cell death in marine phytoplankton.

    PubMed

    Bidle, Kay D

    2015-01-01

    Planktonic, prokaryotic, and eukaryotic photoautotrophs (phytoplankton) share a diverse and ancient evolutionary history, during which time they have played key roles in regulating marine food webs, biogeochemical cycles, and Earth's climate. Because phytoplankton represent the basis of marine ecosystems, the manner in which they die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining upper-ocean biogeochemistry. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of nutrient stressors and are employed by parasitic viruses, play an integral role in determining the cell fate of diverse photoautotrophs in the modern ocean. Indeed, these multifaceted death pathways continue to shape the success and evolutionary trajectory of diverse phytoplankton lineages at sea. Research over the past two decades has employed physiological, biochemical, and genetic techniques to provide a novel, comprehensive, mechanistic understanding of the factors controlling this key process. Here, I discuss the current understanding of the genetics, activation, and regulation of PCD pathways in marine model systems; how PCD evolved in unicellular photoautotrophs; how it mechanistically interfaces with viral infection pathways; how stress signals are sensed and transduced into cellular responses; and how novel molecular and biochemical tools are revealing the impact of PCD genes on the fate of natural phytoplankton assemblages.

  9. Programmed Cell Death Initiation and Execution in Budding Yeast

    PubMed Central

    Strich, Randy

    2015-01-01

    Apoptosis or programmed cell death (PCD) was initially described in metazoans as a genetically controlled process leading to intracellular breakdown and engulfment by a neighboring cell . This process was distinguished from other forms of cell death like necrosis by maintenance of plasma membrane integrity prior to engulfment and the well-defined genetic system controlling this process. Apoptosis was originally described as a mechanism to reshape tissues during development. Given this context, the assumption was made that this process would not be found in simpler eukaryotes such as budding yeast. Although basic components of the apoptotic pathway were identified in yeast, initial observations suggested that it was devoid of prosurvival and prodeath regulatory proteins identified in mammalian cells. However, as apoptosis became extensively linked to the elimination of damaged cells, key PCD regulatory proteins were identified in yeast that play similar roles in mammals. This review highlights recent discoveries that have permitted information regarding PCD regulation in yeast to now inform experiments in animals. PMID:26272996

  10. Only in dying, life: programmed cell death during plant development.

    PubMed

    Van Hautegem, Tom; Waters, Andrew J; Goodrich, Justin; Nowack, Moritz K

    2015-02-01

    Programmed cell death (PCD) is a fundamental process of life. During the evolution of multicellular organisms, the actively controlled demise of cells has been recruited to fulfil a multitude of functions in development, differentiation, tissue homeostasis, and immune systems. In this review we discuss some of the multiple cases of PCD that occur as integral parts of plant development in a remarkable variety of cell types, tissues, and organs. Although research in the last decade has discovered a number of PCD regulators, mediators, and executers, we are still only beginning to understand the mechanistic complexity that tightly controls preparation, initiation, and execution of PCD as a process that is indispensable for successful vegetative and reproductive development of plants. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Functions and Regulation of Programmed Cell Death in Plant Development.

    PubMed

    Daneva, Anna; Gao, Zhen; Van Durme, Matthias; Nowack, Moritz K

    2016-10-06

    Programmed cell death (PCD) is a collective term for diverse processes causing an actively induced, tightly controlled cellular suicide. PCD has a multitude of functions in the development and health of multicellular organisms. In comparison to intensively studied forms of animal PCD such as apoptosis, our knowledge of the regulation of PCD in plants remains limited. Despite the importance of PCD in plant development and as a response to biotic and abiotic stresses, the complex molecular networks controlling different forms of plant PCD are only just beginning to emerge. With this review, we provide an update on the considerable progress that has been made over the last decade in our understanding of PCD as an inherent part of plant development. We highlight both functions of developmental PCD and central aspects of its molecular regulation.

  12. Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

    PubMed

    Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

    2015-01-01

    Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.

  13. Programmed cell death in bacteria and implications for antibiotic therapy

    PubMed Central

    Tanouchi, Yu; Lee, Anna Jisu; Meredith, Hannah; You, Lingchong

    2013-01-01

    It is now well appreciated that programmed cell death (PCD) plays critical roles in the life cycle of diverse bacterial species. It is an apparently paradoxical behavior as it does not benefit the cells undergoing PCD. However, growing evidence suggests that PCD can be ‘altruistic’: the dead cells may directly or indirectly benefit survivors through generation of public goods. This property provides a potential explanation on how PCD can evolve as an extreme form of cooperation, though many questions remain to be addressed. From another perspective, as PCD plays a critical role in bacterial pathogenesis, it has been proposed as a potential target for new antibacterial therapy. To this end, understanding the population and evolutionary dynamics resulting from PCD and public-good production may be a key to the success of designing effective antibiotic treatment. PMID:23684151

  14. On Programmed Cell Death in Plasmodium falciparum: Status Quo

    PubMed Central

    Engelbrecht, Dewaldt; Durand, Pierre Marcel; Coetzer, Thérèsa Louise

    2012-01-01

    Conflicting arguments and results exist regarding the occurrence and phenotype of programmed cell death (PCD) in the malaria parasite Plasmodium falciparum. Inconsistencies relate mainly to the number and type of PCD markers assessed and the different methodologies used in the studies. In this paper, we provide a comprehensive overview of the current state of knowledge and empirical evidence for PCD in the intraerythrocytic stages of P. falciparum. We consider possible reasons for discrepancies in the data and offer suggestions towards more standardised investigation methods in this field. Furthermore, we present genomic evidence for PCD machinery in P. falciparum. We discuss the potential adaptive or nonadaptive role of PCD in the parasite life cycle and its possible exploitation in the development of novel drug targets. Lastly, we pose pertinent unanswered questions concerning the PCD phenomenon in P. falciparum to provide future direction. PMID:22287973

  15. Programmed Cell Death in Animal Development and Disease

    PubMed Central

    Fuchs, Yaron; Steller, Hermann

    2015-01-01

    Programmed Cell Death (PCD) plays a fundamental role in animal development and tissue homeostasis. Abnormal regulation of this process is associated with a wide variety of human diseases, including immunological and developmental disorders, neuro-degeneration, and cancer. Here, we provide a brief historical overview of the field and reflect on myriad functions carried out by PCD during development and explore how PCD is regulated. We also focus on the function and regulation of apoptotic proteins, including caspases, the key executioners of apoptosis, highlighting the non-lethal functions of these proteins in diverse developmental processes including cell differentiation and tissue remodeling. Finally, we explore a growing body of work about the connections between apoptosis, stem cells and cancer, focusing on how apoptotic cells release a variety of signals to communicate with their cellular environment, including factors that promote cell division, tissue regeneration, and wound healing. PMID:22078876

  16. A role for programmed cell death in the microbial loop.

    PubMed

    Orellana, Mónica V; Pang, Wyming L; Durand, Pierre M; Whitehead, Kenia; Baliga, Nitin S

    2013-01-01

    The microbial loop is the conventional model by which nutrients and minerals are recycled in aquatic eco-systems. Biochemical pathways in different organisms become metabolically inter-connected such that nutrients are utilized, processed, released and re-utilized by others. The result is that unrelated individuals end up impacting each others' fitness directly through their metabolic activities. This study focused on the impact of programmed cell death (PCD) on a population's growth as well as its role in the exchange of carbon between two naturally co-occurring halophilic organisms. Flow cytometric, biochemical, ¹⁴C radioisotope tracing assays, and global transcriptomic analyses show that organic algal photosynthate released by Dunalliela salina cells undergoing PCD complements the nutritional needs of other non-PCD D. salina cells. This occurs in vitro in a carbon limited environment and enhances the growth of the population. In addition, a co-occurring heterotroph Halobacterium salinarum re-mineralizes the carbon providing elemental nutrients for the mixoheterotrophic chlorophyte. The significance of this is uncertain and the archaeon can also subsist entirely on the lysate of apoptotic algae. PCD is now well established in unicellular organisms; however its ecological relevance has been difficult to decipher. In this study we found that PCD in D. salina causes the release of organic nutrients such as glycerol, which can be used by others in the population as well as a co-occurring halophilic archaeon. H. salinarum also re-mineralizes the dissolved material promoting algal growth. PCD in D. salina was the mechanism for the flow of dissolved photosynthate between unrelated organisms. Ironically, programmed death plays a central role in an organism's own population growth and in the exchange of nutrients in the microbial loop.

  17. A Role for Programmed Cell Death in the Microbial Loop

    PubMed Central

    Durand, Pierre M.; Whitehead, Kenia; Baliga, Nitin S.

    2013-01-01

    The microbial loop is the conventional model by which nutrients and minerals are recycled in aquatic eco-systems. Biochemical pathways in different organisms become metabolically inter-connected such that nutrients are utilized, processed, released and re-utilized by others. The result is that unrelated individuals end up impacting each others' fitness directly through their metabolic activities. This study focused on the impact of programmed cell death (PCD) on a population's growth as well as its role in the exchange of carbon between two naturally co-occurring halophilic organisms. Flow cytometric, biochemical, 14C radioisotope tracing assays, and global transcriptomic analyses show that organic algal photosynthate released by Dunalliela salina cells undergoing PCD complements the nutritional needs of other non-PCD D. salina cells. This occurs in vitro in a carbon limited environment and enhances the growth of the population. In addition, a co-occurring heterotroph Halobacterium salinarum re-mineralizes the carbon providing elemental nutrients for the mixoheterotrophic chlorophyte. The significance of this is uncertain and the archaeon can also subsist entirely on the lysate of apoptotic algae. PCD is now well established in unicellular organisms; however its ecological relevance has been difficult to decipher. In this study we found that PCD in D. salina causes the release of organic nutrients such as glycerol, which can be used by others in the population as well as a co-occurring halophilic archaeon. H. salinarum also re-mineralizes the dissolved material promoting algal growth. PCD in D. salina was the mechanism for the flow of dissolved photosynthate between unrelated organisms. Ironically, programmed death plays a central role in an organism's own population growth and in the exchange of nutrients in the microbial loop. PMID:23667496

  18. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors.

    PubMed

    Ito, Tetsuhide; Igarashi, Hisato; Uehara, Hirotsugu; Berna, Marc J; Jensen, Robert T

    2013-05-01

    Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature

  19. Caspase-like activity in programmed nuclear death during conjugation of Tetrahymena thermophila.

    PubMed

    Kobayashi, T; Endoh, H

    2003-06-01

    Apoptosis, or programmed cell death, is common in a variety of eucaryotes, from unicellular protozoa to vertebrates. The ciliated protozoan Tetrahymena thermophila has a unique apoptosis-like nuclear death during conjugation, called programmed nuclear death. This death program involves nuclear condensation (pyknosis) and oligonucleosomal DNA fragmentation in the parental macronucleus. Subsequently, the condensed nucleus is entirely resorbed in the autophagosome. Here we demonstrate that caspase-8- and -9-like activity was detected, but no caspase-3-like activity, by in vitro assay during the nuclear resorption process, suggesting that caspase-like activity is associated with both programmed cell death and apoptosis-like nuclear death in Tetrahymena. The use of indicator dye to detect the loss of mitochondrial membrane potential suggested the uptake of mitochondria and the degenerating macronucleus by the autophagosome. An involvement of mitochondria in the programmed nuclear death is discussed.

  20. Programmed cell death in plants: A chloroplastic connection

    PubMed Central

    Ambastha, Vivek; Tripathy, Baishnab C; Tiwari, Budhi Sagar

    2015-01-01

    Programmed cell death (PCD) is an integral cellular program by which targeted cells culminate to demise under certain developmental and pathological conditions. It is essential for controlling cell number, removing unwanted diseased or damaged cells and maintaining the cellular homeostasis. The details of PCD process has been very well elucidated and characterized in animals but similar understanding of the process in plants has not been achieved rather the field is still in its infancy that sees some sporadic reports every now and then. The plants have 2 energy generating sub-cellular organelles- mitochondria and chloroplasts unlike animals that just have mitochondria. The presence of chloroplast as an additional energy transducing and ROS generating compartment in a plant cell inclines to advocate the involvement of chloroplasts in PCD execution process. As chloroplasts are supposed to be progenies of unicellular photosynthetic organisms that evolved as a result of endosymbiosis, the possibility of retaining some of the components involved in bacterial PCD by chloroplasts cannot be ruled out. Despite several excellent reviews on PCD in plants, there is a void on an update of information at a place on the regulation of PCD by chloroplast. This review has been written to provide an update on the information supporting the involvement of chloroplast in PCD process and the possible future course of the field. PMID:25760871

  1. Development of a Microfluidic Platform to Analyze Evolution of Programmed Bacterial Death

    DTIC Science & Technology

    2015-12-20

    SECURITY CLASSIFICATION OF: Evolution of programmed cell death in bacteria is a poorly understood phenomenon in biology. A critical limitation...Final Report: Development of a Microfluidic Platform to Analyze Evolution of Programmed Bacterial Death The views, opinions and/or findings contained...Papers published in non peer-reviewed journals: Final Report: Development of a Microfluidic Platform to Analyze Evolution of Programmed Bacterial Death

  2. Death by a thousand cuts: granzyme pathways of programmed cell death.

    PubMed

    Chowdhury, Dipanjan; Lieberman, Judy

    2008-01-01

    The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.

  3. Using Small Molecules to Dissect Non-apoptotic Programmed Cell Death: Necroptosis, Ferroptosis, and Pyroptosis.

    PubMed

    Dong, Ting; Liao, Daohong; Liu, Xiaohui; Lei, Xiaoguang

    2015-12-01

    Genetically programmed cell death is a universal and fundamental cellular process in multicellular organisms. Apoptosis and necroptosis, two common forms of programmed cell death, play vital roles in maintenance of homeostasis in metazoans. Dysfunction of the regulatory machinery of these processes can lead to carcinogenesis or autoimmune diseases. Inappropriate death of essential cells can lead to organ dysfunction or even death; ischemia-reperfusion injury and neurodegenerative disorders are examples of this. Recently, novel forms of non-apoptotic programmed cell death have been identified. Although these forms of cell death play significant roles in both physiological and pathological conditions, the detailed molecular mechanisms underlying them are still poorly understood. Here, we discuss progress in using small molecules to dissect three forms of non-apoptotic programmed cell death: necroptosis, ferroptosis, and pyroptosis.

  4. Analysis of the Death Gratuity Program: History, Current Issues and Future Implications

    DTIC Science & Technology

    2005-12-01

    11 III. THE EFFECTS OF PUBLIC LAW 109-13 ON THE DEATH GRATUITY...government life insurance policy remained in effect , the death gratuity was no longer necessary. Additional controversy also developed over the debate...III. THE EFFECTS OF PUBLIC LAW 109-13 ON THE DEATH GRATUITY PROGRAM A. INTRODUCTION The purpose

  5. The Evaluation of Two Death Education Programs for EMTs Using the Theory of Planned Behavior

    ERIC Educational Resources Information Center

    Smith-Cumberland, Tracy

    2006-01-01

    The goal of this study was to evaluate the effectiveness of two death education programs by comparing pretest and posttest scores of behavioral intentions and (reported) behavior of EMTs when at the scene of a death. After the interventions, the majority of EMTs intended to change their behavior at the scene of a death when compared to the control…

  6. The Evaluation of Two Death Education Programs for EMTs Using the Theory of Planned Behavior

    ERIC Educational Resources Information Center

    Smith-Cumberland, Tracy

    2006-01-01

    The goal of this study was to evaluate the effectiveness of two death education programs by comparing pretest and posttest scores of behavioral intentions and (reported) behavior of EMTs when at the scene of a death. After the interventions, the majority of EMTs intended to change their behavior at the scene of a death when compared to the control…

  7. Death of Prorocentrum donghaiense may be a programmed autolysis

    NASA Astrophysics Data System (ADS)

    Yang, Guanpin; Liu, Yongjian; Li, Bingjun

    2008-08-01

    Prorocentrum donghaiense, one of the dinoflagellate, has continuously caused large scale red tides along the Chinese coast in recent years. These red tides have brought tremendous loss to the local economy and serious impacts to the local environment. Unfortunately, little was known about the mechanism of the fast appearance and extinction of the red tide caused by this alga. In this study, the full-length cDNA of a caspase encoding gene of P. donghaiense was cloned and characterized, and the transcription of this gene during the senescence of the alga was semi-quantitatively determined. The cDNA was 520 bp in length. It contained a 258 bp open reading frame (ORF) which encoded a peptide of 85 amino acids. The amount of transcripts of the caspase encoding gene increased with the senescence of P. donghaiense and started to decrease gradually when the autolysis of P. donghaiense cells took place. We proposed that the death of P. donghaiense may be a caspase mediated programmed autolysis.

  8. Acetylsalicylic acid induces programmed cell death in Arabidopsis cell cultures.

    PubMed

    García-Heredia, José M; Hervás, Manuel; De la Rosa, Miguel A; Navarro, José A

    2008-06-01

    Acetylsalicylic acid (ASA), a derivative from the plant hormone salicylic acid (SA), is a commonly used drug that has a dual role in animal organisms as an anti-inflammatory and anticancer agent. It acts as an inhibitor of cyclooxygenases (COXs), which catalyze prostaglandins production. It is known that ASA serves as an apoptotic agent on cancer cells through the inhibition of the COX-2 enzyme. Here, we provide evidences that ASA also behaves as an agent inducing programmed cell death (PCD) in cell cultures of the model plant Arabidopsis thaliana, in a similar way than the well-established PCD-inducing agent H(2)O(2), although the induction of PCD by ASA requires much lower inducer concentrations. Moreover, ASA is herein shown to be a more efficient PCD-inducing agent than salicylic acid. ASA treatment of Arabidopsis cells induces typical PCD-linked morphological and biochemical changes, namely cell shrinkage, nuclear DNA degradation, loss of mitochondrial membrane potential, cytochrome c release from mitochondria and induction of caspase-like activity. However, the ASA effect can be partially reverted by jasmonic acid. Taking together, these results reveal the existence of common features in ASA-induced animal apoptosis and plant PCD, and also suggest that there are similarities between the pathways of synthesis and function of prostanoid-like lipid mediators in animal and plant organisms.

  9. Involvement of chloroplasts in the programmed death of plant cells.

    PubMed

    Samuilov, V D; Lagunova, E M; Dzyubinskaya, E V; Izyumov, D S; Kiselevsky, D B; Makarova, Ya V

    2002-06-01

    The effect of cyanide, an apoptosis inducer, on pea leaf epidermal peels was investigated. Illumination stimulated the CN--induced destruction of guard cells (containing chloroplasts and mitochondria) but not of epidermal cells (containing mitochondria only). The process was prevented by antioxidants (alpha-tocopherol, 2,5-di-tret-butyl-4-hydroxytoluene, and mannitol), by anaerobiosis, by the protein kinase C inhibitor staurosporine, and by cysteine and serine protease inhibitors. Electron acceptors (menadione, p-benzoquinone, diaminodurene, TMPD, DCPIP, and methyl viologen) suppressed CN--induced apoptosis of guard cells, but not epidermal cells. Methyl viologen had no influence on the removal of CN--induced nucleus destruction in guard cells under anaerobic conditions. The light activation of CN--induced apoptosis of guard cells was suppressed by DCMU (an inhibitor of the electron transfer in Photosystem II) and by DNP-INT (an antagonist of plastoquinol at the Qo site of the chloroplast cytochrome b6f complex). It is concluded that apoptosis initiation in guard cells depends on the simultaneous availability of two factors, ROS and reduced quinones of the electron transfer chain. The conditions for manifestation of programmed cell death in guard and epidermal cells of the pea leaf were significantly different.

  10. Apoptosis: understanding programmed cell death for the CRNA.

    PubMed

    Bennetts, Paul S; Pierce, Janet D

    2010-06-01

    Apoptosis, or programmed cell death, is a physiologic mechanism employed by most multicellular organisms to maintain homeostasis of body tissues. In balance with the production of new cells by mitosis, apoptosis provides for the orderly destruction and removal of cells that are no longer needed by the organism. Apoptosis occurs by complex pathways involving multiple biochemical signals and processes. Dysfunctional apoptotic mechanisms are the pathologic basis for many human diseases, including common disorders of the heart, lungs, brain, and endocrine systems. Researchers have demonstrated in animal models that neurodegenerative changes after the administration of anesthetic drugs are related to apoptosis. Anesthesia drugs have been found to induce apoptosis, perhaps through the production of reactive oxygen species. Propofol is a drug used in anesthesia that has unique antioxidant qualities that may be beneficial. The purpose of this article is to review, for nurse anesthesia providers, current information about the process of apoptosis, the role of apoptosis in comorbid diseases, and the implications of the effects of anesthesia drugs on normal apoptotic mechanisms that need to be evaluated as potential sources of risk or benefit to surgical patients.

  11. Is programmed cell death required for neural tube closure?

    PubMed

    Weil, M; Jacobson, M D; Raff, M C

    1997-04-01

    Programmed cell death (PCD) plays an important part in animal development. It is responsible for eliminating the cells between developing digits, for example, and is involved in hollowing out solid structures to create cavities (reviewed in [1] [2]). There are many cases, however, where PCD occurs in developing tissues but its function is unknown. Important examples are seen during the folding, pinching off, and fusion of epithelial sheets during vertebrate morphogenesis, as in the formation of the neural tube and lens vesicle [2]; PCD is an invariable accompaniment to these processes, but it is unclear whether it is required for the processes to occur or is just an unavoidable consequence of them. There is increasing evidence that PCD in animals is mediated by a family of cysteine proteases, known as caspases, which are thought to act in a proteolytic cascade, cleaving one another and key intracellular proteins to kill the cell in a controlled way [3] [4]. Inhibitors of caspases are, therefore, potential tools for studying the roles of PCD during animal development [5] [6]. Here, we show that peptide caspase inhibitors block neural tube closure in explanted chick embryos, suggesting that PCD is required for this crucial developmental process.

  12. Gigantic macroautophagy in programmed nuclear death of Tetrahymena thermophila.

    PubMed

    Akematsu, Takahiko; Pearlman, Ronald E; Endoh, Hiroshi

    2010-10-01

    Programmed nuclear death (PND) in Tetrahymena is a unique process during conjugation, in which only the parental macronucleus is degraded and then eliminated from the progeny cytoplasm, but other co-existing nuclei such as new micro- and macronuclei are unaffected. PND through autophagic elimination is expected to be strictly controlled, considering the significant roles in ciliates such as turnover of disused organelles and production of the next generation. Here we demonstrate that PND in Tetrahymena involves peculiar aspects of autophagy, which differ from mammalian or yeast macroautophagy. Drastic change of the parental macronucleus occurs when differentiation of new macronuclei is initiated. Combined use of monodansylcadaverine and a lysosome indicator LysoTracker Red showed that prior to nuclear condensation, the envelope of the parental macronucleus changed its nature as if it is an autophagic membrane, without the accumulation of a pre-autophagosomal structure from the cytoplasm. Subsequently, lysosomes approached only to the parental macronucleus and localized at the envelope until a final resorption stage. In addition, we found that the parental macronucleus exhibits certain sugars and phosphatidylserine on the envelope, which are possible "attack me" signals, that are not found on other types of nuclei. These findings suggest that PND is a highly elaborated process, different from the typical macroautophagy seen in other systems, and is executed through interaction between specific molecular signals on the parental macronuclear envelope and autophagic/lysosomal machineries.

  13. Programmed death-1 pathway in cancer and autoimmunity.

    PubMed

    Pedoeem, Ariel; Azoulay-Alfaguter, Inbar; Strazza, Marianne; Silverman, Gregg J; Mor, Adam

    2014-07-01

    Programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. A major functional role of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune diseases. Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-1 pathway has become an attractive target in cancer therapy. Recent clinical trials have shown that anti-PD-1 agents have profound effects on solid tumor regression. Current approaches include six agents that are either PD-1 and PD-L1 targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-1 blockade in variety of tumor types. In this review we will highlight the basic biology of the PD-1 system and discuss its potential roles in both autoimmunity and cancer. We propose that future research on PD-1 may lead to the translation of fundamental regulatory pathways into the development of practical new approaches for the treatment of autoimmune diseases and cancer.

  14. Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy.

    PubMed

    Ariyasu, Ryo; Horiike, Atsushi; Yoshizawa, Takahiro; Dotsu, Yosuke; Koyama, Junji; Saiki, Masafumi; Sonoda, Tomoaki; Nishikawa, Shingo; Kitazono, Satoru; Yanagitani, Noriko; Nishio, Makoto

    2017-08-01

    Adrenal insufficiency is one of the adverse events (AEs) associated with anti-programmed death-1 (PD1) therapy. Delaying diagnoses can lead to serious conditions. It is necessary to elucidate detailed clinical features of these AEs. Patients treated with anti-PD-1 monotherapy or in combination with anti-cytotoxic T cell lymphocyte-4 therapy at our hospital from January 2013 to December 2016 were identified. The patients' clinical characteristics and laboratory and radiologic findings were collected. Adrenal insufficiency occurred in 3% of the patients. All patients were male. At the onset of symptoms, eosinophilia (>500/μl) was observed in four cases. Eosinophilia was observed more than a month before onset of symptoms in three cases. Other pituitary hormones remained relatively stable. Radiological evidence of pituitary inflammation was detected only in one case. Most anti-PD1-related adrenal insufficiency cases involved an isolated ACTH deficiency. Eosinophilia may be an early indicator before the onset of symptoms. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  15. Bacterial Programmed Cell Death as a Population Phenomenon

    DTIC Science & Technology

    2013-06-11

    Moving in for the kil:Activation of an endoribonuclease toxin by quorum sensing peptide, Molecular Cell, (03 2011): . doi: 06/11/2013 11.00...shown that E. coli mazEF-mediated cell death is a population phenomenon requiring the E. coli quorum sensing factor EDF (Extracellular Death Factor... quorum - sensing factor required for mazEF-mediated cell death in Escherichia coli. Science 318: 652-655. 7) Kolodkin-Gal I, Engelberg-Kulka, H (2008

  16. Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma

    PubMed Central

    Wolchok, Jedd D.; Robert, Caroline; Hwu, Wen-Jen; Weber, Jeffrey S.; Ribas, Antoni; Hodi, F. Stephen; Joshua, Anthony M.; Kefford, Richard; Hersey, Peter; Joseph, Richard; Gangadhar, Tara C.; Dronca, Roxana; Patnaik, Amita; Zarour, Hassane; Roach, Charlotte; Toland, Grant; Lunceford, Jared K.; Li, Xiaoyun Nicole; Emancipator, Kenneth; Dolled-Filhart, Marisa; Kang, S. Peter; Ebbinghaus, Scot; Hamid, Omid

    2016-01-01

    Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti–programmed death 1 (PD-1). This study explored the relationship between anti–PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1–positive tumors. Demographic and staging variables were equally distributed among PD-L1–positive and –negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed (P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1–negative tumors may also achieve durable responses. PMID:27863197

  17. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma.

    PubMed

    Daud, Adil I; Wolchok, Jedd D; Robert, Caroline; Hwu, Wen-Jen; Weber, Jeffrey S; Ribas, Antoni; Hodi, F Stephen; Joshua, Anthony M; Kefford, Richard; Hersey, Peter; Joseph, Richard; Gangadhar, Tara C; Dronca, Roxana; Patnaik, Amita; Zarour, Hassane; Roach, Charlotte; Toland, Grant; Lunceford, Jared K; Li, Xiaoyun Nicole; Emancipator, Kenneth; Dolled-Filhart, Marisa; Kang, S Peter; Ebbinghaus, Scot; Hamid, Omid

    2016-12-01

    Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

  18. Quantitating lymphocyte programmed cell death in vitro using simple kill assays.

    PubMed

    Zheng, Lixin

    2013-01-01

    Programmed cell death is essential to maintaining lymphocyte homeostasis during the contraction phase of the immune response. Activated lymphocytes become susceptible to a variety of programmed cell death (PCD) stimuli over the course of a typical immune response. This chapter outlines two simple approaches for measuring programmed cell death of lymphocytes cultured in vitro, regardless of the stimulus provided. These techniques exploit changes in plasma membrane integrity and/or mitochondrial membrane potential that are characteristic of cells undergoing PCD. The detection methods discussed are generally applicable for assessing cell death in several contexts, expanded upon in further detail in subsequent chapters.

  19. Cell death programs in Yersinia immunity and pathogenesis

    PubMed Central

    Philip, Naomi H.; Brodsky, Igor E.

    2012-01-01

    Cell death plays a central role in host-pathogen interactions, as it can eliminate the pathogen's replicative niche and provide pro-inflammatory signals necessary for an effective immune response; conversely, cell death can allow pathogens to eliminate immune cells and evade anti-microbial effector mechanisms. In response to developmental signals or cell-intrinsic stresses, the executioner caspases-3 and -7 mediate apoptotic cell death, which is generally viewed as immunologically silent or immunosuppressive. A proinflammatory form of cell death that requires caspase-1, termed pyroptosis, is activated in response to microbial products within the host cytosol or disruption of cellular membranes by microbial pathogens. Infection by the bacterial pathogen Yersinia has features of both apoptosis and pyroptosis. Cell death and caspase-1 processing in Yersinia-infected cells occur in response to inhibition of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ. However, the molecular basis of YopJ-induced cell death, and the role of different death pathways in anti-Yersinia immune responses remain enigmatic. Here, we discuss the role that cell death may play in inducing specific pro-inflammatory signals that shape innate and adaptive immune responses against Yersinia infection. PMID:23226685

  20. Cell death programs in Yersinia immunity and pathogenesis.

    PubMed

    Philip, Naomi H; Brodsky, Igor E

    2012-01-01

    Cell death plays a central role in host-pathogen interactions, as it can eliminate the pathogen's replicative niche and provide pro-inflammatory signals necessary for an effective immune response; conversely, cell death can allow pathogens to eliminate immune cells and evade anti-microbial effector mechanisms. In response to developmental signals or cell-intrinsic stresses, the executioner caspases-3 and -7 mediate apoptotic cell death, which is generally viewed as immunologically silent or immunosuppressive. A proinflammatory form of cell death that requires caspase-1, termed pyroptosis, is activated in response to microbial products within the host cytosol or disruption of cellular membranes by microbial pathogens. Infection by the bacterial pathogen Yersinia has features of both apoptosis and pyroptosis. Cell death and caspase-1 processing in Yersinia-infected cells occur in response to inhibition of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ. However, the molecular basis of YopJ-induced cell death, and the role of different death pathways in anti-Yersinia immune responses remain enigmatic. Here, we discuss the role that cell death may play in inducing specific pro-inflammatory signals that shape innate and adaptive immune responses against Yersinia infection.

  1. Blockade of programmed death-1/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells.

    PubMed

    Kamata, Toshiko; Suzuki, Akane; Mise, Naoko; Ihara, Fumie; Takami, Mariko; Makita, Yuji; Horinaka, Atsushi; Harada, Kazuaki; Kunii, Naoki; Yoshida, Shigetoshi; Yoshino, Ichiro; Nakayama, Toshinori; Motohashi, Shinichiro

    2016-12-01

    The role of invariant natural killer T (iNKT) cells in antitumor immunity has been studied extensively, and clinical trials in patients with advanced cancer have revealed a prolonged survival in some cases. In recent years, humanized blocking antibodies against co-stimulatory molecules such as PD-1 have been developed. The enhancement of T cell function is reported to improve antitumor immunity, leading to positive clinical effects. However, there are limited data on the role of PD-1/programmed death ligand (PDL) molecules in human iNKT cells. In this study, we investigated the interaction between PD-1 on iNKT cells and PDL on antigen-presenting cells (APCs) in the context of iNKT cell stimulation. The blockade of PDL1 at the time of stimulation resulted in increased release of helper T cell (Th) 1 cytokines from iNKT cells, leading to the activation of NK cells. The direct antitumor function of iNKT cells was also enhanced after stimulation with anti-PDL1 antibody-treated APCs. According to these results, we conclude that the co-administration of anti-PDL1 antibody and alpha-galactosylceramide (αGalCer)-pulsed APCs enhances iNKT cell-mediated antitumor immunity.

  2. A Traumatic Death Support Group Program: Applying an Integrated Conceptual Framework

    ERIC Educational Resources Information Center

    Walijarvi, Corrine M.; Weiss, Ann H.; Weinman, Maxine L.

    2012-01-01

    This article describes an 8-week, curriculum-based traumatic death support group program that is offered at Bo's Place, a grief and bereavement center in Houston, Texas. The program was implemented in 2006 in an effort to help family members who had experienced a death in the family by suicide, murder, accident, or sudden medical problem. The…

  3. A Traumatic Death Support Group Program: Applying an Integrated Conceptual Framework

    ERIC Educational Resources Information Center

    Walijarvi, Corrine M.; Weiss, Ann H.; Weinman, Maxine L.

    2012-01-01

    This article describes an 8-week, curriculum-based traumatic death support group program that is offered at Bo's Place, a grief and bereavement center in Houston, Texas. The program was implemented in 2006 in an effort to help family members who had experienced a death in the family by suicide, murder, accident, or sudden medical problem. The…

  4. Programmed cell death ligand 1 expression in osteosarcoma.

    PubMed

    Shen, Jacson K; Cote, Gregory M; Choy, Edwin; Yang, Pei; Harmon, David; Schwab, Joseph; Nielsen, G Petur; Chebib, Ivan; Ferrone, Soldano; Wang, Xinhui; Wang, Yangyang; Mankin, Henry; Hornicek, Francis J; Duan, Zhenfeng

    2014-07-01

    Programmed cell death ligand 1 (PDL1, also known as B7H1) is a cell-surface protein that suppresses the cytotoxic CD8(+) T-cell-mediated immune response. PDL1 expression and its clinical relevance in sarcomas are not well understood. Therefore, we sought to measure RNA expression levels for PDL1 in 38 clinically annotated osteosarcoma tumor samples and aimed to determine if PDL1 expression correlates with clinical features and tumor-infiltrating lymphocytes (TIL). Quantitative real-time RT-PCR for PDL1 was optimized in 18 cell lines, of which 5 were osteosarcoma derived. qRT-PCR results were validated via flow cytometry and immunohistochemistry (IHC) in select cell lines. Total RNA was isolated from 38 human osteosarcoma samples for qRT-PCR analysis. Clinical data were sorted, and significance was determined by the Student t test. TILs were examined in patient samples by tissue microarray hematoxylin-eosin staining. We confirmed the constitutive PDL1 mRNA expression in cell lines by qRT-PCR, flow cytometry, and IHC. Across human osteosarcoma samples, PDL1 mRNA gene expression ranged over 4 log (>5,000-fold difference). Relative expression levels were evaluated against clinical factors such as age/gender, metastasis, recurrence, chemotherapy, percentage of necrosis, and survival; no significant associations were identified. The presence of TILs was associated with high PDL1 expression (R(2) = 0.37; P = 0.01). In summary, we developed an RNA-based assay to determine PDL1 expression levels, and we show, for the first time, that high levels of PDL1 are expressed in a subset of osteosarcoma, and PDL1 expression is positively correlated with TILs. Multiple agents targeting PD1/PDL1 are in clinical development, and this may be a novel immunotherapeutic strategy for osteosarcoma clinical trials.

  5. Apoptosis (programmed cell death) as an indicator of xenobiotic toxicity

    SciTech Connect

    Bond, G.P.

    1989-01-01

    Xenobiotics alter the frequency and pattern of apoptosis (programmed cell death). Preliminary studies identified the mouse liver, with normally low levels of apoptosis, as a preferable test system to the chicken embryo limb, with normally high levels of apoptosis. The major purposes of these investigations, using the apoptogen and necrogen 1,1-dichloroethylene (DCE), were to determine if increases in apoptosis, (1) could be quantified as a direct result of treatment, (2) were dose- and time-dependent, (3) were independent of necrosis, (4) were associated with mitosis in the control of cell numbers and (5) were limited to specific areas of the liver. To these ends, food-deprived female, CF-1 mice were administered DCE ip under varying experimental conditions. Increased apoptosis occurred in a dose- and time-dependent manner after treatment with 12.5, 40, and 125 mg/kg for 0.5, 1, 2, 4 and 8 hr. Peak effects were observed at 4 hr. Apoptosis occurred only in the midzonal/pericentral areas of the liver. At 12.5 mg/kg, there were no effects on biochemical (alanine transaminase) and morphological indices of necrosis, establishing apoptosis as a separate phenomenon from necrosis. Increased {sup 3}H-thymidine incorporation (DNA synthesis), mitosis and the percentage of octaploid hepatocytes occurred from 24-48 hr after treatment with the apoptotic but non-necrotic dose of 40 mg/kg. Apoptosis only occurred in the midzonal/pericentral areas of the liver after multiple doses with DCE, indicating the zonal selectivity of the response. In conclusion, apoptosis, a normally occurring homeostatic process associated with mitosis in the control of cell numbers, is affected by selected xenobiotics in a dose-dependent manner. Xenobiotic-induced apoptosis in the liver occurs at low doses of xenobiotics which cause no other effects on tissue structure or function.

  6. Design of a Self-Management Program for Children Aged 6-12 Years with Type 1 Diabetes Mellitus at the Community Hospital Herdecke, Germany.

    PubMed

    Berger, Bettina; Sethe, Dominik; Hilgard, Dörte; Martin, David; Heusser, Peter

    2017-01-01

    Children with type 1 diabetes mellitus (T1DM) must replace lacking endogenous insulin by daily insulin injections or insulin pumps. Standards of treatment include educational programs enabling self-management. The program 'Herdecker Kids with Diabetes' (HeKiDi) is based on an anthroposophic understanding of the human being and intends to provide an individualized, patient-oriented approach to developing diabetes-related and comprehensive human competencies. Analysis of the HeKiDi program for children (6-12 years) with T1DM as the first part of an evaluation of a complex intervention. Ethnographic approach, following the Consolidated Criteria for Reporting Qualitative Research (COREQ), including field observations and interviews with responsible persons, content analysis of materials for determining the structure and the curriculum, presented according to the Template for Intervention Description and Replication (TIDieR). The curriculum follows the standard but adds a learning circle between the child and the therapeutic team comprising 3 stages: (1) perception of the abilities and needs of the individual child supported by adult mentors themselves suffering from T1DM, (2) reflection within the therapeutic team, and (3) daily feedback to the child. Curricular Learning Objectives: Children feel recognized and supported in their individual developmental and diabetes-related competencies and develop motoric, artistic, communicative, and social skills to strengthen their self-efficacy and to understand T1DM as a lifelong awareness process. The curriculum including its associated learning goals and methods was presented. The program was explained and shown to be reproducible. Whether this program truly leads to better outcomes in regard to self-efficacy and hemoglobin A1c (HbA1c, glycated hemoglobin) and how parents and children perceive this will have to be assessed using a comparative interventional study. © 2017 S. Karger GmbH, Freiburg.

  7. A Bereavement Support Program for Survivors of Cancer Deaths: A Description and Evaluation.

    ERIC Educational Resources Information Center

    Souter, Susan J.; Moore, Timothy E.

    1990-01-01

    Describes bereavement support program for survivors of cancer deaths developed by Riverdale Hospital in Toronto, Ontario. Presents detailed program evaluation which asked bereaved survivors who were program participants for one year to evaluate program aspects and facilitation of their grief by volunteers. Recommendations for expansion and…

  8. Programmed death-1/programmed death-L1 signaling pathway and its blockade in hepatitis C virus immunotherapy.

    PubMed

    Salem, Mohamed L; El-Badawy, Ahmed

    2015-10-18

    Chronic hepatitis C virus (HCV) infection is a public health issue that often progresses to life-threatening complications, including liver cirrhosis, fibrosis, and hepatocellular carcinoma. Impaired immune responses to HCV are key features of chronic HCV infection. Therefore, intervention strategies usually involve enhancing the immune responses against HCV. Cytotoxic CD8(+) T lymphocytes (CTLs) play a critical role in the control of HCV infection. However, their cytolytic function can be impaired by the expression of co-inhibitory molecules. Programmed death-1 (PD-1) receptor and its ligand PD-L1 function in a T cell co-inhibitory pathway, which either blocks the function of CTLs or the differentiation of CD8(+) T cells. During chronic HCV infection, the immune inhibitory receptor PD-1 is upregulated on dysfunctional HCV-specific CD8(+) T cells. As such, blockade of the PD-1/PD-L1 pathway in these CD8(+) T cells might restore their functional capabilities. Indeed, clinical trials using therapies to block this pathway have shown promise in the fostering of anti-HCV immunity. Understanding how chronic HCV infection induces upregulation of PD-1 on HCV specific T cells and how the PD-1/PD-L1 interaction develops HCV specific T cell dysfunction will accelerate the development of an efficacious prophylactic and therapeutic vaccination against chronic HCV infections, which will significantly improve HCV treatments and patient survival. In this review, we discuss the relationship between PD-1 expression and clinical responses and the potential use of PD-1 blockade for anti-HCV therapy.

  9. Zinc treatment prevents type 1 diabetes-induced hepatic oxidative damage, endoplasmic reticulum stress, and cell death, and even prevents possible steatohepatitis in the OVE26 mouse model: Important role of metallothionein.

    PubMed

    Liang, Tingting; Zhang, Quan; Sun, Weixia; Xin, Ying; Zhang, Zhiguo; Tan, Yi; Zhou, Shanshan; Zhang, Chi; Cai, Lu; Lu, Xuemian; Cheng, Mingliang

    2015-03-04

    Whether zinc is able to improve diabetes-induced liver injury remains unknown. Transgenic type 1 diabetic (OVE26) mice develop hyperglycemia at 3 weeks old; therefore therapeutic effect of zinc on diabetes-induced liver injury was investigated in OVE26 mice. Three-month old OVE26 and age-matched wild-type mice were treated by gavage with saline or zinc at 5mg/kg body-weight every other day for 3 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level with liver histopathological and biochemical changes. OVE26 mice at 6 months old showed significant increases in serum ALT level and hepatic oxidative damage, endoplasmic reticulum stress and associated cell death, mild inflammation, and fibrosis. However, all these hepatic morphological and functional changes were significantly prevented in 3-month zinc-treated OVE26 mice. Mechanistically, zinc treatment significantly increased hepatic metallothionein, a protein with known antioxidant activity, in both wild-type and OVE26 mice. These results suggest that there were significantly functional, structural and biochemical abnormalities in the liver of OVE26 diabetic mice at 6 months old; however, all these changes could be prevented with zinc treatment, which was associated with the upregulation of hepatic metallothionein expression.

  10. HIV Type 1 Disease Progression to AIDS and Death in a Rural Ugandan Cohort Is Primarily Dependent on Viral Load Despite Variable Subtype and T-Cell Immune Activation Levels

    PubMed Central

    Eller, Michael A.; Opollo, Marc S.; Liu, Michelle; Redd, Andrew D.; Eller, Leigh Anne; Kityo, Cissy; Kayiwa, Joshua; Laeyendecker, Oliver; Wawer, Maria J.; Milazzo, Mark; Kiwanuka, Noah; Gray, Ronald H.; Serwadda, David; Sewankambo, Nelson K.; Quinn, Thomas C.; Michael, Nelson L.; Wabwire-Mangen, Fred; Sandberg, Johan K.; Robb, Merlin L.

    2015-01-01

    Background. Untreated human immunodeficiency virus type 1 (HIV) infection is associated with persistent immune activation, which is an independent driver of disease progression in European and United States cohorts. In Uganda, HIV-1 subtypes A and D and recombinant AD viruses predominate and exhibit differential rates of disease progression. Methods. HIV-1 seroconverters (n = 156) from rural Uganda were evaluated to assess the effects of T-cell activation, viral load, and viral subtype on disease progression during clinical follow-up. Results. The frequency of activated T cells was increased in HIV-1–infected Ugandans, compared with community matched uninfected individuals, but did not differ significantly between viral subtypes. Higher HIV-1 load, subtype D, older age, and high T-cell activation levels were associated with faster disease progression to AIDS or death. In a multivariate Cox regression analysis, HIV-1 load was the strongest predictor of progression, with subtype also contributing. T-cell activation did not emerge an independent predictor of disease progression from this particular cohort. Conclusions. These findings suggest that the independent contribution of T-cell activation on morbidity and mortality observed in European and North American cohorts may not be directly translated to the HIV epidemic in East Africa. In this setting, HIV-1 load appears to be the primary determinant of disease progression. PMID:25404522

  11. Reducing and preventing internalizing and externalizing behavior problems in children with type 1 diabetes: a randomized controlled trial of the Triple P-Positive Parenting Program.

    PubMed

    Westrupp, E M; Northam, E; Lee, K J; Scratch, S E; Cameron, F

    2015-11-01

    Children with type 1 diabetes are at increased risk of mental health problems, which in turn are associated with poor glycemic control, diabetes-related complications, and long-term psychiatric morbidity. We tested the efficacy of the Triple P-Positive Parenting Program in reducing or preventing mental health problems and improving glycemic control in children with type 1 diabetes in a randomized controlled trial. Participants were recruited from the Diabetes Clinic, Royal Children's Hospital, Melbourne, Australia, and randomized to Triple P or standard diabetes care. The primary outcome was child internalizing and externalizing behavior problems 3 and 12 months postrandomization. Secondary outcomes were glycemic control, parent mental health, parenting skills, and family functioning at 3 and 12 months, and glycemic control at 24 months. A total of 76 participants were randomized (38 to intervention and 38 to control), 60 completed 3-month, and 57 completed 12-month assessments. Benefits of Triple P were evident at 3 months for parent mental health, parenting skills, and family functioning (p < 0.05), but not for child mental health or glycemic control, with little effect at 12 months. Prespecified subgroup analyses for children with pre-existing internalizing or externalizing behavior problems indicated greater improvements in child mental health, parent mental health, parenting skills, and diabetes family conflict (p < 0.05), but lower parenting self-efficacy at 3 months. Improvements in parent mental health and parenting competency associated with Triple P were sustained to 12 months for children with pre-existing mental health problems. This study provides some support for the efficacy of Triple P in improving parent and family outcomes, and reducing child internalizing and externalizing behavior problems primarily in children who have pre-existing mental health problems. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Knowledge after five-day teaching program in intensive insulin therapy performed at the onset of type 1 diabetes influence the development of late diabetic complications.

    PubMed

    Araszkiewicz, Aleksandra; Zozulinska-Ziolkiewicz, Dorota; Trepinska, Magdalena; Wierusz-Wysocka, Bogna

    2008-07-01

    We evaluated the influence of baseline diabetic knowledge on clinical course of type 1 diabetes treated with intensive functional insulin therapy (IFIT) from the onset of the disease. 86 subjects with newly diagnosed type 1 diabetes, aged 23.4+/-5.1 attended a five-day structured training program in IFIT at baseline, followed by a test consisting of 20 questions. Patients were divided into subgroups according to test results: group A>16, group B 12-16 and group C<12 scores. At follow-up (7.1+/-1.5 years) metabolic control and development of microangiopathy were assessed. Patients with low knowledge at baseline had higher HbA1c levels than subjects with higher knowledge (group C: 9.2+/-1.9 vs. group A: 7.7+/-1.5%, p<0.05 and vs. group B: 7.8+/-1.6%, p<0.05), higher BMI (group C: 23.9+/-3.2 vs. group A: 21.8+/-3.1 kg/m(2), p<0.05) and lower HDL-cholesterol level (group C: 1.8+/-0.5 vs. group A: 2.0+/-0.3 mmol/l, p<0.05). Patients with retinopathy and albuminuria at follow-up had lower level of diabetic knowledge at baseline (respectively: 12.5+/-3.6 vs. 14.2+/-3.3 scores, p<0.05; and 12.6+/-2.9 vs. 14.1+/-3.5 scores, p<0.05). The development of microangiopathy was associated with lower diabetic knowledge (RR=3.71; 95%CI: 1.15-12.01, p=0.02 for retinopathy and RR=4.33; 95%CI: 0.98-19.10, p=0.04 for microalbuminuria). The higher diabetic knowledge at baseline the better metabolic control and lower risk of microangiopathy in the future.

  13. Type 1 Diabetes

    MedlinePlus

    ... viruses, may trigger the disease. The role of insulin Once a significant number of islet cells are ... sugar level as close to normal as possible. Insulin and other medications Anyone who has type 1 ...

  14. Diabetes Type 1

    MedlinePlus

    ... type 1 diabetes, your pancreas does not make insulin. Insulin is a hormone that helps glucose get into your cells to give them energy. Without insulin, too much glucose stays in your blood. Over ...

  15. Type 1 diabetes

    PubMed Central

    Atkinson, Mark A; Eisenbarth, George S; Michels, Aaron W

    2015-01-01

    Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements in insulin pumps and continuous glucose monitors help patients with type 1 diabetes manage the challenge of lifelong insulin administration. Agents that show promise for averting debilitating disease-associated complications have also been identified. However, despite broad organisational, intellectual, and fiscal investments, no means for preventing or curing type 1 diabetes exists, and, globally, the quality of diabetes management remains uneven. This Seminar discusses current progress in epidemiology, pathology, diagnosis, and treatment of type 1 diabetes, and prospects for an improved future for individuals with this disease. PMID:23890997

  16. A critical role for the programmed death ligand 1 in fetomaternal tolerance.

    PubMed

    Guleria, Indira; Khosroshahi, Arezou; Ansari, Mohammed Javeed; Habicht, Antje; Azuma, Miyuki; Yagita, Hideo; Noelle, Randolph J; Coyle, Anthony; Mellor, Andrew L; Khoury, Samia J; Sayegh, Mohamed H

    2005-07-18

    Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell- but not B cell-dependent because PDL1-specific antibody treatment caused fetal rejection in B cell-deficient but not in RAG-1-deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-gamma-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-gamma levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.

  17. Reducing stress and supporting positive relations in families of young children with type 1 diabetes: A randomized controlled study for evaluating the effects of the DELFIN parenting program

    PubMed Central

    2012-01-01

    Background To assess initial efficacy and feasibility of a structured behavioural group training (DELFIN) for parents of children with diabetes type 1, in order to reduce parenting stress and to improve parenting skills. Methods A randomized controlled study was conducted between July 2008 and September 2010, at a children’s hospital in Hannover with parents of children with type 1 diabetes (2–10 yrs) (intervention group n = 37; control group n = 28). Parenting skills, parents’ psychological burden, children’s behavioural difficulties and quality of metabolic control were assessed before, 3 months after and 12 months after participating in the training program. Results In the intervention group parenting behaviour in conflict situations improved significantly after 3 months (Z = −3.28; p ≤ 0.001). It remained stable over 12 months (Z = −2.94; p ≤ 0.01). Depression and anxiety scores of parents decreased (Z = −1.93; p ≤ .05; Z = −2.02; p ≤ .05). Even though the outcome in the intervention group was more positive, the differences between both study arms failed to reach statistical significance. Unexpectedly parenting behaviour in the control group improved also (Z = −2.45; p ≤ .05). Anxiety as well as stress scores decreased in this group (Z = −2.02; p ≤ .05 and Z = −2.11; p ≤ .05). In both groups the initial metabolic control was good and without significant differences (A1c 7.2±0.8% vs. 7.1±0.4%; p > 0.5). It remained stable in the DELFIN group (A1c 7.1±0.8%; p > 0.5), but it increased slightly in controls (A1c 7.3±0.5%; Z = −2.79; p = .005). Conclusions This study has brought first evidence for the efficacy and feasibility of the program. A multicentre study with a larger sample is necessary to confirm these first results. PMID:22994843

  18. PROGRAMMED CELL DEATH IN EXTRAOCULAR MUSCLE TENDON/SCLERA PRECURSORS

    EPA Science Inventory

    Abstract

    Purpose: This study was designed to examine the occurrence of natural cell death in the periocular mesenchyme of mouse embryos.

    Methods: Vital staining with LysoTracker Red and Nile blue sulphate as well as terminal nick end labeling (TUNEL) were utiliz...

  19. PROGRAMMED CELL DEATH IN EXTRAOCULAR MUSCLE TENDON/SCLERA PRECURSORS

    EPA Science Inventory

    Abstract

    Purpose: This study was designed to examine the occurrence of natural cell death in the periocular mesenchyme of mouse embryos.

    Methods: Vital staining with LysoTracker Red and Nile blue sulphate as well as terminal nick end labeling (TUNEL) were utiliz...

  20. [Differential effects of diabetes education programs by levels of HbA1c and the presence of chronic complications in patients with type 1 diabetes].

    PubMed

    De los Santos Roig, M; Fernández-Alcántara, M; Guardia-Archilla, T; Rodríguez-Morales, S; Molina, A; Casares, D; Ruiz-González, I

    2014-01-01

    Diabetes Education Programs (DEP) that improve metabolic control are applied to a wide variety of patient types. The aim is to test whether DEPs work differently depending on the patient profile. Thirty-six type 1 diabetics participated. They were divided into four groups according to their haemoglobin levels (range: 7-13 %) and into two groups according to the presence or absence of complications. The ECODI scale for assessing diabetes knowledge and the Frequency of Self-Care scale were completed by all patients. The results showed that HbA1c decreased after the DEP, with some areas of self-care also improving. There were no changes, however, to diet or exercise. DEP appear to work better in patients with worse control and with complications, suggesting that they have a certain role to play in prevention. Their lack of impact on diet or exercise, would suggest that the DEPs require improvement to include psychological strategies that motivate lasting lifestyle changes.

  1. Impact of disease-management programs on metabolic control in patients with type 1 diabetes mellitus: A cohort study in Shantou, China.

    PubMed

    Lin, Kun; Yang, Xiaoping; Wu, Yixi; Chen, Shuru; Yin, Guoshu; Zhan, Jianjun; Lin, Chujia; Xu, Wencan; Chen, Yongsong; Lin, Dan; Xie, Peiwen; Fang, Yishan; Lin, Qiuqiang; Lin, Shaoda

    2016-12-01

    The aim of this study is to evaluate the effect of diabetes disease management program (DMP) on glycemic control in type 1 diabetes mellitus (T1DM) patients in Shantou China.A sample of 240 participants recruited from 3C study Shantou subgroup was followed up in DMP for 3 years. The DMP provided self-management education, individualized therapy plan, diabetes complications screening, and laboratory examination periodical according to clinical practice guidelines. Primary outcomes were changes in hemoglobin A1C (HbA1c).Two hundred one of the participants completed the follow-up. There was a significant decrease in the HbA1c levels after DMP implemented. The mean (± SD) pre- and post-intervention HbA1c levels were 10.26% ± 3.30% and 8.57% ± 1.57% respectively with a P value <0.001. General linear mixed model analyse demonstrated that changes in glycemic control were associated with insulin treatment regimen, frequency of Self-Monitoring of Blood Glucose (SMBG), diabetes diet adherence, physical activity, and duration of diabetes.DMP helped to improve glycemic control and should be general implemented in China's T1DM. Individuals with basal-bolus regimen (multiple daily injections or pump therapy), more frequency of SMBG, following a diabetes diet, more physical activity, shorter diabetes duration may derive greater benefits from DMP.

  2. Evaluation of a quality assurance program for quantitation of human immunodeficiency virus type 1 RNA in plasma by the AIDS Clinical Trials Group virology laboratories.

    PubMed

    Yen-Lieberman, B; Brambilla, D; Jackson, B; Bremer, J; Coombs, R; Cronin, M; Herman, S; Katzenstein, D; Leung, S; Lin, H J; Palumbo, P; Rasheed, S; Todd, J; Vahey, M; Reichelderfer, P

    1996-11-01

    A number of quantitative assays have been developed by using amplification techniques to measure human immunodeficiency virus type 1 RNA in the plasma of infected individuals. The Virology Committee of the AIDS Clinical Trials Group in the Division of AIDS, National Institute of Allergy and Infectious Diseases, has established a quality assurance program (QAP) for quantitative assays of HIV-1 RNA levels in plasma. The primary objective of the QAP was to ascertain that a laboratory could maintain the precision required to have a 90% power to detect a fivefold difference in RNA copy number between two samples in the same batch. To achieve this goal, the QAP required an intra-assay standard deviation of no greater than 0.15 log10 RNA copies per ml. Panels for proficiency testing consisted of coded replicate samples and a common set of standards. To date, 41 laboratories have participated in the program and have used both commercial and in-house assays. We demonstrated that 65% of the laboratories were capable of attaining the necessary level of intra-assay precision. The fitted regressions indicated that the differences among laboratories that used the same kit were generally greater than the differences among population-average regressions for the kits themselves. The use of an external QAP and a common set of standards reduced differences both among laboratories that used the same kit and among laboratories that used different kits. Thus, use of a common set of standards across clinical trial protocols would allow for cross-protocol comparisons.

  3. Rational Design of Regulators of Programmed Cell Death in Human Breast Cancer

    DTIC Science & Technology

    2000-07-01

    The purpose of this research is to develop a better understanding of the intricate pathways of cell death and their contributions to breast cancers...basis for a set of molecular interactions that regulate programmed cell death , and allow the design of novel interventional agents that have investigative and therapeutic potential.

  4. Structured type 1 diabetes education delivered in routine care in Australia reduces diabetes-related emergencies and severe diabetes-related distress: The OzDAFNE program.

    PubMed

    Speight, Jane; Holmes-Truscott, Elizabeth; Harvey, Dianne M; Hendrieckx, Christel; Hagger, Virginia L; Harris, Susan E; Knight, Brigid A; McIntyre, Harold D

    2016-02-01

    To evaluate structured type 1 diabetes education delivered in routine practice throughout Australia. Participants attended a five-day training program in insulin dose adjustment and carbohydrate counting between April 2007 and February 2012. Using an uncontrolled before-and-after study design, we investigated: HbA1c (% and mmol/mol); severe hypoglycaemia; diabetes ketoacidosis (DKA) requiring hospitalisation, and diabetes-related distress (Problem Areas in Diabetes scale; PAID), weight (kg); body mass index. Data were collected pre-training and 6-18 months post-training. Change in outcome scores were examined overall as well as between groups stratified by baseline HbA1c quartiles. Data are mean ± SD or % (n). 506 participants had data eligible for analysis. From baseline to follow-up, significant reductions were observed in the proportion of participants reporting at least one severe hypoglycaemic event (24.7% (n=123) vs 12.1% (n=59), p<0.001); and severe diabetes-related distress (29.3% (n=145) vs 12.6% (n=60), p<0.001). DKA requiring hospitalisation in the past year reduced from 4.1% (n=20) to 1.2% (n=6). For those with above target baseline HbA1c there was a small, statistically significant improvement (n=418, 8.4 ± 1.1% (69 ± 12 mmol/mol) to 8.2 ± 1.1% (66 ± 12 mmol/mol). HbA1c improvement was clinically significant among those in the highest baseline quartile (n=122, 9.7 ± 1.1% (82 ± 11 mmol/mol) to 9.0 ± 1.2% (75 ± 13 mmol/mol), p<0.001). The proportion of participants reporting severe hypoglycaemia, DKA and severe diabetes-related distress was at least halved, and HbA1c reduced by 0.7% (7 mmol/mol) among those with highest baseline levels. Structured type 1 diabetes education delivered in routine practice offers clinically important benefits for those with greatest clinical need. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Neurofibromatosis type 1.

    PubMed

    Gutmann, David H; Ferner, Rosalie E; Listernick, Robert H; Korf, Bruce R; Wolters, Pamela L; Johnson, Kimberly J

    2017-02-23

    Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

  6. Programmed death in a unicellular organism has species-specific fitness effects.

    PubMed

    Durand, Pierre M; Choudhury, Rajdeep; Rashidi, Armin; Michod, Richard E

    2014-02-01

    Programmed cell death (PCD) is an ancient phenomenon and its origin and maintenance in unicellular life is unclear. We report that programmed death provides differential fitness effects that are species specific in the model organism Chlamydomonas reinhardtii. Remarkably, PCD in this organism not only benefits others of the same species, but also has an inhibitory effect on the growth of other species. These data reveal that the fitness effects of PCD can depend upon genetic relatedness.

  7. Clinical status of a cohort of patients with type 1 diabetes diagnosed more than 2 decades before. Results of a specific clinical follow-up program.

    PubMed

    Amor, Antonio J; Cabrer, Maria; Giménez, Marga; Vinagre, Irene; Ortega, Emilio; Conget, Ignacio

    2016-01-01

    The clinical course of type 1 diabetes mellitus (T1DM) has changed in recent decades. The aim of our study was to assess the long-term (> 20 years) clinical status of a patient cohort with T1DM under a specific treatment and follow-up program. A single center, observational, cross-sectional study was conducted of a patient cohort diagnosed with T1DM in the 1986-1994 period at our tertiary university hospital. Clinical characteristics, metabolic parameters, and occurrence of chronic complications and comorbidities after > 20 years of follow-up were collected. All subjects entered our specific program for patients with newly-diagnosed T1D and were followed up using the same clinical protocol. Data are shown as mean (standard deviation) or as number of patients and percentage. The appropriate test was used to compare quantitative and qualitative data. A P value <0.05 was considered statistically significant. A total of 279 patients were recorded, of whom 153 (53.6% women; mean age 46.6±8.6 years; age at onset 23.3±8.8 years; disease duration, 23.3±2.6 years) continued to attend our diabetes unit at the time of the analysis. Of these patients, 24.8% were administered continuous subcutaneous insulin infusion (CSII). Mean HbA1c in the past 5 years and in the last year were7.8±0.9% and 7.7±1.1% respectively (7.3±1.5% in those given CSII). Smoking was reported by 19.6% of patients, while 15.7% had high blood pressure and 37.9% dyslipidemia. Diabetic retinopathy was diagnosed in 20.4%, and 11.3% of the total cohort had nephropathy. Only 1.3% of our patients had a history of CVD. Data collected from a cohort of patients with T1DM for more than 2 decades regularly followed up with a specific program in a tertiary university hospital suggest a remarkably low prevalence of diabetic complications. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

    PubMed Central

    McClanahan, Fabienne; Sharp, Thomas G.; Gribben, John G.

    2016-01-01

    Therapeutic strategies targeting the programmed cell death-ligand 1/programmed cell death-1 pathway have shown significant responses and good tolerability in solid malignancies. Although preclinical studies suggest that inhibiting programmed cell death-ligand 1/programmed cell death-1 interactions might also be highly effective in hematological malignancies, remarkably few clinical trials have been published. Determining patients who will benefit most from programmed cell death-ligand 1/programmed cell death-1-directed immunotherapy and whether programmed cell death-ligand 1/programmed cell death-1 are adequate prognostic markers becomes an increasingly important clinical question, especially as aberrant programmed cell death-ligand 1/programmed cell death-1 expression are key mediators of impaired anti-tumor immune responses in a range of B-cell lymphomas. Herein, we systematically review the published literature on the expression and prognostic value of programmed cell death-ligand 1/programmed cell death-1 in these patients and identify considerable differences in expression patterns, distribution and numbers of programmed cell death-ligand 1+/programmed cell death-1+cells, both between and within lymphoma subtypes, which is reflected in conflicting findings regarding the prognostic value of programmed cell death-ligand 1+/programmed cell death-1+ cells. This can be partly explained by differences in methodologies (techniques, protocols, cutoff values) and definitions of positivity. Moreover, lymphomagenesis, disease progression, and prognosis appear to be determined not only by the presence, numbers and distribution of specific subtypes of T cells, but also by other cells and additional immune checkpoints. Collectively, our findings indicate that programmed cell death-ligand 1/programmed cell death-1 interactions play an essential role in B-cell lymphoma biology and are of clinical importance, but that the overall outcome is determined by additional components

  9. Programming cell death in the 1960s: developmental biology beyond dichotomy.

    PubMed

    Park, Hyung Wook

    2015-01-01

    Programmed cell death (PCD) has been one of the most significant topics in modern biomedical research. Its broad importance in many biological and pathological phenomena, including morphogenesis, autoimmune disease, and cancer, demonstrates that its origin deserves a historical examination. By analyzing the role of developmental biology of the 1960s in shaping the notion of a program, this paper explains the emergence of a close correlation between not only life and death, but also the normal and the pathological in the postwar study of cell death. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. How France launched its donation after cardiac death program.

    PubMed

    Antoine, C; Mourey, F; Prada-Bordenave, E

    2014-02-01

    On the basis of the literature and results presented at the 6th International Conference, donation after cardio-circulatory death provides a significant, practical, additional high quality source of transplantable organs. The vast majority of DCD are 'controlled' Maastricht category III donors. In 2010, the parliamentary information mission on the revision of the bioethics laws invited the Intensive Care Societies to debate and to make recommendations to implement controlled donation after circulatory death. They came to the conclusion that such retrieval is possible in France and insisted on the medical criteria that frame it: the writing of the medical procedures, the ethical aspects and the delay. The major recommendations of the ethics committees were firstly, The WLST decision is independent of the possibility of organ donation; secondly, the strict respect of "The dead donor and organ transplantation rule" and the updated national guidance for the WLST; thirdly, the drafting of a nationally agreed protocol defining the mandatory conditions to determine death and to perform procurement and transplantation. Organ donation after WLST will be authorised only in pilot centres with a locally agreed WLST policy including external second opinion and written transcript of the WLST decision, experienced intensive care staff, a local organ procurement coordination team familiar with DBD and DCD protocols and only in hospitals authorised for organ procurement. It is important to have an optimal and standardized national guidance to limit the known risk factors of graft failure (donor and recipient choice, warm and cold ischemia time), to increase acceptance by medical community and civil society and to improve results and allow more powerful analysis. Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

  11. A pilot randomized controlled trial of a post-discharge program to support emerging adults with type 1 diabetes mellitus transition from pediatric to adult care.

    PubMed

    Steinbeck, Katharine S; Shrewsbury, Vanessa A; Harvey, Vanessa; Mikler, Kara; Donaghue, Kim C; Craig, Maria E; Woodhead, Helen J

    2015-12-01

    There is a paucity of randomized controlled trials (RCT) examining transition from pediatric to adult care in type 1 diabetes mellitus (T1DM). This study aimed to determine if transition in T1DM is more effective with a comprehensive transition program (CTP) compared with standard clinical practice (SCP). This RCT recruited as young people left pediatric diabetes services. The trial co-ordinator provided CTP participants with standardized telephone communication support at week 1, and 3, 6, and 12 months post-discharge from pediatric care. SCP participants were briefly contacted at 6 and 12 months post-discharge to confirm transfer status; they received no other post-discharge contact as per usual practice. At 12 months, the primary outcomes were engagement and retention in the adult service and secondary outcomes included hemoglobin A1c (HbA1c), diabetes-related hospitalizations, microvascular complication appearance, and global self-worth. Most CTP participants (11/14) and all SCP (12/12) participants (P = 0.2) transferred to an adult diabetes service; the median time to transfer was 14-15 wk. Overall, participants' frequency of adult diabetes service visits was sub-optimal but their retention in adult care was high. The only group difference was a higher HbA1c at baseline and follow-up in the CTP group. However, a general linear model found that follow-up HbA1c increased by 1.2% for each percentage increase in baseline HbA1c [95% confidence interval (0.4, 1.9; P = 0.01)], independent of treatment group. Despite the challenges in recruiting adequate numbers, these findings provide valuable insights for future T1DM transition RCTs that are needed to build a more solid evidence-base in this field. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Identification of modules related to programmed cell death in CHD based on EHEN.

    PubMed

    Jia, Xu; Li, Wan; Miao, Zhengqiang; Feng, Chenchen; Liu, Zhe; He, Yuehan; Lv, Junjie; Du, Youwen; Hou, Min; He, Weiming; Li, Danbin; Chen, Lina

    2014-01-01

    The formation and death of macrophages and foam cells are one of the major factors that cause coronary heart disease (CHD). In our study, based on the Edinburgh Human Metabolic Network (EHMN) metabolic network, we built an enzyme network which was constructed by enzymes (nodes) and reactions (edges) called the Edinburgh Human Enzyme Network (EHEN). By integrating the subcellular location information for the reactions and refining the protein-reaction relationships based on the location information, we proposed a computational approach to select modules related to programmed cell death. The identified module was in the EHEN-mitochondria (EHEN-M) and was confirmed to be related to programmed cell death, CHD pathogenesis, and lipid metabolism in the literature. We expected this method could analyze CHD better and more comprehensively from the point of programmed cell death in subnetworks.

  13. SPK-1, an SR protein kinase, inhibits programmed cell death in Caenorhabditis elegans

    PubMed Central

    Galvin, Brendan D.; Denning, Daniel P.; Horvitz, H. Robert

    2011-01-01

    To identify genes involved in protecting cells from programmed cell death in Caenorhabditis elegans, we performed a genetic screen to isolate mutations that cause an increase in the number of programmed cell deaths. We screened for suppressors of the cell-death defect caused by a partial loss-of-function mutation in ced-4, which encodes an Apaf-1 homolog that promotes programmed cell death by activating the caspase CED-3. We identified one extragenic ced-4 suppressor, which has a mutation in the gene spk-1. The spk-1 gene encodes a protein homologous to serine-arginine-rich (SR) protein kinases, which are thought to regulate splicing. Previous work suggests that ced-4 can be alternatively spliced and that the splice variants function oppositely, with the longer transcript (ced-4L) inhibiting programmed cell death. spk-1 might promote cell survival by increasing the amount of the protective ced-4L splice variant. We conclude that programmed cell death in C. elegans is regulated by an alternative splicing event controlled by the SR protein kinase SPK-1. PMID:21245325

  14. SPK-1, an SR protein kinase, inhibits programmed cell death in Caenorhabditis elegans.

    PubMed

    Galvin, Brendan D; Denning, Daniel P; Horvitz, H Robert

    2011-02-01

    To identify genes involved in protecting cells from programmed cell death in Caenorhabditis elegans, we performed a genetic screen to isolate mutations that cause an increase in the number of programmed cell deaths. We screened for suppressors of the cell-death defect caused by a partial loss-of-function mutation in ced-4, which encodes an Apaf-1 homolog that promotes programmed cell death by activating the caspase CED-3. We identified one extragenic ced-4 suppressor, which has a mutation in the gene spk-1. The spk-1 gene encodes a protein homologous to serine-arginine-rich (SR) protein kinases, which are thought to regulate splicing. Previous work suggests that ced-4 can be alternatively spliced and that the splice variants function oppositely, with the longer transcript (ced-4L) inhibiting programmed cell death. spk-1 might promote cell survival by increasing the amount of the protective ced-4L splice variant. We conclude that programmed cell death in C. elegans is regulated by an alternative splicing event controlled by the SR protein kinase SPK-1.

  15. A structured therapeutic education program for children and adolescents with type 1 diabetes: an analysis of the efficacy of the "Pediatric Education for Diabetes" project.

    PubMed

    Mauri, Alessandra; Schmidt, Susanna; Sosero, Valentina; Sambataro, Maria; Nollino, Laura; Fabris, Francesco; Corò, Anna; Scantamburlo, Antonella; Cazziola-Merlotto, Michela; Ciani, Tania; Tessarin, Michele; Paccagnella, Agostino

    2017-02-07

    Therapeutic education for Type 1 Diabetes involves the process of transmitting knowledge and developing the skills and behavior required to treat the disease. guidelines agree on stressing the importance of therapeutic educational intervention in teaching self-management skills to children and adolescents with Type 1 Diabetes (T1D). This study presents the results of the "Pediatric Education for Type 1 Diabetes (T1D)" (PED) project, specifically designed for children and adolescents aged 6 to 16, and structured on guidelines indications, as part of a broader clinical-educational intervention for Type 1 diabetes. 24 patients with Type 1 diabetes (mean age: 12,13 y; SD = 1.48 y; range 9- 14) were studied in a 12-month PED structured project followed by a educational summer camp. All the activities were designed and organized by a multidisciplinary team (dietitian, pediatric diabetologist, nurse, psychologist and adult diabetologist). Glycated hemoglobin (HbA1C), knowledge about Type 1 Diabetes (T1D) (self-monitoring and nutrition), self- management (self-monitoring, nutrition and flexibility of medical treatment), and wellbeing were used as outcome measures. Data suggest that the PED had a positive impact on all the targeted levels indicated for recommended care. The results of this study seem to confirm the effectiveness in altering the three levels of "knowing", "know-how" and "wellbeing" required to optimize the quality of life of young patients with Type 1 diabetes. In addition, the proposed model, where a pediatric diabetologist always cooperates with an adult diabetologist, seems to be a permanent solution to the transitional gap widely discussed in the literature.

  16. Role of programmed cell death in normal neuronal development and function.

    PubMed

    Buss, Robert R; Oppenheim, Ronald W

    2004-12-01

    The consequences of eliminating the process of programmed cell death during the development of the nervous system is examined by reviewing studies in the genetic model organisms Caenorhabditis elegans, Drosophila melanogaster, Danio rerio and Mus musculus, where mutations of cell death genes have eliminated or reduced programmed cell death in the nervous system. In many cases, genetic elimination of cell death leads to embryonic mortality or gross anatomical malformations; however, there are cases where animals develop normally but with excess neurons and glia in the nervous system. Undead cells either differentiate and function as working neurons, in some instances being of smaller size, or fail to differentiate and lack normal connections with their targets. Changes in motor control and sensory processing are generally not observed, except for during the most complex of behaviors. Examination of organisms where death genes have been genetically eliminated reveals that programmed cell death may play an important role in sculpting gross brain structure during early development of the neural tube. In contrast, the consequences of preventing neuronal cell death at later developmental stages (e.g. during vertebrate synapse formation) are just beginning to be understood.

  17. USDA Forest Service, Pacific Southwest Research Station Sudden Oak Death Research Program: 2001-2005

    Treesearch

    Patrick J. Shea

    2006-01-01

    The Pacific Southwest Research Station (PSW), U.S. Department of Agriculture (USDA) Forest Service initiated the Sudden Oak Death Research (SOD) Program in late 2000. The program was prompted by late fiscal year funding dedicated directly to begin research on this newly discovered disease. The history of discovery of Phytophthora ramorum, the...

  18. Cucumber Mosaic Virus D Satellite RNA–Induced Programmed Cell Death in Tomato

    PubMed Central

    Xu, Ping; Roossinck, Marilyn J.

    2000-01-01

    D satellite RNA (satRNA) with its helper virus, namely, cucumber mosaic virus, causes systemic necrosis in tomato. The infected plant exhibits a distinct spatial and temporal cell death pattern. The distinct features of chromatin condensation and nuclear DNA fragmentation indicate that programmed cell death is involved. In addition, satRNA localization and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling show that cell death is initiated from the infected phloem or cambium cells and spreads to other nearby infected cells. Timing of the onset of necrosis after inoculation implicates the involvement of cell developmental processes in initiating tomato cell death. Analysis of the accumulation of minus- and plus-strand satRNAs in the infected plants indicates a correlation between high amounts of minus-strand satRNA and tomato cell death. PMID:10899975

  19. Tales of cannibalism, suicide, and murder: Programmed cell death in C. elegans.

    PubMed

    Kinchen, Jason M; Hengartner, Michael O

    2005-01-01

    "Life is pleasant. Death is peaceful. It's the transition that's troublesome," said Isaac Asimov. Indeed, much scientific work over the last hundred years centered around attempts either to stave off or to induce the onset of death, at both the organismal and the cellular levels. In this quest, the nematode C. elegans has proven an invaluable tool, first, in the articulation of the genetic pathway by which programmed cell death proceeds, and also as a continuing source of inspiration. It is our purpose in this Chapter to familiarize the reader with the topic of programmed cell death in C. elegans and its relevance to current research in the fields of apoptosis and cell corpse clearance.

  20. Apoptosis goes on a chip: advances in the microfluidic analysis of programmed cell death

    PubMed Central

    Wlodkowic, Donald; Khoshmanesh, Khashayar; Sharpe, John C; Darzynkiewicz, Zbigniew; Cooper, Jonathan Mark

    2011-01-01

    Summary Recent years have brought enormous progress in cell-based lab-on-a-chip technologies, allowing dynamic studies of cell death with an unprecedented accuracy. As interest in the microfabricated technologies for cell-based bioassays is rapidly gaining momentum, we highlight the most promising technologies that provide a new outlook for the rapid assessment of programmed and accidental cell death and are applicable in drug discovery, high-content drug screening, and personalized clinical diagnostics. PMID:21630641

  1. Lozenge directly activates argos and klumpfuss to regulate programmed cell death.

    PubMed

    Wildonger, Jill; Sosinsky, Alona; Honig, Barry; Mann, Richard S

    2005-05-01

    We show that reducing the activity of the Drosophila Runx protein Lozenge (Lz) during pupal development causes a decrease in cell death in the eye. We identified Lz-binding sites in introns of argos (aos) and klumpfuss (klu) and demonstrate that these genes are directly activated targets of Lz. Loss of either aos or klu reduces cell death, suggesting that Lz promotes apoptosis at least in part by regulating aos and klu. These results provide novel insights into the control of programmed cell death (PCD) by Lz during Drosophila eye development.

  2. Die for the community: an overview of programmed cell death in bacteria

    PubMed Central

    Allocati, N; Masulli, M; Di Ilio, C; De Laurenzi, V

    2015-01-01

    Programmed cell death is a process known to have a crucial role in many aspects of eukaryotes physiology and is clearly essential to their life. As a consequence, the underlying molecular mechanisms have been extensively studied in eukaryotes and we now know that different signalling pathways leading to functionally and morphologically different forms of death exist in these organisms. Similarly, mono-cellular organism can activate signalling pathways leading to death of a number of cells within a colony. The reason why a single-cell organism would activate a program leading to its death is apparently counterintuitive and probably for this reason cell death in prokaryotes has received a lot less attention in the past years. However, as summarized in this review there are many reasons leading to prokaryotic cell death, for the benefit of the colony. Indeed, single-celled organism can greatly benefit from multicellular organization. Within this forms of organization, regulation of death becomes an important issue, contributing to important processes such as: stress response, development, genetic transformation, and biofilm formation. PMID:25611384

  3. IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

    PubMed Central

    Stephen-Victor, Emmanuel; Sharma, Varun Kumar; Das, Mrinmoy; Karnam, Anupama; Saha, Chaitrali; Lecerf, Maxime; Galeotti, Caroline; Kaveri, Srinivas V.; Bayry, Jagadeesh

    2016-01-01

    The programed death-1 (PD-1)–programed death ligand-1 (PD-L1) and PD-L2 co-inhibitory pathway has been implicated in the evasion strategies of Mycobacterium tuberculosis. Specifically, M. tuberculosis-induced PD-L1 orchestrates expansion of regulatory T cells and suppression of Th1 response. However, the role of PD pathway in regulating Th17 response to M. tuberculosis has not been investigated. In the present report, we demonstrate that M. tuberculosis and M. tuberculosis-derived antigen fractions have differential abilities to mediate human monocyte- and dendritic cell (DC)-mediated Th17 response and were independent of expression of PD-L1 or PD-L2 on aforementioned antigen-presenting cells. Importantly, we observed that blockade of PD-L1 or PD-1 did not significantly modify either the frequencies of Th17 cells or the production of IL-17 from CD4+ T cells though IFN-γ response was significantly enhanced. On the contrary, IL-1β from monocytes and DCs were critical for the Th17 response to M. tuberculosis. Together, our results indicate that IL-1β, but not members of the programed death pathway, is critical for human Th17 response to M. tuberculosis. PMID:27867382

  4. Neurofibromatosis type 1

    PubMed Central

    Boyd, Kevin P.; Korf, Bruce R.; Theos, Amy

    2009-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder affecting approximately 1 in 3500 people. Significant advances in the understanding of the pathophysiology of NF1 have been made in the last decade. While no medical therapies are currently available, trials are ongoing to discover and test medical treatments for the various manifestations of NF1, primarily plexiform neurofibromas, learning disabilities, and optic pathway gliomas. Additionally, mutational analysis has become available on a clinical basis and is useful for diagnostic confirmation in individuals who do not fulfill diagnostic criteria or when prenatal diagnosis is desired. There are several disorders which may share overlapping features with NF1; in 2007, a disorder with cutaneous findings similar to NF1 was described. This paper addresses the dermatologist's role in diagnosis and management of NF1 and describes the variety of cutaneous and extracutaneous findings in NF1 to which the dermatologist may be exposed. PMID:19539839

  5. Herceptin Conjugates Linked by EDC Boost Direct Tumor Cell Death via Programmed Tumor Cell Necrosis

    PubMed Central

    Hughes, Dennis; Esteva, Francisco J.; Liu, Bolin; Chandra, Joya; Li, Shulin

    2011-01-01

    Tumor-targeted antibody therapy is one of the safest biological therapeutics for cancer patients, but it is often ineffective at inducing direct tumor cell death and is ineffective against resistant tumor cells. Currently, the antitumor efficacy of antibody therapy is primarily achieved by inducing indirect tumor cell death, such as antibody-dependent cell cytotoxicity. Our study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride), are capable of engendering human epidermal growth factor receptor 2 (Her2) positive tumor cells death. Using a high-performance liquid chromatography (HPLC) system, three peaks with estimated molecular weights of antibody monomer, dimer, and trimer were isolated. Both Herceptin trimer and dimer separated by HPLC induced significant levels of necrotic tumor cell death, although the trimer was more effective than the dimer. Notably, the Herceptin trimer also induced Herceptin-resistant tumor cell death. Surprisingly different from the known cell death mechanism that often results from antibody treatment, the Herceptin trimer elicited effective and direct tumor cell death via a novel mechanism: programmed cell necrosis. In Her2-positive cells, inhibition of necrosis pathways significantly reversed Herceptin trimer-induced cell death. In summary, the Herceptin trimer reported herein harbors great potential for overcoming tumor cell resistance to Herceptin treatment. PMID:21853100

  6. Programmed cell death during metamorphosis in the blow-fly Calliphora vomitoria.

    PubMed

    Bowen, I D; Mullarkey, K; Morgan, S M

    1996-06-15

    During metamorphosis, the salivary glands of the blow-fly undergo programmed cell death. Data is presented indicating that this programmed cell death does not in many respects emulate classical apoptosis. The cells are seen to vacuolate and swell rather than condense and shrink. There appears to be a transient enhancement in autophagy and an increase in acid phosphatase activity. This is followed by the characteristic appearance of ribosomal and extracisternal sources of the enzyme leading to autolysis. There appears to be no lysosomal leakage of acid phosphatase. As in apoptosis, the mitochondria persist until the cell fragments. The nucleus, however, does not show the distinct chromatin margination and blebbing that is typical of apoptosis. These changes are compared with necrotic changes induced by experimental anoxia. Overall the results show that a programmed cell death distinct from classical apoptosis is taking place.

  7. Programmed cell death of retinal cone bipolar cells is independent of afferent or target control.

    PubMed

    Keeley, Patrick W; Madsen, Nils R; St John, Ace J; Reese, Benjamin E

    2014-10-15

    Programmed cell death contributes to the histogenesis of the nervous system, and is believed to be modulated through the sustaining effects of afferents and targets during the period of synaptogenesis. Cone bipolar cells undergo programmed cell death during development, and we confirm that the numbers of three different types are increased when the pro-apoptotic Bax gene is knocked out. When their cone afferents are selectively eliminated, or when the population of retinal ganglion cells is increased, however, cone bipolar cell number remains unchanged. Programmed cell death of the cone bipolar cell populations, therefore, may be modulated cell-intrinsically rather than via interactions with these synaptic partners. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Programmed cell death in host-symbiont associations, viewed through the Gene Ontology

    PubMed Central

    Chibucos, Marcus C; Collmer, Candace W; Torto-Alalibo, Trudy; Gwinn-Giglio, Michelle; Lindeberg, Magdalen; Li, Donghui; Tyler, Brett M

    2009-01-01

    Manipulation of programmed cell death (PCD) is central to many host microbe interactions. Both plant and animal cells use PCD as a powerful weapon against biotrophic pathogens, including viruses, which draw their nutrition from living tissue. Thus, diverse biotrophic pathogens have evolved many mechanisms to suppress programmed cell death, and mutualistic and commensal microbes may employ similar mechanisms. Necrotrophic pathogens derive their nutrition from dead tissue, and many produce toxins specifically to trigger programmed cell death in their hosts. Hemibiotrophic pathogens manipulate PCD in a most exquisite way, suppressing PCD during the biotrophic phase and stimulating it during the necrotrophic phase. This mini-review will summarize the mechanisms that have evolved in diverse microbes and hosts for controlling PCD and the Gene Ontology terms developed by the Plant-Associated Microbe Gene Ontology (PAMGO) Consortium for describing those mechanisms. PMID:19278553

  9. Inhibition of programmed cell death by cyclosporin A; preferential blocking of cell death induced by signals via TCR/CD3 complex and its mode of action.

    PubMed Central

    Yasutomi, D; Odaka, C; Saito, S; Niizeki, H; Kizaki, H; Tadakuma, T

    1992-01-01

    Cyclosporin A (CsA) is reported to inhibit programmed cell death. We confirmed this by using T-cell hybridomas which are inducible to programmed cell death by activation with immobilized anti-CD3 antibody or with anti-Thy 1.2 antibody. Cell death and DNA fragmentation, characteristic features of programmed cell death, were almost completely blocked by CsA or FK506. To investigate whether CsA inhibits only the cell death through the signals via the TCR/CD3 complex or all of the programmed cell death induced by various reagents, we further established CD4+8+ thymic lymphomas which result in programmed cell death after activation with calcium ionophore, dexamethasone, cyclic AMP or anti-CD3 antibody. It was revealed that CsA could block only the cell death mediated by the TCR/CD3 complex. For the clarification of the site of action of CsA, Ca2+ influx and endocytosis of receptors after stimulation with anti-CD3 antibody were monitored in the presence of CsA, and no significant effects of CsA were observed. Furthermore, prevention of cell death was examined by adding CsA at various periods of time after initiation of culture. CsA was found to exert its effect even when added after 4 h of cultivation, and the kinetic pattern of suppression was similar to that of the suppressive effect on IL-2 production. These observations indicate that in the events of programmed cell death, the major site of action of CsA will not be the inhibition of the immediate membrane events after activation of the TCR/CD3 complex but rather the interference in the function of molecules that transmit signals between membrane events and the activation of genes in the nucleus. Images Figure 2 Figure 3 PMID:1383138

  10. Implementing a Death with Dignity program at a comprehensive cancer center.

    PubMed

    Loggers, Elizabeth Trice; Starks, Helene; Shannon-Dudley, Moreen; Back, Anthony L; Appelbaum, Frederick R; Stewart, F Marc

    2013-04-11

    The majority of Death with Dignity participants in Washington State and Oregon have received a diagnosis of terminal cancer. As more states consider legislation regarding physician-assisted death, the experience of a comprehensive cancer center may be informative. We describe the implementation of a Death with Dignity program at Seattle Cancer Care Alliance, the site of care for the Fred Hutchinson-University of Washington Cancer Consortium, a comprehensive cancer center in Seattle that serves the Pacific Northwest. Institution-level data were compared with publicly available statewide data from Oregon and Washington. A total of 114 patients inquired about our Death with Dignity program between March 5, 2009, and December 31, 2011. Of these, 44 (38.6%) did not pursue the program, and 30 (26.3%) initiated the process but either elected not to continue or died before completion. Of the 40 participants who, after counseling and upon request, received a prescription for a lethal dose of secobarbital (35.1% of the 114 patients who inquired about the program), all died, 24 after medication ingestion (60% of those obtaining prescriptions). The participants at our center accounted for 15.7% of all participants in the Death with Dignity program in Washington (255 persons) and were typically white, male, and well educated. The most common reasons for participation were loss of autonomy (97.2%), inability to engage in enjoyable activities (88.9%), and loss of dignity (75.0%). Eleven participants lived for more than 6 months after prescription receipt. Qualitatively, patients and families were grateful to receive the lethal prescription, whether it was used or not. Overall, our Death with Dignity program has been well accepted by patients and clinicians.

  11. A Conserved Core of Programmed Cell Death Indicator Genes Discriminates Developmentally and Environmentally Induced Programmed Cell Death in Plants1[OPEN

    PubMed Central

    Van Bel, Michiel; Van Hautegem, Tom; Fendrych, Matyáš; Simaskova, Maria; van Durme, Matthias; Buscaill, Pierre; Rivas, Susana; S. Coll, Nuria; Maere, Steven

    2015-01-01

    A plethora of diverse programmed cell death (PCD) processes has been described in living organisms. In animals and plants, different forms of PCD play crucial roles in development, immunity, and responses to the environment. While the molecular control of some animal PCD forms such as apoptosis is known in great detail, we still know comparatively little about the regulation of the diverse types of plant PCD. In part, this deficiency in molecular understanding is caused by the lack of reliable reporters to detect PCD processes. Here, we addressed this issue by using a combination of bioinformatics approaches to identify commonly regulated genes during diverse plant PCD processes in Arabidopsis (Arabidopsis thaliana). Our results indicate that the transcriptional signatures of developmentally controlled cell death are largely distinct from the ones associated with environmentally induced cell death. Moreover, different cases of developmental PCD share a set of cell death-associated genes. Most of these genes are evolutionary conserved within the green plant lineage, arguing for an evolutionary conserved core machinery of developmental PCD. Based on this information, we established an array of specific promoter-reporter lines for developmental PCD in Arabidopsis. These PCD indicators represent a powerful resource that can be used in addition to established morphological and biochemical methods to detect and analyze PCD processes in vivo and in planta. PMID:26438786

  12. Melatonin, a natural programmed cell death inducer in cancer.

    PubMed

    Sánchez-Hidalgo, M; Guerrero, J M; Villegas, I; Packham, G; de la Lastra, C A

    2012-01-01

    Melatonin, an indolamine derived from the amino-acid tryptophan, participates in diverse physiological functions and has great functional versatility related to the regulation of circadian rhythms and seasonal behaviour, sexual development, retinal physiology, tumour inhibition, as an antioxidant, immunomodulatory and anti-aging properties. In relation to its oncostatic properties, there is evidence that tumor initiation, promotion or progression may be restrained by the night-time physiological surge of melatonin in the blood or extracellular fluid. In addition, depressed nocturnal melatonin concentrations or nocturnal excretion of the main melatonin metabolite, 6-sulfatoxymelatonin, were found in individuals with various tumor types. In the majority of studies, melatonin was shown to inhibit development and/or growth of various experimental animal tumors and some human cell lines in vitro. Many tumors do not respond to drug treatment due to their resistance to undergo apoptosis thereby contributing to the development of cancer. Thus, given the importance of the apoptotic program in cancer treatment, the role of melatonin in influencing apoptosis in tumor cells attracted attention because it seems that it actually promotes apoptosis in most tumor cells, in contrast to the obvious inhibition of apoptotic processes in normal cells. Thus, this paper is also intended to provide to the reader an up-date of all the researches that have been carried out to date, which investigate the proapoptotic effects of melatonin in experimental preclinical models of cancer (in vitro and in vivo) and the underlying proposed action mechanism of this effects. If melatonin uniformly induces apoptosis in cancer cells, the findings could have important clinical implications to improve the quality of live while preventing the appearance of cancer.

  13. Mastoparan-induced programmed cell death in the unicellular alga Chlamydomonas reinhardtii

    PubMed Central

    Yordanova, Zhenya P.; Woltering, Ernst J.; Kapchina-Toteva, Veneta M.; Iakimova, Elena T.

    2013-01-01

    Background and Aims Under stress-promoting conditions unicellular algae can undergo programmed cell death (PCD) but the mechanisms of algal cellular suicide are still poorly understood. In this work, the involvement of caspase-like proteases, DNA cleavage and the morphological occurrence of cell death in wasp venom mastoparan (MP)-treated Chlamydomonas reinhardtii were studied. Methods Algal cells were exposed to MP and cell death was analysed over time. Specific caspase inhibitors were employed to elucidate the possible role of caspase-like proteases. YVADase activity (presumably a vacuolar processing enzyme) was assayed by using a fluorogenic caspase-1 substrate. DNA breakdown was evaluated by DNA laddering and Comet analysis. Cellular morphology was examined by confocal laser scanning microscopy. Key Results MP-treated C. reinhardtii cells expressed several features of necrosis (protoplast shrinkage) and vacuolar cell death (lytic vesicles, vacuolization, empty cell-walled corpse-containing remains of digested protoplast) sometimes within one single cell and in different individual cells. Nucleus compaction and DNA fragmentation were detected. YVADase activity was rapidly stimulated in response to MP but the early cell death was not inhibited by caspase inhibitors. At later time points, however, the caspase inhibitors were effective in cell-death suppression. Conditioned medium from MP-treated cells offered protection against MP-induced cell death. Conclusions In C. reinhardtii MP triggered PCD of atypical phenotype comprising features of vacuolar and necrotic cell deaths, reminiscent of the modality of hypersensitive response. It was assumed that depending on the physiological state and sensitivity of the cells to MP, the early cell-death phase might be not mediated by caspase-like enzymes, whereas later cell death may involve caspase-like-dependent proteolysis. The findings substantiate the hypothesis that, depending on the mode of induction and sensitivity of

  14. p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death.

    PubMed

    Crighton, D; O'Prey, J; Bell, H S; Ryan, K M

    2007-06-01

    Evading programmed cell death is a common event in tumour development. The p53 family member, p73, is a potent inducer of death and a determinant of chemotherapeutic response, but different to p53, is rarely mutated in cancer. Understanding cell death pathways downstream of p53 and p73 is therefore pivotal to understand both the development and treatment of malignant disease. Recently, p53 has been shown to modulate autophagy--a membrane trafficking process, which degrades long-lived proteins and organelles. This requires a p53 target gene, DRAM, and both DRAM and autophagy are critical for p53-mediated death. We report here that TA-p73 also regulates DRAM and autophagy, with different TA-p73 isoforms regulating DRAM and autophagy to varying extents. RNAi knockdown of DRAM, however, revealed that p73's modulation of autophagy is DRAM-independent. Also, p73's ability to induce death, again different to p53, is neither dependent on DRAM nor autophagy. In contrast to TA-p73, deltaN-p73 is a negative regulator of p53-induced and p73-induced autophagy, but does not affect autophagy induced by amino-acid starvation. These studies, therefore, represent not only the first report that p73 modulates autophagy but also highlight important differences in the mechanism by which starvation, p53 and p73 regulate autophagy and how this contributes to programmed cell death.

  15. Type 1 diabetes mellitus.

    PubMed

    Katsarou, Anastasia; Gudbjörnsdottir, Soffia; Rawshani, Araz; Dabelea, Dana; Bonifacio, Ezio; Anderson, Barbara J; Jacobsen, Laura M; Schatz, Desmond A; Lernmark, Åke

    2017-03-30

    Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in β-cells - are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.

  16. Programmed necrosis in the Cross Talk of Cell Death and Inflammation

    PubMed Central

    Chan, Francis Ka-Ming; Luz, Nivea Farias; Moriwaki, Kenta

    2015-01-01

    Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity or immuno-deficiency. Programmed necrosis or necroptosis is a form of non-apoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF or DAI to signal for necroptosis in response to death receptor or toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membrane. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury. PMID:25493335

  17. Nuclear alterations associated to programmed cell death in larval salivary glands of Apis mellifera (Hymenoptera: Apidae).

    PubMed

    Silva-Zacarin, E C M; Taboga, S R; Silva de Moraes, R L M

    2008-01-01

    The silk glands of bees are a good model for the study of cell death in insects. With the objective to detect the nuclear features during glandular regression stage, larvae at the last instar and pre-pupae were collected and their silk glands were dissected and processed for ultrastructural analysis and histologically for cytochemical and imunocytochemical analysis. The results showed that the cellular nuclei exhibited characteristics of death by atypical apoptosis as well as autophagic cell death. Among the apoptosis characteristic were: nuclear strangulation with bleb formation in some nuclei, DNA fragmentation in most of the nuclei and nucleolar fragmentation. Centripetal chromatin compaction was observed in many nuclei, forming a perichromatin halo differing from typical apoptotic nuclei. With regards to the characteristics of autophagic-programmed cell death, most relevant was the delay in the collapse of many nuclei.

  18. Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.

    PubMed Central

    Gulbins, E; Brenner, B; Schlottmann, K; Welsch, J; Heinle, H; Koppenhoefer, U; Linderkamp, O; Coggeshall, K M; Lang, F

    1996-01-01

    Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death. Images Figure 1 Figure 3 PMID:8943716

  19. Programmed death-1(+) T cells inhibit effector T cells at the pathological site of miliary tuberculosis.

    PubMed

    Singh, A; Mohan, A; Dey, A B; Mitra, D K

    2017-02-01

    Optimal T cell activation is vital for the successful resolution of microbial infections. Programmed death-1 (PD-1) is a key immune check-point receptor expressed by activated T cells. Aberrant/excessive inhibition mediated by PD-1 may impair host immunity to Mycobacterium tuberculosis infection, leading to disseminated disease such as miliary tuberculosis (MTB). PD-1 mediated inhibition of T cells in pulmonary tuberculosis and TB pleurisy is reported. However, their role in MTB, particularly at the pathological site, remains to be addressed. The objective of this study was to investigate the role of PD-1-PD-ligand 1 (PD-L1) in T cell responses at the pathological site from patients of TB pleurisy and MTB as clinical models of contained and disseminated forms of tuberculosis, respectively. We examined the expression and function of PD-1 and its ligands (PD-L1-PD-L2) on host immune cells among tuberculosis patients. Bronchoalveolar lavage-derived CD3 T cells in MTB expressed PD-1 (54·2 ± 27·4%, P ≥ 0·0009) with significantly higher PD-1 ligand-positive T cells (PD-L1: 19·8 ± 11·8%; P ≥ 0·019, PD-L2: 12·6 ± 6·2%; P ≥ 0·023), CD19(+) B cells (PD-L1: 14·4 ± 10·4%; P ≥ 0·042, PD-L2: 2·6 ± 1·43%; not significant) and CD14(+) monocytes (PD-L1: 40·2 ± 20·1%; P ≥ 0·047, PD-L2: 22·4 ± 15·6%; P ≥ 0·032) compared with peripheral blood (PB) of MTB and healthy controls. The expression of PD-1 was associated with a diminished number of cells producing effector cytokines interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-2 and elevated apoptosis. Locally accumulated T cells were predominantly PD-1(+) -PD-L1(+) , and blocking this pathway restores the protective T cell response. We conclude that M. tuberculosis exploits the PD-1 pathway to evade the host immune response by altering the T helper type 1 (Th1) and Th2 balance at the pathological site of MTB, thereby

  20. The Impact of a Death Education Program for Nurses in a Long-Term Care Hospital.

    ERIC Educational Resources Information Center

    Fleming, Stephen; Brown, Isabel

    1983-01-01

    Assessed the impact of a death education program for nursing staff (N=130) of a long-term care institution. Analysis of nurses' chart entries (problem-oriented record format-POR) revealed a statistically significant increase from pre- to post-course in charting of patients' subjective state. (Author/JAC)

  1. New Method for Monitoring Programmed Cell Death and Differentiation in Submerged Streptomyces Cultures▿ †

    PubMed Central

    Yagüe, Paula; Manteca, Angel; Simon, Alejandro; Diaz-Garcia, Marta Elena; Sanchez, Jesus

    2010-01-01

    Vital stains were used in combination with fluorimetry for the elaboration of a new method to quantify Streptomyces programmed cell death, one of the key events in Streptomyces differentiation. The experimental approach described opens the possibility of designing online protocols for automatic monitoring of industrial fermentations. PMID:20348294

  2. Local initiation of caspase activation in Drosophila salivary gland programmed cell death in vivo

    PubMed Central

    Takemoto, Kiwamu; Kuranaga, Erina; Tonoki, Ayako; Nagai, Takeharu; Miyawaki, Atsushi; Miura, Masayuki

    2007-01-01

    Programmed cell death, or apoptosis, is an essential event in animal development. Spatiotemporal analysis of caspase activation in vivo could provide new insights into programmed cell death occurring during development. Here, using the FRET-based caspase-3 indicator, SCAT3, we report the results of live-imaging analysis of caspase activation in developing Drosophila in vivo. In Drosophila, the salivary gland is sculpted by caspase-mediated programmed cell death initiated by the steroid hormone 20-hydroxyecdysone (ecdysone). Using a SCAT3 probe, we observed that caspase activation in the salivary glands begins in the anterior cells and is then propagated to the posterior cells in vivo. In vitro salivary gland culture experiments indicated that local exposure of ecdysone to the anterior salivary gland reproduces the caspase activation gradient as observed in vivo. In βFTZ-F1 mutants, caspase activation was delayed and occurred in a random pattern in vivo. In contrast to the in vivo response, the salivary glands from βFTZ-F1 mutants showed a normal in vitro response to ecdysone, suggesting that βFTZ-F1 may be involved in ecdysteroid biosynthesis and secretion of ecdysone from the ring gland for local initiation of programmed cell death. These results imply a role of βFTZ-F1 in coordinating the initiation of salivary gland apoptosis in development. PMID:17679695

  3. Researching "good death" in a Hong Kong palliative care program: a clinical data-mining study.

    PubMed

    Chan, Wallace C H; Epstein, I

    This study operationalizes and assesses the percentage of "good deaths" achieved among Chinese cancer patients in a palliative care program, the profile of these patients, the relationship between patients with a good death and psychosocial factors, and the differences in background factors, and physical and psychosocial conditions between patients who experienced a good death and those who did not. Clinical data mining was the research method used. Records of deceased cancer patients between 2003 and 2005 in a palliative care unit were the sole data source. Good death was operationally defined as the patient's record indicating no pain (physical) or anxiety (psychological), and having open and honest communication with family (social) in the final assessment by the Support Team Assessment Schedule (STAS) just before death. Using these criteria, about one-fifth of patients (21.5%; 137 out of 638) experienced a good death. Those with a good death were significantly older and were in palliative care longer. Their records also indicated lower levels of constipation, insomnia, oral discomfort, and family anxiety at their first and at their final STAS assessments. Good death was positively associated with recorded indicators of fullness in life, caregivers' acceptance and support, and negatively with reported feelings of upset about changes in the course of their illness. The results heighten awareness among social workers and other healthcare professionals about the value of good death in patients in palliative care. This empirically-based awareness can foster professionals' ability to set intervention objectives to help patients in palliative care achieve this universally accepted goal.

  4. The 600-step program for type 1 diabetes self-management in youth: the magnitude of the self-management task.

    PubMed

    Coffen, Ronald D

    2009-09-01

    This article demonstrates the complexity of the type 1 diabetes regimen and describes the physician's role in safely promoting self-management of diabetes by youth. Literature describing type 1 diabetes and the required regimen, issues related to regimen adherence by youth, demonstration of the magnitude of the regimen, and implications for physicians are addressed. A task analysis and tool for physicians is presented that contains over 600 tasks. Given the magnitude of the regimen, issues related to the physician's promotion of the gradual transfer of regimen control to youth are illustrated. The importance of understanding broad areas of the regimen (eg, "insulin injection") as not one task but many is emphasized, as is the need to explore adherence within regimen areas to pinpoint problems related to poor metabolic control. The article also examines how managed care influences the approach that a physician may take to communicate the requirements of the complex regimen to youth and parents. It is concluded that a developmentally sensitive approach must be taken that promotes youths' internalization of the importance of regimen tasks, and suggestions are provided for accomplishing this in a gradual manner that promotes developmentally appropriate involvement of youth in the regimen without premature responsibility.

  5. When supply does not meet demand-ER stress and plant programmed cell death

    PubMed Central

    Williams, Brett; Verchot, Jeanmarie; Dickman, Martin B.

    2014-01-01

    The endoplasmic reticulum (ER) is the central organelle in the eukaryotic secretory pathway. The ER functions in protein synthesis and maturation and is crucial for proper maintenance of cellular homeostasis and adaptation to adverse environments. Acting as a cellular sentinel, the ER is exquisitely sensitive to changing environments principally via the ER quality control machinery. When perturbed, ER-stress triggers a tightly regulated and highly conserved, signal transduction pathway known as the unfolded protein response (UPR) that prevents the dangerous accumulation of unfolded/misfolded proteins. In situations where excessive UPR activity surpasses threshold levels, cells deteriorate and eventually trigger programmed cell death (PCD) as a way for the organism to cope with dysfunctional or toxic signals. The programmed cell death that results from excessive ER stress in mammalian systems contributes to several important diseases including hypoxia, neurodegeneration, and diabetes. Importantly, hallmark features and markers of cell death that are associated with ER stress in mammals are also found in plants. In particular, there is a common, conserved set of chaperones that modulate ER cell death signaling. Here we review the elements of plant cell death responses to ER stress and note that an increasing number of plant-pathogen interactions are being identified in which the host ER is targeted by plant pathogens to establish compatibility. PMID:24926295

  6. A Kunitz-type protease inhibitor regulates programmed cell death during flower development in Arabidopsis thaliana.

    PubMed

    Boex-Fontvieille, Edouard; Rustgi, Sachin; Reinbothe, Steffen; Reinbothe, Christiane

    2015-10-01

    Flower development and fertilization are tightly controlled in Arabidopsis thaliana. In order to permit the fertilization of a maximum amount of ovules as well as proper embryo and seed development, a subtle balance between pollen tube growth inside the transmitting tract and pollen tube exit from the septum is needed. Both processes depend on a type of programmed cell death that is still poorly understood. Here, it is shown that a Kunitz protease inhibitor related to water-soluble chlorophyll proteins of Brassicaceae (AtWSCP, encoded by At1g72290) is involved in controlling cell death during flower development in A. thaliana. Genetic, biochemical, and cell biology approaches revealed that WSCP physically interacts with RD21 (RESPONSIVE TO DESICCATION) and that this interaction in turn inhibits the activity of RD21 as a pro-death protein. The regulatory circuit identified depends on the restricted expression of WSCP in the transmitting tract and the septum epidermis. In a respective Atwscp knock-out mutant, flowers exhibited precocious cell death in the transmitting tract and unnatural death of septum epidermis cells. As a consequence, apical-basal pollen tube growth, fertilization of ovules, as well as embryo development and seed formation were perturbed. Together, the data identify a unique mechanism of cell death regulation that fine-tunes pollen tube growth.

  7. The deafness gene DFNA5 induces programmed cell death through mitochondria and MAPK-related pathways

    PubMed Central

    Van Rossom, Sofie; Op de Beeck, Ken; Hristovska, Vesna; Winderickx, Joris; Van Camp, Guy

    2015-01-01

    Cell death exists in many different forms. Some are accidental, but most of them have some kind of regulation and are called programmed cell death. Programmed cell death (PCD) is a very diverse and complex mechanism and must be tightly regulated. This study investigated PCD induced by DFNA5, a gene responsible for autosomal dominant hearing loss (HL) and a tumor suppressor gene (TSG) involved in frequent forms of cancer. Mutations in DFNA5 lead to exon 8 skipping and result in HL in several families. Expression of mutant DFNA5, a cDNA construct where exon 8 is deleted, was linked to PCD both in human cell lines and in Saccharomyces cerevisiae. To further investigate the cell death mechanism induced by mutant DFNA5, we performed a microarray study in both models. We used wild-type DFNA5, which does not induce cell death, as a reference. Our data showed that the yeast pathways related to mitochondrial ATP-coupled electron transport chain, oxidative phosphorylation and energy metabolism were up-regulated, while in human cell lines, MAP kinase-related activity was up-regulated. Inhibition of this pathway was able to partially attenuate the resulting cell death induced by mutant DFNA5 in human cell lines. In yeast, the association with mitochondria was demonstrated by up-regulation of several cytochrome c oxidase (COX) genes involved in the cellular oxidative stress production. Both models show a down-regulation of protein sorting- and folding-related mechanisms suggesting an additional role for the endoplasmic reticulum (ER). The exact relationship between ER and mitochondria in DFNA5-induced cell death remains unknown at this moment, but these results suggest a potential link between the two. PMID:26236191

  8. Increased anion channel activity is an unavoidable event in ozone-induced programmed cell death.

    PubMed

    Kadono, Takashi; Tran, Daniel; Errakhi, Rafik; Hiramatsu, Takuya; Meimoun, Patrice; Briand, Joël; Iwaya-Inoue, Mari; Kawano, Tomonori; Bouteau, François

    2010-10-13

    Ozone is a major secondary air pollutant often reaching high concentrations in urban areas under strong daylight, high temperature and stagnant high-pressure systems. Ozone in the troposphere is a pollutant that is harmful to the plant. By exposing cells to a strong pulse of ozonized air, an acute cell death was observed in suspension cells of Arabidopsis thaliana used as a model. We demonstrated that O(3) treatment induced the activation of a plasma membrane anion channel that is an early prerequisite of O(3)-induced cell death in A. thaliana. Our data further suggest interplay of anion channel activation with well known plant responses to O(3), Ca(2+) influx and NADPH-oxidase generated reactive oxygen species (ROS) in mediating the oxidative cell death. This interplay might be fuelled by several mechanisms in addition to the direct ROS generation by O(3); namely, H(2)O(2) generation by salicylic and abscisic acids. Anion channel activation was also shown to promote the accumulation of transcripts encoding vacuolar processing enzymes, a family of proteases previously reported to contribute to the disruption of vacuole integrity observed during programmed cell death. Collectively, our data indicate that anion efflux is an early key component of morphological and biochemical events leading to O(3)-induced programmed cell death. Because ion channels and more specifically anion channels assume a crucial position in cells, an understanding about the underlying role(s) for ion channels in the signalling pathway leading to programmed cell death is a subject that warrants future investigation.

  9. Axon Guidance Gene lola is Required for Programmed Cell Death in the Drosophila Ovary

    PubMed Central

    Bass, B. Paige; Cullen, Kristen; McCall, Kimberly

    2007-01-01

    longitudinals-lacking (lola) was identified in Drosophila as a gene encoding several alternatively spliced transcription factors involved in axon guidance. Here we report that lola also plays a critical role in programmed cell death in the ovary. lola mutant germline clones show a high percentage of egg chambers with nurse cell nuclei persisting past stage 13, indicating a block in developmental nurse cell death. Mutants also show a disruption in the induced programmed cell death that occurs during mid-oogenesis in response to starvation. Further characterization revealed that lola germline clones exhibit abnormal nuclear organization which becomes increasingly severe with age. Chromatin appears diffuse and fails to condense properly or undergo DNA fragmentation in dying nurse cells. Masses of nuclear material accumulate in the ovaries of older flies containing lola germline clones. We propose that lola is necessary for complete chromatin condensation which occurs during programmed cell death in the ovary. Alleles differed in the strength of their phenotypes but interestingly, the severity of their ovarian phenotypes was independent of the strength of their neuronal phenotypes, suggesting a differential requirement for individual lola isoforms in the ovary and nervous system. PMID:17336958

  10. Induction of DNA damage and caspase-independent programmed cell death by vitamin E.

    PubMed

    Constantinou, C; Neophytou, C M; Vraka, P; Hyatt, J A; Papas, K A; Constantinou, A I

    2012-01-01

    Vitamin E comprises 8 functionally unique isoforms and may be a suitable candidate for the adjuvant treatment of prostate cancer. In this study, we examined the ability of 2 vitamin E isoforms [α-tocotrienol (γ-TT) and δ-tocotrienol (δ-TT)] and 4 synthetic derivatives [γ- and δ-tocotrienol succinate (γ-TS, δ-TS), α-tocopheryl polyethylene glycol succinate (TPGS), and α-tocopheryl polyethylene glycol ether (TPGS-e)] of vitamin E to induce cell death in AR- (DU145 and PC-3) and AR+ (LNCaP) prostate cancer cell lines. Our results show that δ-TT and TPGS-e are the most effective isoform and synthetic derivative, respectively, of all compounds examined. Overall, the results of our study suggest that isoforms and synthetic derivatives of vitamin E have the potency to trigger both caspase-dependent and -independent DNA damage and dominant caspase-independent programmed cell death. The capacity of vitamin E to trigger caspase-independent programmed cell death suggests that it may be useful in the chemotherapy of prostate cancer since it may prevent the tumor resistance commonly associated with the use of classical chemotherapeutic agents that trigger caspase-dependent programmed cell death.

  11. The programmed death phenomena, aging, and the Samurai law of biology.

    PubMed

    Skulachev, V P

    2001-07-01

    Analysis of the programmed death phenomena from mitochondria (mitoptosis) to whole organisms (phenoptosis) clearly shows that suicide programs are inherent at various levels of organization of living systems. Such programs perform very important functions, purifying (i) cells from damaged (or unwanted for other reasons) organelles, (ii) tissues from unwanted cells, (iii) organisms from organs transiently appearing during ontogenesis, and (iv) communities of organisms from unwanted individuals. Defence against reactive oxygen species (ROS) is probably one of primary evolutionary functions of programmed death mechanisms. So far, it seems that ROS play a key role in the mito-, apo-, organo- and phenoptoses. Here a concept is described which tries to unite Weismann's concept of aging as an adaptive programmed death mechanism and the alternative point of view considering aging as an inevitable result of accumulation in an organism of occasional injuries. It is suggested that injury accumulation is monitored by special system sending a death signal to actuate a phenoptotic program when the number of injuries reaches some critical level. The system in question is organized in such a way that the lethal case appears to be a result of phenoptosis long before occasional injuries make the functioning of the organism impossible. This strategy is supposed to prevent the appearance of asocial monsters capable to ruining kin, community and entire population. These relationships are regarded as an example of the Samurai law of biology: 'It is better to die than to be wrong'. It is stressed that for humans these cruel regulations look like an atavism that should be overcome to prolong the human life span.

  12. Programmed cell death protein-1/programmed cell death ligand-1 pathway inhibition and predictive biomarkers: understanding transforming growth factor-beta role

    PubMed Central

    González-Cao, María; Viteri, Santiago; Karachaliou, Niki; Altavilla, Giuseppe; Rosell, Rafael

    2015-01-01

    A deeper understanding of the key role of the immune system in regulating tumor growth and progression has led to the development of a number of immunotherapies, including cancer vaccines and immune checkpoint inhibitors. Immune checkpoint inhibitors target molecular pathways involved in immunosuppression, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, with the goal to enhance the host’s own immune anticancer response. In phase I–III trials, anti-PD-1/PD-L1 antibodies have demonstrated to be effective treatment strategies by inducing significant durable tumor responses, with manageable toxicities, in patients with various malignancies, including those traditionally considered non-immunogenic, such as non-small cell lung cancer (NSCLC). Identification of predictive biomarkers to select patients for immune therapies is currently being investigated to improve their therapeutic efficacy. Transforming growth factor-β (TGF-β), a pleiotropic cytokine with immunosuppressive effects on multiple cell types of the innate and adaptive immune system, has emerged as one of the potential key factors modulating response to immune checkpoint inhibitors. However, due to the complexity of the anti-cancer immune response, the predictive value of many other factors related to cancer cells or tumor microenvironment needs to be further explored. PMID:26798582

  13. Update on Programmed Death-1 and Programmed Death-Ligand 1 Inhibition in the Treatment of Advanced or Metastatic Non-Small Cell Lung Cancer.

    PubMed

    Iafolla, Marco A J; Juergens, Rosalyn A

    2017-01-01

    Non-small-cell lung cancer (NSCLC) has a large worldwide prevalence with a high mortality rate. Chemotherapy has offered modest improvements in survival over the past two decades. Immune checkpoint modulation with programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition has shown the promise of changing the future landscape of cancer therapy. This update reviews recent advances in the treatment of NSCLC with immune checkpoint modulation. Publications and proceedings were identified from searching PubMed and proceedings from the annual meetings of the American Society of Clinical Oncology, European Society for Medical Oncology, and European Lung Cancer Conference. Atezolizumab, nivolumab, and pembrolizumab increase overall survival in second-line treatment of Stage III/IV squamous and non-squamous NSCLC when compared to docetaxel. Pembrolizumab increases progression-free survival in the first-line treatment of Stage IV NSCLC with 50% PD-L1 expression when compared to platinum-based chemotherapy. Combination therapy with chemotherapy and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors has shown promise in early trials. Immune checkpoint modulation produces durable responses and overall survival benefits with less toxicity compared to conventional chemotherapy. Future investigations are combining PD-1/L1 inhibition with chemotherapy, targeted therapy, or other immuno-oncology agents in an effort to further improve efficacy.

  14. Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: Association with extent of skin sclerosis.

    PubMed

    Yanaba, Koichi; Hayashi, Mitsuha; Yoshihara, Yuki; Nakagawa, Hidemi

    2016-08-01

    The interaction of programmed death-1 (PD-1) with its ligand, programmed death ligand-1 (PD-L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD-1 (sPD-1) than those with limited cutaneous SSc and healthy individuals. Serum sPD-1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD-L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD-L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD-1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD-1/PD-L1 interaction may contribute to the development of skin sclerosis in SSc.

  15. High fat programming of beta cell compensation, exhaustion, death and dysfunction.

    PubMed

    Cerf, Marlon E

    2015-03-01

    Programming refers to events during critical developmental windows that shape progeny health outcomes. Fetal programming refers to the effects of intrauterine (in utero) events. Lactational programming refers to the effects of events during suckling (weaning). Developmental programming refers to the effects of events during both fetal and lactational life. Postnatal programming refers to the effects of events either from birth (lactational life) to adolescence or from weaning (end of lactation) to adolescence. Islets are most plastic during the early life course; hence programming during fetal and lactational life is most potent. High fat (HF) programming is the maintenance on a HF diet (HFD) during critical developmental life stages that alters progeny metabolism and physiology. HF programming induces variable diabetogenic phenotypes dependent on the timing and duration of the dietary insult. Maternal obesity reinforces HF programming effects in progeny. HF programming, through acute hyperglycemia, initiates beta cell compensation. However, HF programming eventually leads to chronic hyperglycemia that triggers beta cell exhaustion, death and dysfunction. In HF programming, beta cell dysfunction often co-presents with insulin resistance. Balanced, healthy nutrition during developmental windows is critical for preserving beta cell structure and function. Thus early positive nutritional interventions that coincide with the development of beta cells may reduce the overwhelming burden of diabetes and metabolic disease. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. A traumatic death support group program: applying an integrated conceptual framework.

    PubMed

    Walijarvi, Corrine M; Weiss, Ann H; Weinman, Maxine L

    2012-02-01

    This article describes an 8-week, curriculum-based traumatic death support group program that is offered at Bo's Place, a grief and bereavement center in Houston, Texas. The program was implemented in 2006 in an effort to help family members who had experienced a death in the family by suicide, murder, accident, or sudden medical problem. The program provides the opportunity for families to come to the center and engage in selected activities as a unit, while also providing adults and children the opportunity to participate in separate support groups with curricula adapted to different age levels. The program uses an integrated conceptual framework that draws upon elements from a variety of theoretical and conceptual models related to grief. The purpose of the program is to provide multiple paths for progress in the grief journey for the bereaved. In 2008, Bo's Place incorporated a brief questionnaire into the weekly meetings, in an effort to gain a better understanding of the perceptions of adult participants of the program and their own progress in their grief. The questionnaire asked adults to provide self-ratings of their perceptions of support from the program and of their progress in their grief journey. The positive results from this pilot study have encouraged Bo's Place to develop plans for more rigorous research into the mechanisms that contribute to progress in the grief journey for bereaved adults and children.

  17. Epidemiology of type 1 Diabetes Mellitus.

    PubMed

    Rewers, Marian; Norris, Jill; Dabelea, Dana

    2004-01-01

    Type 1 diabetes can be diagnosed at any age, but dinical course, genetic, and environmental determinants appear to be heterogenous by age. The common pathway begins with preclinical beta-cell autoimmunity with progressive defect of insulin secretion, followed by onset of hyperglycemia, transient usually partial remission, and finally complete insulinopenia associated with acute and chronic complications and premature death. Current research effort is focused on identification of the genetic and environmental determinants of this process and the ways they interact.

  18. Programmed cell death in Leishmania: biochemical evidence and role in parasite infectivity

    PubMed Central

    Gannavaram, Sreenivas; Debrabant, Alain

    2012-01-01

    Demonstration of features of a programmed cell death (PCD) pathway in protozoan parasites initiated a great deal of interest and debate in the field of molecular parasitology. Several of the markers typical of mammalian apoptosis have been shown in Leishmania which suggested the existence of an apoptosis like death in these organisms. However, studies to elucidate the downstream events associated with phosphotidyl serine exposure, loss of mitochondrial membrane potential, cytochrome c release, and caspase-like activities in cells undergoing such cell death remain an ongoing challenge. Recent advances in genome sequencing, chemical biology should help to solve some of these challenges. Leishmania genetic mutants that lack putative regulators/effectors of PCD pathway should not only help to demonstrate the mechanisms of PCD but also provide tools to better understand the putative role for this pathway in population control and in the establishment of a successful infection of the host. PMID:22919685

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

    PubMed

    Giannattasio, Sergio; Guaragnella, Nicoletta; Zdralević, Maša; Marra, Ersilia

    2013-01-01

    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.

  20. Ethylene signaling pathway and MAPK cascades are required for AAL toxin-induced programmed cell death.

    PubMed

    Mase, Keisuke; Mizuno, Takahito; Ishihama, Nobuaki; Fujii, Takayuki; Mori, Hitoshi; Kodama, Motoichiro; Yoshioka, Hirofumi

    2012-08-01

    Programmed cell death (PCD), known as hypersensitive response cell death, has an important role in plant defense response. The signaling pathway of PCD remains unknown. We employed AAL toxin and Nicotiana umbratica to analysis plant PCD. AAL toxin is a pathogenicity factor of the necrotrophic pathogen Alternaria alternata f. sp. lycopersici. N. umbratica is sensitive to AAL toxin, susceptible to pathogens, and effective in Tobacco rattle virus-based virus-induced gene silencing (VIGS). VIGS analyses indicated that AAL toxin-triggered cell death (ACD) is dependent upon the mitogen-activated protein (MAP) kinase kinase MEK2, which is upstream of both salicylic acid-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK) responsible for ethylene (ET) synthesis. ET treatment of MEK2-silenced N. umbratica re-established ACD. In SIPK- and WIPK-silenced N. umbratica, ACD was compromised and ET accumulation was not observed. However, in contrast to the case of MEK2-silenced plants, ET treatment did not induce cell death in SIPK- and WIPK-silenced plants. This work showed that ET-dependent pathway and MAP kinase cascades are required in ACD. Our results suggested that MEK2-SIPK/WIPK cascades have roles in ET biosynthesis; however, SIPK and WIPK have other roles in ET signaling or another pathway leading to cell death by AAL toxin.

  1. BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

    SciTech Connect

    Nagy, Gabor; Szarka, Andras; Lotz, Gabor; Doczi, Judit; Wunderlich, Livius; Kiss, Andras; Jemnitz, Katalin; Veres, Zsuzsa; Banhegyi, Gabor; Schaff, Zsuzsa; Suemegi, Balazs; Mandl, Jozsef

    2010-02-15

    It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

  2. BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury.

    PubMed

    Nagy, Gábor; Szarka, András; Lotz, Gábor; Dóczi, Judit; Wunderlich, Lívius; Kiss, András; Jemnitz, Katalin; Veres, Zsuzsa; Bánhegyi, Gábor; Schaff, Zsuzsa; Sümegi, Balázs; Mandl, József

    2010-02-15

    It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death. Copyright 2009 Elsevier Inc. All rights reserved.

  3. Cutting edge: regulatory T cells do not mediate suppression via programmed cell death pathways.

    PubMed

    Szymczak-Workman, Andrea L; Delgoffe, Greg M; Green, Douglas R; Vignali, Dario A A

    2011-11-01

    Regulatory T cells (Tregs) play a critical role in the immune system to regulate peripheral tolerance and prevent autoimmunity. However, the relative importance of different mechanisms of Treg function remains obscure. In this article, we reveal a limited role for programmed cell death pathways in mediating Treg suppression of conventional T cells. We show that Tregs are able to suppress the proliferation of conventional T cells that are resistant to apoptosis (Bim(-/-), Bim(-/-)Puma(-/-), Bcl-2 transgenic) or receptor-interacting serine-threonine kinase-dependent necrosis (also referred to as regulated necrosis or necroptosis) (Ripk3(-/-)) in several in vitro and in vivo assays. These data suggest that programmed cell death pathways, such as apoptosis and receptor-interacting serine-threonine kinase-dependent necrosis, are not required for Treg-mediated suppression.

  4. Targeting programmed cell death ligand 1 in osteosarcoma: an auto-commentary on therapeutic potential.

    PubMed

    Shen, Jacson K; Cote, Gregory M; Choy, Edwin; Hornicek, Francis J; Duan, Zhenfeng

    Programmed cell death ligand 1 (PDL1) expression was recently shown to correlate with tumor-infiltrating lymphocytes (TILs) in a subset of osteosarcoma patients. Among clinical factors evaluated across human osteosarcoma samples, a pulmonary origin of metastases correlated with high PDL1 expression and prominent TILs. Considering that multiple agents targeting PD-1/PDL1 are under development, targeting this immune checkpoint may be a novel immunotherapeutic route for osteosarcoma in future clinical trials.

  5. An Evidence-Based Infant Safe Sleep Program to Reduce Sudden Unexplained Infant Deaths.

    PubMed

    Zachritz, Whitney; Fulmer, Megan; Chaney, Nicole

    2016-11-01

    : Objective: The purpose of this project was to design, implement, and evaluate a safe sleep program for expectant mothers and the families of infants discharged from our hospital's neonatal intensive care unit (NICU). It was prompted by the sleep-related deaths of two infants in the community, both of whom had been discharged from our NICU. A six-member interdisciplinary team comprising nurses, a physician, an occupational therapist, and a respiratory therapist developed a safe sleep program in an effort to identify and implement evidence-based safe sleep practices for infants in the NICU. The team examined the literature on sleep-related death and safe sleep practices, consulted with colleagues in NICUs at nearby hospitals and clinics, and conducted an audit of practices related to putting infants to sleep in the NICU. The initiative included the use of infant sleep sacks, the development of a clinical practice guideline to promote safe sleep, and the delivery of standardized discharge education for caregivers in the NICU and safe sleep classes for expectant mothers and caregivers in the community. The team educated NICU staff on the new practice guideline in November and December 2014, and implemented the clinical intervention in January 2015. Random unit audits showed that prior to implementation of the safe sleep program, NICU nurses had followed safe sleep practices only 20% of the time; after implementation, however, safe sleep practices were followed an average of about 90% of the time. In-hospital and community-oriented evidence-based teaching on safe sleep practices and environments was associated with no sleep-related infant deaths after discharge from our NICU in calendar year 2015. A multifaceted safe sleep program offers many benefits to both the NICU and its patients. The implementation of a standardized safe sleep program provides an enormous opportunity to improve the health and well-being of the community. All hospitals that care for mothers and

  6. The myonuclear domain is not maintained in skeletal muscle during either atrophy or programmed cell death.

    PubMed

    Schwartz, Lawrence M; Brown, Christine; McLaughlin, Kevin; Smith, Wendy; Bigelow, Carol

    2016-10-01

    Skeletal muscle mass can increase during hypertrophy or decline dramatically in response to normal or pathological signals that trigger atrophy. Many reports have documented that the number of nuclei within these cells is also plastic. It has been proposed that a yet-to-be-defined regulatory mechanism functions to maintain a relatively stable relationship between the cytoplasmic volume and nuclear number within the cell, a phenomenon known as the "myonuclear domain" hypothesis. While it is accepted that hypertrophy is typically associated with the addition of new nuclei to the muscle fiber from stem cells such as satellite cells, the loss of myonuclei during atrophy has been controversial. The intersegmental muscles from the tobacco hawkmoth Manduca sexta are composed of giant syncytial cells that undergo sequential developmental programs of atrophy and programmed cell death at the end of metamorphosis. Since the intersegmental muscles lack satellite cells or regenerative capacity, the tissue is not "contaminated" by these nonmuscle nuclei. Consequently, we monitored muscle mass, cross-sectional area, nuclear number, and cellular DNA content during atrophy and the early phases of cell death. Despite a ∼75-80% decline in muscle mass and cross-sectional area during the period under investigation, there were no reductions in nuclear number or DNA content, and the myonuclear domain was reduced by ∼85%. These data suggest that the myonuclear domain is not an intrinsic property of skeletal muscle and that nuclei persist through atrophy and programmed cell death. Copyright © 2016 the American Physiological Society.

  7. Holocrine Secretion of Sebum Is a Unique DNase2-Dependent Mode of Programmed Cell Death.

    PubMed

    Fischer, Heinz; Fumicz, Judith; Rossiter, Heidemarie; Napirei, Markus; Buchberger, Maria; Tschachler, Erwin; Eckhart, Leopold

    2017-03-01

    Sebaceous glands produce sebum via holocrine secretion, a largely uncharacterized mode of programmed cell death that contributes to the homeostasis and barrier function of the skin. To determine the mechanism of DNA degradation during sebocyte cell death, we have inactivated candidate DNA-degrading enzymes by targeted gene deletions in mice. DNase1 and DNase1-like 2 were dispensable for nuclear DNA degradation in sebocytes. By contrast, epithelial cell-specific deletion of lysosomal DNase2 blocked DNA degradation in these cells. DNA breakdown during sebocyte differentiation coincided with the loss of LAMP1 and was accelerated by the abrogation of autophagy, the central cellular program of lysosome-dependent catabolism. Suppression of DNA degradation by the deletion of DNase2 resulted in aberrantly increased concentrations of residual DNA and decreased amounts of the DNA metabolite uric acid in secreted sebum. These results define holocrine secretion as a DNase2-mediated form of programmed cell death and suggest that autophagy-dependent metabolism, DNA degradation, and the molecular composition of sebum are mechanistically linked. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Overcoming Hospital Resistance to Create a Successful Donation After Circulatory Death Program.

    PubMed

    O'Meeghan, R; Pedral, L

    2016-09-01

    In the setting of an ever-increasing transplantation need, and a relatively static number of brain dead donors, donation after circulatory death (DCD) has heightened importance as a process to increase the number of organs available for transplantation. This article describes the barriers to the DCD process at a community hospital, what occurred to change the situation, and how data were used to overcome administrative and cultural barriers to create a successful DCD program. The program has become a role model in the local community. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. T-bet regulates differentiation of forkhead box protein 3+ regulatory T cells in programmed cell death-1-deficient mice

    PubMed Central

    Tahara, M; Kondo, Y; Yokosawa, M; Tsuboi, H; Takahashi, S; Shibayama, S; Matsumoto, I; Sumida, T

    2015-01-01

    Programmed cell death-1 (PD-1) plays an important role in peripheral T cell tolerance, but whether or not it affects the differentiation of helper T cell subsets remains elusive. Here we describe the importance of PD-1 in the control of T helper type 1 (Th1) cell activation and development of forkhead box protein 3 (FoxP3+) regulatory T cells (Tregs). PD-1-deficient T cell-specific T-bet transgenic (P/T) mice showed growth retardation, and the majority died within 10 weeks. P/T mice showed T-bet over-expression, increased interferon (IFN)-γ production by CD4+ T cells and significantly low FoxP3+ Treg cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3+ Treg count. The study identified a unique, previously undescribed role for PD-1 in Th1 and Treg differentiation, with potential implication in the development of Th1 cell-targeted therapy. PMID:25219397

  10. Increased Level of Myeloid-Derived Suppressor Cells, Programmed Death Receptor Ligand 1/Programmed Death Receptor 1, and Soluble CD25 in Sokal High Risk Chronic Myeloid Leukemia

    PubMed Central

    Christiansson, Lisa; Söderlund, Stina; Svensson, Emma; Mustjoki, Satu; Bengtsson, Mats; Simonsson, Bengt; Olsson-Strömberg, Ulla; Loskog, Angelica S. I.

    2013-01-01

    Immunotherapy (eg interferon α) in combination with tyrosine kinase inhibitors is currently in clinical trials for treatment of chronic myeloid leukemia (CML). Cancer patients commonly have problems with so called immune escape mechanisms that may hamper immunotherapy. Hence, to study the function of the immune system in CML is of interest. In the present paper we have identified immune escape mechanisms in CML with focus on those that directly hamper T cells since these cells are important to control tumor progression. CML patient samples were investigated for the presence of myeloid-derived suppressor cells (MDSCs), expression of programmed death receptor ligand 1/programmed death receptor 1 (PD-L1/PD-1), arginase 1 and soluble CD25. MDSC levels were increased in samples from Sokal high risk patients (p<0,05) and the cells were present on both CD34 negative and CD34 positive cell populations. Furthermore, expression of the MDSC-associated molecule arginase 1, known to inhibit T cells, was increased in the patients (p = 0,0079). Myeloid cells upregulated PD-L1 (p<0,05) and the receptor PD-1 was present on T cells. However, PD-L1 blockade did not increase T cell proliferation but upregulated IL-2 secretion. Finally, soluble CD25 was increased in high risk patients (p<0,0001). In conclusion T cells in CML patients may be under the control of different immune escape mechanisms that could hamper the use of immunotherapy in these patients. These escape mechanisms should be monitored in trials to understand their importance and how to overcome the immune suppression. PMID:23383287

  11. Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type.

    PubMed

    Jo, Jae-Cheol; Kim, Misung; Choi, Yunsuk; Kim, Hyun-Jung; Kim, Ji Eun; Chae, Seoung Wan; Kim, Hawk; Cha, Hee Jeong

    2017-01-01

    Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are new therapeutic targets in cancer immunotherapy. The aim of this study was to investigate the clinicopathological characteristics of PD-1 and PD-L1 expression in extranodal natural killer/T‑cell lymphoma, nasal type (ENKTL). We performed PD-1 and PD-L1 immunostaining in 79 ENKTL biopsy samples and retrospectively analyzed medical records of all 79 patients from four tertiary referral hospitals. The expression of PD-1 and PD-L1 by tumor cells and/or infiltrating immune cells was evaluated. The expression rates of PD-L1 in tumor cells and infiltrating immune cells were 79.7 and 78.5 %, respectively, whereas PD-1 in tumor cells and infiltrating immune cells were 1.3 and 11.4 %. The PD-L1 positivity in tumor cells and infiltrating immune cells was significantly associated with low international prognostic index (IPI) (P = 0.044 and 0.037, respectively). Patients with normal range of serum lactate dehydrogenase demonstrated a significantly higher PD-L1 positivity in tumor cells (P = 0.020). PD-L1-positive patients had a trend toward better overall survival compared with that in patients with PD-L1-negative in tumor cells and infiltrating immune cells (P = 0.498 and 0.435, respectively). The expression rate of PD-L1 was up to 79.7 % in ENKTL, while PD-1 expression rate was very low. This is the first report describing the clinicopathological features and survival outcome according to expression of PD-1 and PD-L1 in ENKTL.

  12. Increased level of myeloid-derived suppressor cells, programmed death receptor ligand 1/programmed death receptor 1, and soluble CD25 in Sokal high risk chronic myeloid leukemia.

    PubMed

    Christiansson, Lisa; Söderlund, Stina; Svensson, Emma; Mustjoki, Satu; Bengtsson, Mats; Simonsson, Bengt; Olsson-Strömberg, Ulla; Loskog, Angelica S I

    2013-01-01

    Immunotherapy (eg interferon α) in combination with tyrosine kinase inhibitors is currently in clinical trials for treatment of chronic myeloid leukemia (CML). Cancer patients commonly have problems with so called immune escape mechanisms that may hamper immunotherapy. Hence, to study the function of the immune system in CML is of interest. In the present paper we have identified immune escape mechanisms in CML with focus on those that directly hamper T cells since these cells are important to control tumor progression. CML patient samples were investigated for the presence of myeloid-derived suppressor cells (MDSCs), expression of programmed death receptor ligand 1/programmed death receptor 1 (PD-L1/PD-1), arginase 1 and soluble CD25. MDSC levels were increased in samples from Sokal high risk patients (p<0.05) and the cells were present on both CD34 negative and CD34 positive cell populations. Furthermore, expression of the MDSC-associated molecule arginase 1, known to inhibit T cells, was increased in the patients (p = 0.0079). Myeloid cells upregulated PD-L1 (p<0.05) and the receptor PD-1 was present on T cells. However, PD-L1 blockade did not increase T cell proliferation but upregulated IL-2 secretion. Finally, soluble CD25 was increased in high risk patients (p<0.0001). In conclusion T cells in CML patients may be under the control of different immune escape mechanisms that could hamper the use of immunotherapy in these patients. These escape mechanisms should be monitored in trials to understand their importance and how to overcome the immune suppression.

  13. Involvement of ethylene and lipid signalling in cadmium-induced programmed cell death in tomato suspension cells.

    PubMed

    Yakimova, E T; Kapchina-Toteva, V M; Laarhoven, L-J; Harren, F M; Woltering, E J

    2006-10-01

    Cadmium-induced cell death was studied in suspension-cultured tomato (Lycopersicon esculentum Mill.) cells (line MsK8) treated with CdSO(4). Within 24 h, cadmium treatment induced cell death in a concentration-dependent manner. Cell cultures showed recovery after 2-3 days which indicates the existence of an adaptation mechanism. Cadmium-induced cell death was alleviated by the addition of sub muM concentrations of peptide inhibitors specific to human caspases indicating that cell death proceeds through a mechanism with similarities to animal programmed cell death (PCD, apoptosis). Cadmium-induced cell death was accompanied by an increased production of hydrogen peroxide (H(2)O(2)) and simultaneous addition of antioxidants greatly reduced cell death. Inhibitors of phospholipase C (PLC) and phospholipase D (PLD) signalling pathway intermediates reduced cadmium-induced cell death. Treatment with the G-protein activator mastoparan and a cell permeable analogue of the lipid signal second messenger phosphatidic acid (PA) induced cell death. Ethylene, while not inducing cell death when applied alone, stimulated cadmium-induced cell death. Application of the ethylene biosynthesis inhibitor aminoethoxy vinylglycine (AVG) reduced cadmium-induced cell death, and this effect was alleviated by simultaneous treatment with ethylene. Together the results show that cadmium induces PCD exhibiting apoptotic-like features. The cell death process requires increased H(2)O(2) production and activation of PLC, PLD and ethylene signalling pathways.

  14. Injury Deaths Among U.S. Females: CDC Resources and Programs.

    PubMed

    Mack, Karin A; Peterson, Cora; Zhou, Chao; MacConvery, Elliane; Wilkins, Natalie

    2017-04-01

    Injury death rates are lower for women than for men at all ages, but we have a long way to go in understanding the circumstances of injury fatalities among females. This article presents resources that can be used to examine the most recent data on injury fatalities among females and highlights activities of CDC's Injury Center. The National Center for Injury Prevention and Control's (NCIPC's) Web-based Injury Statistics Query and Reporting System, an online surveillance database, can be used to examine injury deaths. We present examples that show the 2015 number of female fatal injuries by age group and injury cause and method, as well as a 2008-2014 county-level map of female fatal injury rates. In 2015, there were 68,572 injury fatalities of females of age ≥1 year, equivalent to 1 death every 7 minutes. Injuries were the leading cause of death for females of ages 1-41 years and the sixth-ranked cause of female death overall. Falls were the leading cause of injury death overall (and for women ≥70 years), unintentional poisonings were second, and motor vehicle traffic injuries were third. NCIPC funds national organizations, state health agencies, and other groups to develop, implement, and promote effective injury and violence prevention and control practices. Five key programs are discussed. Presenting data on injury fatalities is an essential element in identifying meaningful prevention efforts. Further investigation of the causes and impact of female injury fatalities can refine the public health approach to reduce this injury burden.

  15. Photodynamic therapy-induced programmed cell death in carcinoma cell lines

    NASA Astrophysics Data System (ADS)

    He, Xiao-Yan; Sikes, Robert A.; Thomsen, Sharon L.; Chung, L.; Jacques, Steven L.

    1993-06-01

    The mode of cell death following photodynamic therapy (PDT) was investigated from the perspective of programmed cell death (apoptosis). Human prostate carcinoma cells (PC3), human non-small cell lung carcinoma (H322a), and rat mammary carcinoma (MTF7) were treated by PDT following sensitization with dihematoporphyrin ether (DHE). The response of these carcinoma cell lines to PDT was variable. An examination of extracted cellular DNA by gel electrophoresis showed the characteristic DNA ladder pattern indicative of internucleosomal cleavage of DNA during apoptosis. MTF7 and PC3 responded to PDT by inducing apoptosis while H322a had no apoptotic response. The magnitude of the response and the PDT dosage required to induce the effect were different in PC3 and MTF7. MTF7 cells responded with rapid apoptosis at the dose of light and drug that yielded 50% cell death (LD50). In contrast, PC3 showed only marginal apoptosis at the LD50 but had a marked response at the LD85. Furthermore, the onset of apoptosis followed slower kinetics in PC3 (2 hr - 4 hr) than in MTF7 (< 1 hr). H322a cells were killed by PDT but failed to exhibit any apoptotic response. This study indicates that apoptosis may occur during PDT induced cell death, but this pathway is not universal for all cancer cell lines.

  16. Increased Resistance of Complex I Mutants to Phytosphingosine-induced Programmed Cell Death*S⃞

    PubMed Central

    Castro, Ana; Lemos, Catarina; Falcão, Artur; Glass, N. Louise; Videira, Arnaldo

    2008-01-01

    We have studied the effects of phytosphingosine (PHS) on cells of the filamentous fungus Neurospora crassa. Highly reduced viability, impairment of asexual spore germination, DNA condensation and fragmentation, and production of reactive oxygen species were observed in conidia treated with the drug, suggesting that PHS induces an apoptosis-like death in this fungus. Interestingly, we found that complex I mutants are more resistant to PHS treatment than the wild type strain. This effect appears to be specific because it was not observed in mutants defective in other components of the mitochondrial respiratory chain, pointing to a particular involvement of complex I in cell death. The response of the mutant strains to PHS correlated with their response to hydrogen peroxide. The fact that complex I mutants generate fewer reactive oxygen species than the wild type strain when exposed to PHS likely explains the PHS-resistant phenotype. As compared with the wild type strain, we also found that a strain containing a deletion in the gene encoding an AIF (apoptosis-inducing factor)-like protein is more resistant to PHS and H2O2. In contrast, a strain containing a deletion in a gene encoding an AMID (AIF-homologous mitochondrion-associated inducer of death)-like polypeptide is more sensitive to both drugs. These results indicate that N. crassa has the potential to be a model organism to investigate the molecular basis of programmed cell death in eukaryotic species. PMID:18474589

  17. Increased resistance of complex I mutants to phytosphingosine-induced programmed cell death.

    PubMed

    Castro, Ana; Lemos, Catarina; Falcão, Artur; Glass, N Louise; Videira, Arnaldo

    2008-07-11

    We have studied the effects of phytosphingosine (PHS) on cells of the filamentous fungus Neurospora crassa. Highly reduced viability, impairment of asexual spore germination, DNA condensation and fragmentation, and production of reactive oxygen species were observed in conidia treated with the drug, suggesting that PHS induces an apoptosis-like death in this fungus. Interestingly, we found that complex I mutants are more resistant to PHS treatment than the wild type strain. This effect appears to be specific because it was not observed in mutants defective in other components of the mitochondrial respiratory chain, pointing to a particular involvement of complex I in cell death. The response of the mutant strains to PHS correlated with their response to hydrogen peroxide. The fact that complex I mutants generate fewer reactive oxygen species than the wild type strain when exposed to PHS likely explains the PHS-resistant phenotype. As compared with the wild type strain, we also found that a strain containing a deletion in the gene encoding an AIF (apoptosis-inducing factor)-like protein is more resistant to PHS and H2O2. In contrast, a strain containing a deletion in a gene encoding an AMID (AIF-homologous mitochondrion-associated inducer of death)-like polypeptide is more sensitive to both drugs. These results indicate that N. crassa has the potential to be a model organism to investigate the molecular basis of programmed cell death in eukaryotic species.

  18. Infertility in the hyperplasic ovary of freshwater planarians: the role of programmed cell death.

    PubMed

    Harrath, Abdel Halim; Semlali, Abdelhabib; Mansour, Lamjed; Ahmed, Mukhtar; Sirotkin, Alexander V; Al Omar, Suliman Y; Arfah, Maha; Al Anazi, Mohamed S; Alhazza, Ibrahim M; Nyengaard, Jens R; Alwasel, Saleh

    2014-11-01

    Ex-fissiparous planarians produce infertile cocoons or, in very rare cases, cocoons with very low fertility. Here, we describe the features of programmed cell death (PCD) occurring in the hyperplasic ovary of the ex-fissiparous freshwater planarian Dugesia arabica that may explain this infertility. Based on TEM results, we demonstrate a novel extensive co-clustering of cytoplasmic organelles, such as lysosomes and microtubules, and their fusion with autophagosomes during the early stage of oocyte cell death occurring through an autophagic pattern. During a later stage of cell death, the generation of apoptotic vesicles in the cytoplasm can be observed. The immunohistochemical labeling supports the ultrastructural results because it has been shown that the proapoptotic protein bax was more highly expressed in the hyperplasic ovary than in the normal one, whereas the anti-apoptotic protein bcl2 was slightly more highly expressed in the normal ovary compared to the hyperplasic one. TUNEL analysis of the hyperplasic ovary confirmed that the nuclei of the majority of differentiating oocytes were TUNEL-positive, whereas the nuclei of oogonia and young oocytes were TUNEL-negative; in the normal ovary, oocytes are TUNEL-negative. Considering all of these data, we suggest that the cell death mechanism of differentiating oocytes in the hyperplasic ovary of freshwater planarians is one of the most important factors that cause ex-fissiparous planarian infertility. We propose that autophagy precedes apoptosis during oogenesis, whereas apoptotic features can be observed later.

  19. Control of adult neurogenesis by programmed cell death in the mammalian brain.

    PubMed

    Ryu, Jae Ryun; Hong, Caroline Jeeyeon; Kim, Joo Yeon; Kim, Eun-Kyoung; Sun, Woong; Yu, Seong-Woon

    2016-04-21

    The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases.

  20. Alaska's model program for surveillance and prevention of occupational injury deaths.

    PubMed Central

    Conway, G A; Lincoln, J M; Husberg, B J; Manwaring, J C; Klatt, M L; Thomas, T K

    1999-01-01

    The National Institute for Occupational Safety and Health (NIOSH) established its Alaska Field Station in Anchorage in 1991 after identifying Alaska as the highest-risk state for traumatic worker fatalities. Since then, the Field Station, working in collaboration with other agencies, organizations, and individuals, has established a program for occupational injury surveillance in Alaska and formed interagency working groups to address the risk factors leading to occupational death and injury in the state. Collaborative efforts have contributed to reducing crash rates and mortality in Alaska's rapidly expanding helicopter logging industry and have played an important supportive role in the substantial progress made in reducing the mortality rate in Alaska's commercial fishing industry (historically Alaska's and America's most dangerous industry). Alaska experienced a 46% overall decline in work-related acute traumatic injury deaths from 1991 to 1998, a 64% decline in commercial fishing deaths, and a very sharp decline in helicopter logging-related deaths. Extending this regional approach to other parts of the country and applying these strategies to the entire spectrum of occupational injury and disease hazards could have a broad effect on reducing occupational injuries. PMID:10670623

  1. Chloroplast Activity and 3'phosphadenosine 5'phosphate Signaling Regulate Programmed Cell Death in Arabidopsis.

    PubMed

    Bruggeman, Quentin; Mazubert, Christelle; Prunier, Florence; Lugan, Raphaël; Chan, Kai Xun; Phua, Su Yin; Pogson, Barry James; Krieger-Liszkay, Anja; Delarue, Marianne; Benhamed, Moussa; Bergounioux, Catherine; Raynaud, Cécile

    2016-03-01

    Programmed cell death (PCD) is a crucial process both for plant development and responses to biotic and abiotic stress. There is accumulating evidence that chloroplasts may play a central role during plant PCD as for mitochondria in animal cells, but it is still unclear whether they participate in PCD onset, execution, or both. To tackle this question, we have analyzed the contribution of chloroplast function to the cell death phenotype of the myoinositol phosphate synthase1 (mips1) mutant that forms spontaneous lesions in a light-dependent manner. We show that photosynthetically active chloroplasts are required for PCD to occur in mips1, but this process is independent of the redox state of the chloroplast. Systematic genetic analyses with retrograde signaling mutants reveal that 3'-phosphoadenosine 5'-phosphate, a chloroplast retrograde signal that modulates nuclear gene expression in response to stress, can inhibit cell death and compromises plant innate immunity via inhibition of the RNA-processing 5'-3' exoribonucleases. Our results provide evidence for the role of chloroplast-derived signal and RNA metabolism in the control of cell death and biotic stress response. © 2016 American Society of Plant Biologists. All Rights Reserved.

  2. mazEF-mediated programmed cell death in bacteria: "what is this?".

    PubMed

    Ramisetty, Bhaskar Chandra Mohan; Natarajan, Bhargavi; Santhosh, Ramachandran Sarojini

    2015-02-01

    Toxin-antitoxin (TA) systems consist of a bicistronic operon, encoding a toxin and an antitoxin. They are widely distributed in the prokaryotic kingdom, often in multiple numbers. TAs are implicated in contradicting phenomena of persistence and programmed cell death (PCD) in bacteria. mazEF TA system, one of the widely distributed type II toxin-antitoxin systems, is particularly implicated in PCD of Escherichia coli. Nutrient starvation, antibiotic stress, heat shock, DNA damage and other kinds of stresses are shown to elicit mazEF-mediated-PCD. ppGpp and extracellular death factor play a central role in regulating mazEF-mediated PCD. The activation of mazEF system is achieved through inhibition of transcription or translation of mazEF loci. Upon activation, MazF cleaves RNA in a ribosome-independent fashion and subsequent processes result in cell death. It is hypothesized that PCD aids in perseverance of the population during stress; the surviving minority of the cells can scavenge the nutrients released by the dead cells, a kind of "nutritional-altruism." Issues regarding the strains, reproducibility of experimental results and ecological plausibility necessitate speculation. We review the molecular mechanisms of the activation of mazEF TA system, the consequences leading to cell death and the pros and cons of the altruism hypothesis from an ecological perspective.

  3. Type 1 Diabetes and Sleep.

    PubMed

    Farabi, Sarah S

    2016-02-01

    IN BRIEF In people with type 1 diabetes, sleep may be disrupted as a result of both behavioral and physiological aspects of diabetes and its management. This sleep disruption may negatively affect disease progression and development of complications. This review highlights key research findings regarding sleep in people with type 1 diabetes.

  4. Developmental programmed cell death during asymmetric microsporogenesis in holocentric species of Rhynchospora (Cyperaceae)

    PubMed Central

    Rocha, Danilo M.; Marques, André; Andrade, Celia G.T.J.; Guyot, Romain; Chaluvadi, Srinivasa R.; Pedrosa-Harand, Andrea; Houben, Andreas; Bennetzen, Jeffrey L.; Vanzela, André L.L.

    2016-01-01

    Members of the Cyperaceae family exhibit an asymmetric microsporogenesis that results in the degeneration of three out of four meiotic products. Efforts have been made previously to describe the resulting structure, named the pseudomonad, but mechanisms concerning the establishment of cell domains, nuclear development, and programmed cell death are largely unknown. Using the Rhynchospora genus as a model, evidence for cell asymmetry, cytoplasmic isolation, and programmed cell death was obtained by a combination of electron microscopic, cytochemical, immunocytochemical, in situ hybridization, and flow cytometric methods. Degenerative cells were identified at the abaxial region, with the cytoskeleton marking their delimitation from the functional domain after meiosis. After attempting to initiate cell division with an unreplicated genome and abnormal spindle assembly, these cells exhibited a gradual process of cytoplasmic contraction associated with hypermethylation of cytosines and differential loss of DNA. These results indicate that the asymmetric tetrad establishes a functional cell, where one nucleus is preferentially selected to survive. Degenerative haploid cells are then eliminated in a multistep process associated with mitotic disorder, non-random elimination of repetitive DNA, vacuolar cell death, and DNA fragmentation. PMID:27492982

  5. Remodelling of lace plant leaves: antioxidants and ROS are key regulators of programmed cell death.

    PubMed

    Dauphinee, Adrian N; Fletcher, Jacob I; Denbigh, Georgia L; Lacroix, Christian R; Gunawardena, Arunika H L A N

    2017-07-01

    Antioxidants and reactive oxygen species are integral for programmed cell death signaling during perforation formation in the lace plant ( Aponogeton madagascariensis ). The lace plant is an excellent model system for studying developmentally regulated programmed cell death (PCD). During early lace plant leaf development, PCD systematically deletes cells resulting in a perforated leaf morphology that is unique in planta. A distinct feature in young lace plant leaves is an abundance of anthocyanins, which have antioxidant properties. The first sign of PCD induction is the loss of anthocyanin pigmentation in cells that are targeted for destruction, which results in a visible gradient of cell death. The cellular dynamics and time course of lace plant PCD are well documented; however, the signals involved in the pathway remain elusive. This study investigates the roles of antioxidants and ROS in developmental PCD signaling during lace plant perforation formation. The involvement of antioxidants and ROS in the pathway was determined using a variety of techniques including pharmacological whole plant experimentation, long-term live cell imaging, the 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid anti-radical activity assay, and western blot analysis. Results indicate that antioxidants and ROS are key regulators of PCD during the remodelling of lace plant leaves.

  6. Effect of Ca2+ on programmed death of guard and epidermal cells of pea leaves.

    PubMed

    Kiselevsky, D B; Kuznetsova, Yu E; Vasil'ev, L A; Lobysheva, N V; Zinovkin, R A; Nesov, A V; Shestak, A A; Samuilov, V D

    2010-05-01

    The effect of Ca2+ on programmed death of guard cells (GC) and epidermal cells (EC) determined from destruction of the cell nucleus was investigated in epidermis of pea leaves. Ca2+ at concentrations of 1-100 microM increased and at a concentration of 1 mM prevented the CN(-)-induced destruction of the nucleus in GC, disrupting the permeability barrier of GC plasma membrane for propidium iodide (PI). Ca2+ at concentrations of 0.1-1 mM enhanced drastically the number of EC nuclei stained by PI in epidermis treated with chitosan, an inducer of programmed cell death. The internucleosomal DNA fragmentation caused by CN(-) was suppressed by 2 mM Ca2+ on 6 h incubation, but fragmentation was stimulated on more prolonged treatment (16 h). Presumably, the disruption of the permeability barrier of plasma membrane for PI is not a sign of necrosis in plant cells. Quinacrine and diphenylene iodonium at 50 microM concentration prevented GC death induced by CN(-) or CN(-) + 0.1 mM Ca2+ but had no influence on respiration and photosynthetic O2 evolution in pea leaf slices. The generation of reactive oxygen species determined from 2',7'-dichlorofluorescein fluorescence was promoted by Ca2+ in epidermal peels from pea leaves.

  7. Causes of Death of Residents in ACGME-Accredited Programs 2000 Through 2014: Implications for the Learning Environment.

    PubMed

    Yaghmour, Nicholas A; Brigham, Timothy P; Richter, Thomas; Miller, Rebecca S; Philibert, Ingrid; Baldwin, DeWitt C; Nasca, Thomas J

    2017-07-01

    To systematically study the number of U.S. resident deaths from all causes, including suicide. The more than 9,900 programs accredited by the Accreditation Council for Graduate Medical Education (ACGME) annually report the status of residents. The authors aggregated ACGME data on 381,614 residents in training during years 2000 through 2014. Names of residents reported as deceased were submitted to the National Death Index to learn causes of death. Person-year calculations were used to establish resident death rates and compare them with those in the general population. Between 2000 and 2014, 324 individuals (220 men, 104 women) died while in residency. The leading cause of death was neoplastic disease, followed by suicide, accidents, and other diseases. For male residents the leading cause was suicide, and for female residents, malignancies. Resident death rates were lower than in the age- and gender-matched general population. Temporal patterns showed higher rates of death early in residency. Deaths by suicide were higher early in training, and during the first and third quarters of the academic year. There was no upward or downward trend in resident deaths over the 15 years of this study. Neoplastic disease and suicide were the leading causes of death in residents. Data for death by suicide suggest added risk early in residency and during certain months of the academic year. Providing trainees with a supportive environment and with medical and mental health services is integral to reducing preventable deaths and fostering a healthy physician workforce.

  8. Suicide, guns, and buyback programs: an epidemiologic analysis of firearm-related deaths in Connecticut.

    PubMed

    Baumann, Laura; Clinton, Heather; Berntsson, Rob; Williams, Susan; Rovella, James C; Shapiro, David; Thaker, Shefali; Borrup, Kevin; Lapidus, Garry; Campbell, Brendan T

    2017-05-22

    Gun buyback programs aim to remove unwanted firearms from the community with the goal of preventing firearm injury and death. Buyback programs are held in many communities, but evidence demonstrating their effectiveness is lacking. The purpose of this study is to compare firearms collected at buyback events to crime guns and firearms used in homicides and suicides. Detailed firearm and case data was obtained from the Hartford Police Department and the CDC's National Violent Death Reporting System from January through December of 2015. Information was reviewed for guns collected at buyback events, crime guns confiscated by police, and for weapons associated with firearm fatalities. Detailed firearm data included type, manufacturer, model, and caliber (SMALL ≤ .32 caliber, MEDIUM = .357 caliber to 9 millimeter, LARGE ≥ .40 caliber). Chi-square analyses were used for comparisons between groups. In 2015, 224 crime guns were seized by the Hartford Police, 169 guns were collected at four community buyback events, and there were 187 firearm-related deaths statewide (105 suicides, 81 homicides, 1 legal intervention). Comparisons between buyback, crime and fatality-related firearms are shown in the table below. Medium caliber handguns account for the majority of crime guns and fatalities, and buyback programs collected smaller caliber handguns. The demographics of individuals who turn in guns at buyback events and commit suicide are similar: age (buyback=63±11, suicide=52±18, homicide=34±12 years), sex (buyback=81%, suicide=91%, homicide=84% male), and race (buyback=80%, suicide=97%, homicide=47% white). Handguns account for the majority of crime guns and firearm-related fatalities in Connecticut. Buyback programs are both an opportunity to remove unwanted handguns from the community, and to remove firearms from the homes of individuals at increased risk of suicide. Epidemiologic study, level III.

  9. Acetic acid induces a programmed cell death process in the food spoilage yeast Zygosaccharomyces bailii.

    PubMed

    Ludovico, Paula; Sansonetty, Filipe; Silva, Manuel T; Côrte-Real, Manuela

    2003-03-01

    Here we show that 320-800 mM acetic acid induces in Zygosaccharomyces bailii a programmed cell death (PCD) process that is inhibited by cycloheximide, is accompanied by structural and biochemical alterations typical of apoptosis, and occurs in cells with preserved mitochondrial and plasma membrane integrity (as revealed by rhodamine 123 (Rh123) and propidium iodide (PI) staining, respectively). Mitochondrial ultrastructural changes, namely decrease of the cristae number, formation of myelinic bodies and swelling were also seen. Exposure to acetic acid above 800 mM resulted in killing by necrosis. The occurrence of an acetic acid-induced active cell death process in Z. bailii reinforces the concept of a physiological role of the PCD in the normal yeast life cycle.

  10. Detection of programmed cell death in cells exposed to genotoxic agents using a caspase activation assay.

    PubMed

    Gupta, Madhu; Santra, Madhumita; Koty, Patrick P

    2014-01-01

    Many toxins that individuals are exposed to cause DNA damage. Cells that have sustained DNA damage may attempt to repair the damage prior to replication. However, if a cell has sustained serious damage it cannot repair, it will commit suicide through a genetically regulated programmed cell death (PCD) pathway. Crucial to the ultimate execution of PCD is a family of cysteine proteases called caspases. Activation of these enzymes occurs late enough in the PCD pathway that a cell can no longer avoid cell death, but still earlier than PCD-associated morphological changes or DNA fragmentation. This protocol details a method for using fluorochrome-conjugated caspase inhibitors for the detection of activated caspases in intact cells. The analysis and documentation is performed using fluorescence microscopy.

  11. Detection of programmed cell death in cells exposed to genotoxic agents using a caspase activation assay.

    PubMed

    Gehring, Michael E; Koty, Patrick P

    2005-01-01

    Many environmental toxins cause DNA damage. Cells that have sustained significant DNA damage must attempt to repair the damage prior to replication, in which aberrant base incorporation can result in an irreversible mutation. If a cell cannot repair the damage, however, it may commit suicide through a genetically regulated programmed cell death (PCD) pathway. Crucial to the ultimate execution of PCD is a family of cysteine proteases called caspases. Activation of these enzymes occurs late in the PCD pathway, when a cell can no longer avoid cell death, but earlier than other PCD markers, such as morphological changes or DNA fragmentation. This protocol details a method for using fluorochrome-conjugated caspase inhibitors for the detection of activated caspases in intact cells using fluorescent microscopy.

  12. Cross-talk of nitric oxide and reactive oxygen species in plant programed cell death

    PubMed Central

    Wang, Yiqin; Loake, Gary J.; Chu, Chengcai

    2013-01-01

    In plants, programed cell death (PCD) is an important mechanism to regulate multiple aspects of growth and development, as well as to remove damaged or infected cells during responses to environmental stresses and pathogen attacks. Under biotic and abiotic stresses, plant cells exhibit a rapid synthesis of nitric oxide (NO) and a parallel accumulation of reactive oxygen species (ROS). Frequently, these responses trigger a PCD process leading to an intrinsic execution of plant cells. The accumulating evidence suggests that both NO and ROS play key roles in PCD. These redox active small molecules can trigger cell death either independently or synergistically. Here we summarize the recent progress on the cross-talk of NO and ROS signals in the hypersensitive response, leaf senescence, and other kinds of plant PCD caused by diverse cues. PMID:23967004

  13. Cyclic programmed cell death stimulates hormone signaling and root development in Arabidopsis.

    PubMed

    Xuan, Wei; Band, Leah R; Kumpf, Robert P; Van Damme, Daniël; Parizot, Boris; De Rop, Gieljan; Opdenacker, Davy; Möller, Barbara K; Skorzinski, Noemi; Njo, Maria F; De Rybel, Bert; Audenaert, Dominique; Nowack, Moritz K; Vanneste, Steffen; Beeckman, Tom

    2016-01-22

    The plant root cap, surrounding the very tip of the growing root, perceives and transmits environmental signals to the inner root tissues. In Arabidopsis thaliana, auxin released by the root cap contributes to the regular spacing of lateral organs along the primary root axis. Here, we show that the periodicity of lateral organ induction is driven by recurrent programmed cell death at the most distal edge of the root cap. We suggest that synchronous bursts of cell death in lateral root cap cells release pulses of auxin to surrounding root tissues, establishing the pattern for lateral root formation. The dynamics of root cap turnover may therefore coordinate primary root growth with root branching in order to optimize the uptake of water and nutrients from the soil.

  14. Programmed cell death during development of cowpea (Vigna unguiculata (L.) Walp.) seed coat.

    PubMed

    Lima, Nathália Bastos; Trindade, Fernanda Gomes; da Cunha, Maura; Oliveira, Antônia Elenir Amâncio; Topping, Jennifer; Lindsey, Keith; Fernandes, Kátia Valevski Sales

    2015-04-01

    The seed coat develops primarily from maternal tissues and comprises multiple cell layers at maturity, providing a metabolically dynamic interface between the developing embryo and the environment during embryogenesis, dormancy and germination of seeds. Seed coat development involves dramatic cellular changes, and the aim of this research was to investigate the role of programmed cell death (PCD) events during the development of seed coats of cowpea [Vigna unguiculata (L.) Walp.]. We demonstrate that cells of the developing cowpea seed coats undergo a programme of autolytic cell death, detected as cellular morphological changes in nuclei, mitochondria, chloroplasts and vacuoles, DNA fragmentation and oligonucleosome accumulation in the cytoplasm, and loss of membrane viability. We show for the first time that classes 6 and 8 caspase-like enzymes are active during seed coat development, and that these activities may be compartmentalized by translocation between vacuoles and cytoplasm during PCD events. © 2014 John Wiley & Sons Ltd.

  15. Cytotoxic T lymphocyte-mediated cytolysis: an example of programmed cell death in the immune system

    SciTech Connect

    Duke, R.C.

    1985-01-01

    Target cells are programmed to die following interaction with cytotoxic T lymphocytes (CTLs). Within minutes of exposure to CTL the target cell's nuclear DNA is fragmented. Target cell lysis, as measured by /sup 51/Cr release, occurs about 60 minutes after induction of DNA fragmentation. DNA fragmentation results from the action of an endonuclease which cleaves DNA in the linker region between nucleosomes. The origin of this nuclease, whether transferred to the target by the CTL or endogenous to the target cell, has not been resolved. DNA fragmentation occurs only when appropriately sensitized CTL are used and is not merely the result of cell death because killing of target cells by extreme deviation from homeostasis, by interruption of energy production, or by lysis with antibody and complement does not induce DNA cleavage. When Triton X-100 is added to target cells which have interacted with CTL, the DNA fragments do not remain in association with the nucleus. This observation suggests that breakdown of overall nuclear structure is induced concomitantly with DNA fragmentation. Morphologically, disruption of nuclear structure and DNA fragmentation are observed as widespread chromatin condensation (apoptosis). Apoptosis is observed in metabolically active target cells and is not a consequence of cell death. A cell whose DNA is extensively fragmented is condemmed to die. Induction of oligonucleosome-sized DNA is also an early event in glucocorticoid-induced thymocyte death and death of T cells upon removal of growth factor. Several similarities exist between these systems and CTL-mediated cytolysis suggesting a final common biochemical pathway for all three types of cell death.

  16. Cellular and Molecular Changes Associated with Onion Skin Formation Suggest Involvement of Programmed Cell Death.

    PubMed

    Galsurker, Ortal; Doron-Faigenboim, Adi; Teper-Bamnolker, Paula; Daus, Avinoam; Fridman, Yael; Lers, Amnon; Eshel, Dani

    2016-01-01

    Skin formation of onion (Allium cepa L.) bulb involves scale desiccation accompanied by scale senescence, resulting in cell death and tissue browning. Understanding the mechanism of skin formation is essential to improving onion skin and bulb qualities. Although onion skin plays a crucial role in postharvest onion storage and shelf life, its formation is poorly understood. We investigated the mode of cell death in the outermost scales that are destined to form the onion skin. Surprisingly, fluorescein diacetate staining and scanning electron microscopy indicated that the outer scale desiccates from the inside out. This striking observation suggests that cell death in the outer scales, during skin formation, is an internal and organized process that does not derive only from air desiccation. DNA fragmentation, a known hallmark of programmed cell death (PCD), was revealed in the outer scales and gradually decreased toward the inner scales of the bulb. Transmission electron microscopy further revealed PCD-related structural alterations in the outer scales which were absent from the inner scales. De novo transcriptome assembly for three different scales: 1st (outer), 5th (intermediate) and 8th (inner) fleshy scales identified 2,542 differentially expressed genes among them. GO enrichment for cluster analysis revealed increasing metabolic processes in the outer senescent scale related to defense response, PCD processes, carbohydrate metabolism and flavonoid biosynthesis, whereas increased metabolism and developmental growth processes were identified in the inner scales. High expression levels of PCD-related genes were identified in the outer scale compared to the inner ones, highlighting the involvement of PCD in outer-skin development. These findings suggest that a program to form the dry protective skin exists and functions only in the outer scales of onion.

  17. Cellular and Molecular Changes Associated with Onion Skin Formation Suggest Involvement of Programmed Cell Death

    PubMed Central

    Galsurker, Ortal; Doron-Faigenboim, Adi; Teper-Bamnolker, Paula; Daus, Avinoam; Fridman, Yael; Lers, Amnon; Eshel, Dani

    2017-01-01

    Skin formation of onion (Allium cepa L.) bulb involves scale desiccation accompanied by scale senescence, resulting in cell death and tissue browning. Understanding the mechanism of skin formation is essential to improving onion skin and bulb qualities. Although onion skin plays a crucial role in postharvest onion storage and shelf life, its formation is poorly understood. We investigated the mode of cell death in the outermost scales that are destined to form the onion skin. Surprisingly, fluorescein diacetate staining and scanning electron microscopy indicated that the outer scale desiccates from the inside out. This striking observation suggests that cell death in the outer scales, during skin formation, is an internal and organized process that does not derive only from air desiccation. DNA fragmentation, a known hallmark of programmed cell death (PCD), was revealed in the outer scales and gradually decreased toward the inner scales of the bulb. Transmission electron microscopy further revealed PCD-related structural alterations in the outer scales which were absent from the inner scales. De novo transcriptome assembly for three different scales: 1st (outer), 5th (intermediate) and 8th (inner) fleshy scales identified 2,542 differentially expressed genes among them. GO enrichment for cluster analysis revealed increasing metabolic processes in the outer senescent scale related to defense response, PCD processes, carbohydrate metabolism and flavonoid biosynthesis, whereas increased metabolism and developmental growth processes were identified in the inner scales. High expression levels of PCD-related genes were identified in the outer scale compared to the inner ones, highlighting the involvement of PCD in outer-skin development. These findings suggest that a program to form the dry protective skin exists and functions only in the outer scales of onion. PMID:28119713

  18. Knockout of Arabidopsis ACCELERATED-CELL-DEATH11 encoding a sphingosine transfer protein causes activation of programmed cell death and defense

    PubMed Central

    Brodersen, Peter; Petersen, Morten; Pike, Helen M.; Olszak, Brian; Skov, Søren; Ødum, Niels; Jørgensen, Lise Bolt; Brown, Rhoderick E.; Mundy, John

    2002-01-01

    We describe the lethal, recessive accelerated-cell-death11 Arabidopsis mutant (acd11). Cell death in acd11 exhibits characteristics of animal apoptosis monitored by flow cytometry, and acd11 constitutively expresses defense-related genes that accompany the hypersensitive response normally triggered by avirulent pathogens. Global transcriptional changes during programmed cell death (PCD) and defense activation in acd11 were monitored by cDNA microarray hybridization. The PCD and defense pathways activated in acd11 are salicylic acid (SA) dependent, but do not require intact jasmonic acid or ethylene signaling pathways. Light is required for PCD execution in acd11, as application of an SA-analog to SA-deficient acd11 induced death in the light, but not in the dark. Epistatic analysis showed that the SA-dependent pathways require two regulators of SA-mediated resistance responses, PAD4 and EDS1. Furthermore, acd11 PR1 gene expression, but not cell death, depends on the SA signal tranducer NPR1, suggesting that the npr1-1 mutation uncouples resistance responses and cell death in acd11. The acd11 phenotype is caused by deletion of the ACD11 gene encoding a protein homologous to a mammalian glycolipid transfer protein (GLTP). In contrast to GLTP, ACD11 accelerates the transfer of sphingosine, but not of glycosphingolipids, between membranes in vitro. PMID:11850411

  19. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas.

    PubMed

    Pollack, Seth M; He, Qianchuan; Yearley, Jennifer H; Emerson, Ryan; Vignali, Marissa; Zhang, Yuzheng; Redman, Mary W; Baker, Kelsey K; Cooper, Sara; Donahue, Bailey; Loggers, Elizabeth T; Cranmer, Lee D; Spraker, Matthew B; Seo, Y David; Pillarisetty, Venu G; Ricciotti, Robert W; Hoch, Benjamin L; McClanahan, Terrill K; Murphy, Erin; Blumenschein, Wendy M; Townson, Steven M; Benzeno, Sharon; Riddell, Stanley R; Jones, Robin L

    2017-09-01

    Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited. The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vβ gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated. UPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T-cell infiltration. UPS were found to have higher levels of PD-L1 (P≤.001) and PD-1 (P≤.05) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing, significantly more than SS, which had the lowest (P≤.05). T-cell infiltrates in UPS also were more oligoclonal compared with SS and liposarcoma (P≤.05). A model adjusted for STS histologic subtype found that for all sarcomas, T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels (P≤.01). In the current study, the authors provide the most detailed overview of the immune microenvironment in sarcoma subtypes to date. UPS, which is a more highly mutated STS subtype, provokes a substantial immune response, suggesting that it may be well suited to treatment with immune checkpoint inhibitors. The SS and liposarcoma subsets are less mutated but do express immunogenic self-antigens, and therefore strategies to improve antigen presentation and T-cell infiltration may allow for successful immunotherapy in patients with these diagnoses. Cancer 2017;123:3291-304. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc

  20. FK506 augments activation-induced programmed cell death of T lymphocytes in vivo.

    PubMed Central

    Migita, K; Eguchi, K; Kawabe, Y; Tsukada, T; Mizokami, A; Nagataki, S

    1995-01-01

    FK506 is an immunosuppressive drug that inhibits T cell receptor-mediated signal transduction. This drug can induce immunological tolerance in allograft recipients. In this study, we investigated the in vivo effects of FK506 on T cell receptor-mediated apoptosis induction. Injection of anti-CD3 antibody (Ab) in mice resulted in the elimination of CD4+ CD8+ thymocytes by DNA fragmentation. FK506 treatment significantly augmented thymic apoptosis induced by in vivo anti-CD3 Ab administration. Increased thymic apoptosis resulted in the disappearance of CD4+ CD8+ thymocytes after anti-CD3 Ab/FK506 treatment. DNA fragmentation triggered by FK506 was induced exclusively in antigen-stimulated T cells, since enhanced DNA fragmentation induced by in vivo staphylococcal enterotoxin B (SEB) injection was confirmed in SEB-reactive V beta 8+ thymocytes but not in SEB-nonreactive V beta 6+ thymocytes. In addition to thymocytes, mature peripheral T cells also die by activation-induced programmed cell death. A similar effect of FK506 on activation-induced programmed cell death was observed in SEB-activated peripheral spleen T cells. In contrast, cyclosporin A treatment did not enhance activation-induced programmed cell death of thymocytes and peripheral T cells. Apoptosis is required for the generation and maintenance of self-tolerance in the immune system. Our findings suggest that FK506-triggered apoptosis after elimination of antigen-activated T cells may represent a potential mechanism of the immunological tolerance achieved by FK506 treatment. Images PMID:7543492

  1. Birth Weight in Type 1 Diabetic Pregnancy

    PubMed Central

    Yves, Jacquemyn; Valerie, Vandermotte; Katrien, Van Hoorick; Guy, Martens

    2010-01-01

    Our aim was to investigate whether birth weight in mothers with diabetes mellitus type 1 is higher as compared to nondiabetic controls. Methods. A retrospective study was performed using an existing database covering the region of Flanders, Belgium. Data included the presence of diabetes type 1, hypertension, parity, maternal age, the use artificial reproductive technology, fetal- neonatal death, congenital anomalies, admission to a neonatal intensive care unit, and delivery by Caesarean section or vaginally. Results. In the period studied, 354 women with diabetes type 1 gave birth and were compared with 177.471 controls. Women with type 1 diabetes more often had a maternal age of over 35 years (16.7% versus 12.0%, P = .008, OR 1.46; 95% CI 1.09–1.95). They more frequently suffered hypertension in pregnancy (19.5% versus 4.7%, P < .0001, OR 4.91; 95% CI 3.73–6.44). Perinatal death was significantly higher in the diabetes mellitus group (3.05% versus 0.73%, P < .0001, OR 4.28; 95% CI 2.22–8.01). Caesarean section was performed almost 5 times as frequently in the diabetes versus the control group (OR 4.57; 95% CI 3.70–5.65). Birth weight was significantly higher in diabetic pregnant women from 33 until 38 weeks included, but those reaching 39 weeks and later were not different with control groups. Conclusion. In Belgium, diabetic pregnancy still carries a high risk for fetal and maternal complications; in general birth weight is significantly higher but for those reaching term there is no significant difference in birth weight. PMID:21234396

  2. Birth weight in type 1 diabetic pregnancy.

    PubMed

    Yves, Jacquemyn; Valerie, Vandermotte; Katrien, Van Hoorick; Guy, Martens

    2010-01-01

    Our aim was to investigate whether birth weight in mothers with diabetes mellitus type 1 is higher as compared to nondiabetic controls. Methods. A retrospective study was performed using an existing database covering the region of Flanders, Belgium. Data included the presence of diabetes type 1, hypertension, parity, maternal age, the use artificial reproductive technology, fetal- neonatal death, congenital anomalies, admission to a neonatal intensive care unit, and delivery by Caesarean section or vaginally. Results. In the period studied, 354 women with diabetes type 1 gave birth and were compared with 177.471 controls. Women with type 1 diabetes more often had a maternal age of over 35 years (16.7% versus 12.0%, P = .008, OR 1.46; 95% CI 1.09-1.95). They more frequently suffered hypertension in pregnancy (19.5% versus 4.7%, P < .0001, OR 4.91; 95% CI 3.73-6.44). Perinatal death was significantly higher in the diabetes mellitus group (3.05% versus 0.73%, P < .0001, OR 4.28; 95% CI 2.22-8.01). Caesarean section was performed almost 5 times as frequently in the diabetes versus the control group (OR 4.57; 95% CI 3.70-5.65). Birth weight was significantly higher in diabetic pregnant women from 33 until 38 weeks included, but those reaching 39 weeks and later were not different with control groups. Conclusion. In Belgium, diabetic pregnancy still carries a high risk for fetal and maternal complications; in general birth weight is significantly higher but for those reaching term there is no significant difference in birth weight.

  3. Dermatomyositis and Type 1 Interferons

    PubMed Central

    2010-01-01

    Dermatomyositis is a poorly understood multisystem disease predominantly affecting skin and muscle. This review focuses on the potential role of a group of related cytokines, the type 1 interferons, in the pathogenesis of dermatomyositis. Type 1 interferon–inducible transcripts and proteins are uniquely elevated in dermatomyositis muscle compared with all other muscle diseases studied to date. The endothelial cell tubuloreticular inclusions present in affected dermatomyositis muscle are biomarkers of type 1 interferon exposure. The cell-poor lichenoid reaction in skin with predominant involvement of the basal epidermal cell layer and its topologic equivalent in muscle, perifascicular atrophy, may be lesions that develop directly in response to type 1 interferon signaling. PMID:20425524

  4. Nivolumab as Programmed Death-1 (PD-1) Inhibitor for Targeted Immunotherapy in Tumor

    PubMed Central

    Guo, Liting; Zhang, Haijun; Chen, Baoan

    2017-01-01

    Targeted immunotherapy has become the most promising approach for tumor patients. Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, can reverse immune suppression and release T cell activation. Nivolumab, a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody, blocks PD-1 and promotes antitumor immunity, and it is effective for treating non-small-cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC) and other cancers. The present review summarizes the efficacy and current status of clinical trials of nivolumab and that enabled nivolumab to be investigated in patients. PMID:28261342

  5. Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target?

    PubMed

    Jimenez, V; Kemmerling, U; Paredes, R; Maya, J D; Sosa, M A; Galanti, N

    2014-09-25

    Chagas disease or American Trypanosomiasis is caused by the flagellated protozoan parasite Trypanosoma cruzi (T. cruzi) and is recognized by the WHO as one of the world's 17 neglected tropical diseases. Only two drugs (Benznidazol, Bz and Nifurtimox, Nx) are currently accepted for treatment, however they cause severe adverse effects and their efficacy is still controversial. It is then important to explore for new drugs. Programmed cell death (PCD) in parasites offers interesting new therapeutic targets. The aim of this work was to evaluate the induction of PCD in T. cruzi by two natural sesquiterpene lactones (STLs), dehydroleucodine (DhL) and helenalin (Hln) as compared with the two conventional drugs, Bz and Nx. Hln and DhL were isolated from aerial parts of Gaillardia megapotamica and Artemisia douglassiana Besser, respectively. Purity of compounds (greater than 95%) was confirmed by (13)C-nuclear magnetic resonance, melting point analysis, and optical rotation. Induction of PCD in T. cruzi epimastigotes and trypomastigotes by DhL, Hln, Bz and Nx was assayed by phosphatidylserine exposure at the parasite surface and by detection of DNA fragmentation using the TUNEL assay. Trypanocidal activity of natural and synthetic compounds was assayed by measuring parasite viability using the MTT method. The two natural STLs, DhL and Hln, induce programmed cell death in both, the replicative epimastigote form and the infective trypomastigote form of T. cruzi. Interestingly, the two conventional antichagasic drugs (Bz and Nx) do not induce programmed cell death. A combination of DhL and either Bz or Nx showed an increased effect of natural compounds and synthetic drugs on the decrease of parasite viability. DhL and Hln induce programmed cell death in T. cruzi replicative epimastigote and infective trypomastigote forms, which is a different mechanism of action than the conventional drugs to kill the parasite. Therefore DhL and Hln may offer an interesting option for the

  6. Sulfated lentinan induced mitochondrial dysfunction leads to programmed cell death of tobacco BY-2 cells.

    PubMed

    Wang, Jie; Wang, Yaofeng; Shen, Lili; Qian, Yumei; Yang, Jinguang; Wang, Fenglong

    2017-04-01

    Sulphated lentinan (sLTN) is known to act as a resistance inducer by causing programmed cell death (PCD) in tobacco suspension cells. However, the underlying mechanism of this effect is largely unknown. Using tobacco BY-2 cell model, morphological and biochemical studies revealed that mitochondrial reactive oxygen species (ROS) production and mitochondrial dysfunction contribute to sLNT induced PCD. Cell viability, and HO/PI fluorescence imaging and TUNEL assays confirmed a typical cell death process caused by sLNT. Acetylsalicylic acid (an ROS scavenger), diphenylene iodonium (an inhibitor of NADPH oxidases) and protonophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (a protonophore and an uncoupler of mitochondrial oxidative phosphorylation) inhibited sLNT-induced H2O2 generation and cell death, suggesting that ROS generation linked, at least partly, to a mitochondrial dysfunction and caspase-like activation. This conclusion was further confirmed by double-stained cells with the mitochondria-specific marker MitoTracker RedCMXRos and the ROS probe H2DCFDA. Moreover, the sLNT-induced PCD of BY-2 cells required cellular metabolism as up-regulation of the AOX family gene transcripts and induction of the SA biosynthesis, the TCA cycle, and miETC related genes were observed. It is concluded that mitochondria play an essential role in the signaling pathway of sLNT-induced ROS generation, which possibly provided new insight into the sLNT-mediated antiviral response, including PCD.

  7. Induction of a ricinosomal-protease and programmed cell death in tomato endosperm by gibberellic acid.

    PubMed

    Trobacher, Christopher P; Senatore, Adriano; Holley, Christine; Greenwood, John S

    2013-03-01

    Several examples of programmed cell death (PCD) in plants utilize ricinosomes, organelles that appear prior to cell death and store inactive KDEL-tailed cysteine proteinases. Upon cell death, the contents of ricinosomes are released into the cell corpse where the proteinases are activated and proceed to degrade any remaining protein for use in adjacent cells or, in the case of nutritive seed tissues, by the growing seedling. Ricinosomes containing pro-SlCysEP have been observed in anther tissues prior to PCD and ricinosome-like structures have been observed in imbibed seeds within endosperm cells of tomato. The present study confirms that the structures in tomato endosperm cells contain pro-SlCysEP making them bona fide ricinosomes. The relative abundance of pro- versus mature SlCysEP is suggested to be a useful indicator of the degree of PCD that has occurred in tomato endosperm, and is supported by biochemical and structural data. This diagnostic tool is used to demonstrate that a sub-region of the micropylar endosperm surrounding the emerged radical is relatively long-lived and may serve to prevent loss of mobilized reserves from the lateral endosperm. We also demonstrate that GA-induced reserve mobilization, SlCysEP accumulation and processing, and PCD in tomato endosperm are antagonized by ABA.

  8. Expression analysis of KDEL-CysEPs programmed cell death markers during reproduction in Arabidopsis.

    PubMed

    Zhou, Liang-Zi; Höwing, Timo; Müller, Benedikt; Hammes, Ulrich Z; Gietl, Christine; Dresselhaus, Thomas

    2016-09-01

    CEP cell death markers. Programmed cell death (PCD) is essential for proper plant growth and development. Plant-specific papain-type KDEL-tailed cysteine endopeptidases (KDEL-CysEPs or CEPs) have been shown to be involved in PCD during vegetative development as executors for the last step in the process. The Arabidopsis genome encodes three KDEL-CysEPs: AtCEP1, AtCEP2 and AtCEP3. With the help of fluorescent fusion reporter lines, we report here a detailed expression analysis of KDEL-CysEP (pro)proteins during reproductive processes, including flower organ and germline development, fertilization and seed development. AtCEP1 is highly expressed in different reproductive tissues including nucellus cells of mature ovule and the connecting edge of anther and filament. After fertilization, AtCEP1 marks integument cell layers of the seeds coat as well as suspensor and columella cells of the developing embryo. Promoter activity of AtCEP2 is detected in the style of immature and mature pistils, in other floral organs including anther, sepal and petal. AtCEP2 mainly localizes to parenchyma cells next to xylem vessels. Although there is no experimental evidence to demonstrate that KDEL-CysEPs are involved in PCD during fertilization, the expression pattern of AtCEPs, which were previously shown to represent cell death markers during vegetative development, opens up new avenues to investigate PCD in plant reproduction.

  9. Ricinosomes predict programmed cell death leading to anther dehiscence in tomato.

    PubMed

    Senatore, Adriano; Trobacher, Christopher P; Greenwood, John S

    2009-02-01

    Successful development and dehiscence of the anther and release of pollen are dependent upon the programmed cell death (PCD) of the tapetum and other sporophytic tissues. Ultrastructural examination of the developing and dehiscing anther of tomato (Solanum lycopersicum) revealed that cells of the interlocular septum, the connective tissue, the middle layer/endothecium, and the epidermal cells surrounding the stomium all exhibit features consistent with progression through PCD. Ricinosomes, a subset of precursor protease vesicles that are unique to some incidents of plant PCD, were also present in all of these cell types. These novel organelles are known to harbor KDEL-tailed cysteine proteinases that act in the final stages of corpse processing following cell death. Indeed, a tomato KDEL-tailed cysteine proteinase, SlCysEP, was identified and its gene was cloned, sequenced, and characterized. SlCysEP transcript and protein were restricted to the anthers of the senescing tomato flower. Present in the interlocular septum and in the epidermal cells surrounding the stomium relatively early in development, SlCysEP accumulates later in the sporophytic tissues surrounding the locules as dehiscence ensues. At the ultrastuctural level, immunogold labeling localized SlCysEP to the ricinosomes within the cells of these tissues, but not in the tapetum. It is suggested that the accumulation of SlCysEP and the appearance of ricinosomes act as very early predictors of cell death in the tomato anther.

  10. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality

    PubMed Central

    Saha, Asim; Aoyama, Kazutoshi; Taylor, Patricia A.; Koehn, Brent H.; Veenstra, Rachelle G.; Panoskaltsis-Mortari, Angela; Munn, David H.; Murphy, William J.; Azuma, Miyuki; Yagita, Hideo; Fife, Brian T.; Sayegh, Mohammed H.; Najafian, Nader; Socie, Gerard; Ahmed, Rafi; Freeman, Gordon J.; Sharpe, Arlene H.

    2013-01-01

    Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD. PMID:24030385

  11. Possible involvement of programmed cell death pathways in the neuroprotective action of polyphenols.

    PubMed

    Bastianetto, S; Krantic, S; Chabot, J-G; Quirion, R

    2011-08-01

    One of the hallmarks of Alzheimer's disease is the accumulation of senile plaques composed of extra-cellular aggregates of beta-amyloid (Aβ) peptides. It is well established that at least in vitro, Aβ triggers apoptotic cell death via the activation of caspase-dependent and -independent cell death effectors, namely caspase-3 and apoptosis inducing factor (AIF), respectively. Epidemiological studies have reported that elderly people have a lower risk (up to 50%) of developing dementia if they regularly eat fruits and vegetables and drink tea and red wine (in moderation). Numerous studies indicate that polyphenols derived from these foods and beverages account for the observed neuroprotective effects. In particular, we have reported that polyphenols extracted from green tea (i.e. epigallocatechin gallate or EGCG) and red wine (i.e. resveratrol) block Aβ-induced hippocampal cell death, by at least partially inhibiting Aβ fibrillisation. It has been shown that polyphenols may also modulate caspase-dependent and -independent programmed cell death (PCD) pathways. Indeed, polyphenols including resveratrol, EGCG and luteolin significantly inhibit the activation of the key apoptotic executioner, caspase-3 and are able to modulate mitogen-activated protein kinases known to play an important role in neuronal apoptosis. Moreover, it has been reported that polyphenols may exert their anti-apoptotic action by inhibiting AIF release from mitochondria, thus providing new mechanism of action for polyphenols. This review aims to update the current knowledge regarding the differential effects of polyphenols on PCD pathways and discuss their putative neuroprotective action resulting from their capacity to modulate these pathways.

  12. Regulation of programmed cell death during neural induction in the chick embryo.

    PubMed

    Gibson, Anna; Robinson, Neil; Streit, Andrea; Sheng, Guojun; Stern, Claudio D

    2011-01-01

    To study early responses to neural inducing signals from the organizer (Hensen's node), a differential screen was performed in primitive streak stage chick embryos, comparing cells that had or had not been exposed to a node graft for 5 hours. Three of the genes isolated have been implicated in Programmed Cell Death (PCD): Defender Against Cell Death (Dad1), Polyubiquitin II (UbII) and Ferritin Heavy chain (fth1). We therefore explored the potential involvement of PCD in neural induction. Dad1, UbII and fth1 are expressed in partly overlapping domains during early neural plate development, along with the pro-apoptotic gene Cas9 and the death effector Cas3. Dad1 and UbII are induced by a node graft within 3 hours. TUNEL staining revealed that PCD is initially random, but both during normal development and following neural induction by a grafted node, it becomes concentrated at the border of the forming neural plate and anterior non-neural ectoderm and downregulated from the neural plate itself. PCD was observed in regions of Caspase expression that are free from Dad1, consistent with the known anti-apoptotic role of Dad1. However, gain- and loss-of-function of any of these genes had no detectable effect on cell identity or on neural plate development. This study reveals that early development of the neural plate is accompanied by induction of putative pro- and anti-apoptotic genes in distinct domains. We suggest that the neural plate is protected against apoptosis, confining cell death to its border and adjacent non-neural ectoderm.

  13. Sunlight inhibits growth and induces markers of programmed cell death in Plasmodium falciparum in vitro.

    PubMed

    Engelbrecht, Dewaldt; Coetzer, Thérèsa Louise

    2015-09-29

    Plasmodium falciparum is responsible for the majority of global malaria deaths. During the pathogenic blood stages of infection, a rapid increase in parasitaemia threatens the survival of the host before transmission of slow-maturing sexual parasites to the mosquito vector to continue the life cycle. Programmed cell death (PCD) may provide the parasite with the means to control its burden on the host and thereby ensure its own survival. Various environmental stress factors encountered during malaria may induce PCD in P. falciparum. This study is the first to characterize parasite cell death in response to natural sunlight. The 3D7 strain of P. falciparum was cultured in vitro in donor erythrocytes. Synchronized and mixed-stage parasitized cultures were exposed to sunlight for 1 h and compared to cultures maintained in the dark, 24 h later. Mixed-stage parasites were also subjected to a second one-hour exposure at 24 h and assessed at 48 h. Parasitaemia was measured daily by flow cytometry. Biochemical markers of cell death were assessed, including DNA fragmentation, mitochondrial membrane polarization and phosphatidylserine externalization. Sunlight inhibited P. falciparum growth in vitro. Late-stage parasites were more severely affected than early stages. However, some late-stage parasites survived exposure to sunlight to form new rings 24 h later, as would be expected during PCD whereby only a portion of the population dies. DNA fragmentation was observed at 24 and 48 h and preceded mitochondrial hyperpolarization in mixed-stage parasites at 48 h. Mitochondrial hyperpolarization likely resulted from increased oxidative stress. Although data suggested increased phosphatidylserine externalization in mixed-stage parasites, results were not statistically significant. The combination of biochemical markers and the survival of some parasites, despite exposure to a lethal stimulus, support the occurrence of PCD in P. falciparum.

  14. Identification of a novel cell death-inducing domain reveals that fungal amyloid-controlled programmed cell death is related to necroptosis

    PubMed Central

    Daskalov, Asen; Habenstein, Birgit; Sabaté, Raimon; Berbon, Mélanie; Martinez, Denis; Chaignepain, Stéphane; Coulary-Salin, Bénédicte; Hofmann, Kay; Loquet, Antoine; Saupe, Sven J.

    2016-01-01

    Recent findings have revealed the role of prion-like mechanisms in the control of host defense and programmed cell death cascades. In fungi, HET-S, a cell death-inducing protein containing a HeLo pore-forming domain, is activated through amyloid templating by a Nod-like receptor (NLR). Here we characterize the HELLP protein behaving analogously to HET-S and bearing a new type of N-terminal cell death-inducing domain termed HeLo-like (HELL) and a C-terminal regulatory amyloid motif known as PP. The gene encoding HELLP is part of a three-gene cluster also encoding a lipase (SBP) and a Nod-like receptor, both of which display the PP motif. The PP motif is similar to the RHIM amyloid motif directing formation of the RIP1/RIP3 necrosome in humans. The C-terminal region of HELLP, HELLP(215-278), encompassing the motif, allows prion propagation and assembles into amyloid fibrils, as demonstrated by X-ray diffraction and FTIR analyses. Solid-state NMR studies reveal a well-ordered local structure of the amyloid core residues and a primary sequence that is almost entirely arranged in a rigid conformation, and confirm a β-sheet structure in an assigned stretch of three amino acids. HELLP is activated by amyloid templating and displays membrane-targeting and cell death-inducing activity. HELLP targets the SBP lipase to the membrane, suggesting a synergy between HELLP and SBP in membrane dismantling. Remarkably, the HeLo-like domain of HELLP is homologous to the pore-forming domain of MLKL, the cell death-execution protein in necroptosis, revealing a transkingdom evolutionary relationship between amyloid-controlled fungal programmed cell death and mammalian necroptosis. PMID:26903619

  15. Identification of a novel cell death-inducing domain reveals that fungal amyloid-controlled programmed cell death is related to necroptosis.

    PubMed

    Daskalov, Asen; Habenstein, Birgit; Sabaté, Raimon; Berbon, Mélanie; Martinez, Denis; Chaignepain, Stéphane; Coulary-Salin, Bénédicte; Hofmann, Kay; Loquet, Antoine; Saupe, Sven J

    2016-03-08

    Recent findings have revealed the role of prion-like mechanisms in the control of host defense and programmed cell death cascades. In fungi, HET-S, a cell death-inducing protein containing a HeLo pore-forming domain, is activated through amyloid templating by a Nod-like receptor (NLR). Here we characterize the HELLP protein behaving analogously to HET-S and bearing a new type of N-terminal cell death-inducing domain termed HeLo-like (HELL) and a C-terminal regulatory amyloid motif known as PP. The gene encoding HELLP is part of a three-gene cluster also encoding a lipase (SBP) and a Nod-like receptor, both of which display the PP motif. The PP motif is similar to the RHIM amyloid motif directing formation of the RIP1/RIP3 necrosome in humans. The C-terminal region of HELLP, HELLP(215-278), encompassing the motif, allows prion propagation and assembles into amyloid fibrils, as demonstrated by X-ray diffraction and FTIR analyses. Solid-state NMR studies reveal a well-ordered local structure of the amyloid core residues and a primary sequence that is almost entirely arranged in a rigid conformation, and confirm a β-sheet structure in an assigned stretch of three amino acids. HELLP is activated by amyloid templating and displays membrane-targeting and cell death-inducing activity. HELLP targets the SBP lipase to the membrane, suggesting a synergy between HELLP and SBP in membrane dismantling. Remarkably, the HeLo-like domain of HELLP is homologous to the pore-forming domain of MLKL, the cell death-execution protein in necroptosis, revealing a transkingdom evolutionary relationship between amyloid-controlled fungal programmed cell death and mammalian necroptosis.

  16. Intrauterine infection induces programmed cell death in rabbit periventricular white matter.

    PubMed

    Debillon, T; Gras-Leguen, C; Vérielle, V; Winer, N; Caillon, J; Rozé, J C; Gressens, P

    2000-06-01

    An association between chorioamnionitis and periventricular leukomalacia has been reported in human preterm infants. However, whether this link is causal has not been convincingly established, and the underlying molecular mechanisms remain unclear. The objective of this study was to establish a reproducible model of cerebral white matter disease in preterm rabbits after intrauterine infection. Escherichia coli was inoculated into both uterine horns of laparotomized pregnant rabbits when gestation was 80% complete. The fetuses were delivered by cesarean section and killed 12, 24, or 48 h after the inoculation. Programmed cell death in the white matter was evaluated by hematoxylin-eosin-saffron staining and in situ fragmented DNA labeling (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). In a first group of 14 pregnant rabbits not treated with antibiotics, all fetuses delivered 48 h after inoculation were stillborn, whereas fetuses extracted 12 or 24 h after inoculation were alive. No significant cell death was detected in the live fetuses compared with the control noninfected rabbits. In a second group of five pregnant rabbits treated with ceftriaxone initiated 24 h after the inoculation and continued until cesarean section was performed 48 h after inoculation, 13 fetuses were alive, but all showed evidence of extensive programmed cell death in the white matter by hematoxylin-eosin-saffron staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. White matter damage became histologically detectable only 48 h after inoculation. Three of the 13 brains displayed periventricular white matter cysts mimicking human cystic periventricular leukomalacia. The high reproducibility of white matter damage in our model should permit further studies aimed at unraveling the molecular mechanisms of periventricular leukomalacia.

  17. Regulation of oogenesis in honey bee workers via programed cell death.

    PubMed

    Ronai, Isobel; Barton, Deborah A; Oldroyd, Benjamin P; Vergoz, Vanina

    2015-10-01

    Reproductive division of labour characterises eusociality. Currently little is known about the mechanisms that underlie the 'sterility' of the worker caste, but queen pheromone plays a major role in regulating the reproductive state. Here we investigate oogenesis in the young adult honey bee worker ovary in the presence of queen pheromone and in its absence. When queen pheromone is absent, workers can activate their ovaries and have well-developed follicles. When queen pheromone is present, even though workers have non-activated ovaries, they continually produce oocytes which are aborted at an early stage. Therefore, irrespective of the presence of the queen, the young adult worker ovary contains oocytes. By this means young workers retain reproductive plasticity. The degeneration of the germ cells in the ovarioles of workers in the presence of queen pheromone has the morphological hallmarks of programmed cell death. Therefore the mechanistic basis of 'worker sterility' relies in part on the regulation of oogenesis via programmed cell death. Our results suggest that honey bees have co-opted a highly conserved checkpoint at mid-oogenesis to regulate the fertility of the worker caste.

  18. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity.

    PubMed

    Ostrand-Rosenberg, Suzanne; Horn, Lucas A; Haile, Samuel T

    2014-10-15

    Programmed death ligand 1 (PD-L1, also known as B7 homolog 1 or CD274) is a major obstacle to antitumor immunity because it tolerizes/anergizes tumor-reactive T cells by binding to its receptor programmed death-1 (CD279), renders tumor cells resistant to CD8(+) T cell- and FasL-mediated lysis, and tolerizes T cells by reverse signaling through T cell-expressed CD80. PD-L1 is abundant in the tumor microenvironment, where it is expressed by many malignant cells, as well as by immune cells and vascular endothelial cells. The critical role of PD-L1 in obstructing antitumor immunity has been demonstrated in multiple animal models and in recent clinical trials. This article reviews the mechanisms by which PD-L1 impairs antitumor immunity and discusses established and experimental strategies for maintaining T cell activation in the presence of PD-L1-expressing cells in the tumor microenvironment.

  19. Tuberculosis-Related Deaths within a Well-Functioning DOTS Control Program

    PubMed Central

    García-García, Maria de Lourdes; Ponce-de-León, Alfredo; García-Sancho, Maria Cecilia; Ferreyra-Reyes, Leticia; Palacios-Martínez, Manuel; Fuentes, Javier; Kato-Maeda, Midori; Bobadilla, Miriam; Small, Peter; Sifuentes-Osornio, José

    2002-01-01

    To describe the molecular epidemiology of tuberculosis (TB)-related deaths in a well-managed program in a low-HIV area, we analyzed data from a cohort of 454 pulmonary TB patients recruited between March 1995 and October 2000 in southern Mexico. Patients who were sputum acid-fast bacillus smear positive underwent clinical and mycobacteriologic evaluation (isolation, identification, drug-susceptibility testing, and IS6110-based genotyping and spoligotyping) and received treatment from the local directly observed treatment strategy (DOTS) program. After an average of 2.3 years of follow-up, death was higher for clustered cases (28.6 vs. 7%, p=0.01). Cox analysis revealed that TB-related mortality hazard ratios included treatment default (8.9), multidrug resistance (5.7), recently transmitted TB (4.1), weight loss (3.9), and having less than 6 years of formal education (2). In this community, TB is associated with high mortality rates. PMID:12453365

  20. Dealing with death: an audit of family bereavement programs in Australian intensive care units.

    PubMed

    Valks, Katrina; Mitchell, Marion Lucy; Inglis-Simons, Chris; Limpus, Anthony

    2005-11-01

    Patient death in Intensive Care Units (ICU) can be sudden and unexpected, leading to emotionally charged situations and life changing circumstances for family members. Supporting families during and after this critical period is particularly challenging for ICU nurses who often feel dissatisfied with the way they deal with the situation. Bereavement programs in various areas of nursing have been reported to be beneficial in promoting normal grief patterns. There is, however, a lack of research in the area of evaluation of bereavement programs in adult ICUs. This paper presents the results of an Australia-wide audit on current practices in the area of bereavement programs within adult ICUs. Surveys were sent to 117 adult Australian ICUs; 99 surveys were returned completed (84.6% response rate). It was identified that most surveyed units offer minimal components of bereavement programs, such as viewing of the deceased and communicating with family members. Less than one third (n=26) provide additional follow-up services in the form of telephone calls and sympathy cards or referral to additional services. Ten units employ some form of program evaluation. Verbal feedback from staff and families is the primary assessment method. Over half of responding ICUs indicated they are considering or interested in providing a bereavement program in their unit. This study highlights the need for research-based data to support the introduction or deletion of strategies for bereavement programs using family-centred outcome measures. ICU nurses are interested in this area of clinical practice and require considerable support. It is recommended that this support can come via postgraduate and on-going education, hospital policies and procedures.

  1. Nature of type 1 Supernovae

    NASA Technical Reports Server (NTRS)

    Shklovskiy, I. S.

    1980-01-01

    The nature of type 1 supernovae (SN 1) is discussed through a comparison of observational evidence and theoretical perspectives relating to both type 1 and 2 supernovae. In particular two hypotheses relating to SN 1 phenomenon are examined: the first proposing that SN 1 are components of binary systems in which, at a comparatively late stage of evolution, overflow of the mass occurs; the second considers pre-SN 1 to be recently evolved stars with a mass greater than 1.4 solar mass (white dwarfs). In addition, an explanation of the reduced frequency of flares of SN 1 in spiral galaxies as related to that in elliptical galaxies is presented.

  2. Type-1.5 superconductivity.

    PubMed

    Moshchalkov, Victor; Menghini, Mariela; Nishio, T; Chen, Q H; Silhanek, A V; Dao, V H; Chibotaru, L F; Zhigadlo, N D; Karpinski, J

    2009-03-20

    We demonstrate the existence of a novel superconducting state in high quality two-component MgB2 single crystalline superconductors where a unique combination of both type-1 (lambda{1}/xi{1}<1/sqrt[2]) and type-2 (lambda{2}/xi{2}>1/sqrt[2]) superconductor conditions is realized for the two components of the order parameter. This condition leads to a vortex-vortex interaction attractive at long distances and repulsive at short distances, which stabilizes unconventional stripe- and gossamerlike vortex patterns that we have visualized in this type-1.5 superconductor using Bitter decoration and also reproduced in numerical simulations.

  3. Exploring diabetes type 1-related stigma

    PubMed Central

    Abdoli, Samereh; Abazari, Parvaneh; Mardanian, Leila

    2013-01-01

    Background: Empowerment of people with diabetes means integrating diabetes with identity. However, others’ stigmatization can influence it. Although diabetes is so prevalent among Iranians, there is little knowledge about diabetes-related stigma in Iran. The present study explored diabetes-related stigma in people living with type 1 diabetes in Isfahan. Materials and Methods: A conventional content analysis was used with in-depth interview with 26 people with and without diabetes from November 2011 to July 2012. Results: A person with type 1 diabetes was stigmatized as a miserable human (always sick and unable, death reminder, and intolerable burden), rejected marriage candidate (busy spouse, high-risk pregnant), and deprived of a normal life [prisoner of (to must), deprived of pleasure]. Although, young adults with diabetes undergo all aspects of the social diabetes-related stigma; in their opinion they were just deprived of a normal life Conclusion: It seems that in Isfahan, diabetes-related stigma is of great importance. In this way, conducting an appropriate intervention is necessary to improve the empowerment process in people with type 1 diabetes in order to reduce the stigma in the context. PMID:23983731

  4. In situ and in silico kinetic analyses of the Programmed Cell Death 1, Programmed Cell Death-Ligands, and B7-1 interaction network.

    PubMed

    Li, Kaitao; Cheng, Xiaoxiao; Tilevik, Andreas; Davis, Simon J; Zhu, Cheng

    2017-03-06

    Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance, and among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1, requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-1 ligands/B7-1 system. Consistent with previous solution measurements, we observed higher in situ affinities for human (h) than murine (m) PD-1 interactions, stronger binding of hPD-1 to hPD-L2 than hPD-L1, and comparable binding of mPD-1 to both ligands. However, in contrast to the relatively weak solution affinities, the in situ affinities of PD-1 are as high as those of the TCR for agonist pMHC and of LFA-1 for ICAM-1, but significantly lower than that of the B7-1-CTLA-4 interaction, suggesting a distinct basis for PD-1 versus CTLA-4 mediated inhibition. Notably, the in situ interactions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, the in situ affinity ranking greatly depends on the on-rate instead of the off-rate. In silico simulations predict that PD-1-PD-L1 interactions dominate at interfaces between activated T cells and mature dendritic cells, and that these interactions will be highly sensitive to the dynamics of PD-L1 and PD-L2 expression. Our results provide a kinetic framework for better understanding inhibitory PD-1 activity in health and disease.

  5. Causes of Death of Residents in ACGME-Accredited Programs 2000 Through 2014: Implications for the Learning Environment

    PubMed Central

    Yaghmour, Nicholas A.; Brigham, Timothy P.; Richter, Thomas; Miller, Rebecca S.; Philibert, Ingrid; Baldwin, DeWitt C.

    2017-01-01

    Purpose To systematically study the number of U.S. resident deaths from all causes, including suicide. Method The more than 9,900 programs accredited by the Accreditation Council for Graduate Medical Education (ACGME) annually report the status of residents. The authors aggregated ACGME data on 381,614 residents in training during years 2000 through 2014. Names of residents reported as deceased were submitted to the National Death Index to learn causes of death. Person-year calculations were used to establish resident death rates and compare them with those in the general population. Results Between 2000 and 2014, 324 individuals (220 men, 104 women) died while in residency. The leading cause of death was neoplastic disease, followed by suicide, accidents, and other diseases. For male residents the leading cause was suicide, and for female residents, malignancies. Resident death rates were lower than in the age- and gender-matched general population. Temporal patterns showed higher rates of death early in residency. Deaths by suicide were higher early in training, and during the first and third quarters of the academic year. There was no upward or downward trend in resident deaths over the 15 years of this study. Conclusions Neoplastic disease and suicide were the leading causes of death in residents. Data for death by suicide suggest added risk early in residency and during certain months of the academic year. Providing trainees with a supportive environment and with medical and mental health services is integral to reducing preventable deaths and fostering a healthy physician workforce. PMID:28514230

  6. Induction of programmed cell death in Arabidopsis and rice by single-wall carbon nanotubes.

    PubMed

    Shen, Cong-Xiang; Zhang, Quan-Fang; Li, Jian; Bi, Fang-Cheng; Yao, Nan

    2010-10-01

    Single-walled carbon nanotubes (SWCNTs) have many unique structural and mechanical properties. Their potential applications, especially in biomedical engineering and medical chemistry, have been increasing in recent years, but the toxicological impact of nanoparticles has rarely been studied in plants. • We exposed Arabidopsis and rice leaf protoplasts to SWCNTs and examined cell viability, DNA damage, reactive oxygen species generation, and related gene expression. We also tested the effects of nanoparticles on Arabidopsis leaves after injecting a SWCNT solution. EM-TUNEL (electron-microscopic terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) and a cerium chloride staining method were used. • SWCNTs caused adverse cellular responses including cell aggregation, chromatin condensation along with a TUNEL-positive reaction, plasma membrane deposition, and H(2)O(2) accumulation. The effect of SWCNTs on the survival of cells was dose dependent, with 25 μg/mL inducing 25% cell death in 6 h. In contrast, activated carbon, which is not a nano-sized carbon particle, did not induce cell death even 24 h after treatments. The data indicated that the nano-size of the particle is a critical factor for toxicity. Moreover, endocytosis-like structures with cerium chloride deposits formed after SWCNT treatment, suggesting a possible pathway for nanoparticles to traverse the cell membrane. • Consequently, SWCNTs have an adverse effect on protoplasts and leaves through oxidative stress, leading to a certain amount of programmed cell death. Although nanomaterials have great advantages in many respects, the benefits and side effects still need to be assessed carefully.

  7. Programmed cell death in type II neuroblast lineages is required for central complex development in the Drosophila brain.

    PubMed

    Jiang, Yanrui; Reichert, Heinrich

    2012-01-18

    The number of neurons generated by neural stem cells is dependent upon the regulation of cell proliferation and by programmed cell death. Recently, novel neural stem cells that amplify neural proliferation through intermediate neural progenitors, called type II neuroblasts, have been discovered, which are active during brain development in Drosophila. We investigated programmed cell death in the dorsomedial (DM) amplifying type II lineages that contribute neurons to the development of the central complex in Drosophila, using clonal mosaic analysis with a repressible cell marker (MARCM) and lineage-tracing techniques. A significant number of the adult-specific neurons generated in these DM lineages were eliminated by programmed cell death. Programmed cell death occurred during both larval and pupal stages. During larval development, approximately one-quarter of the neuronal (but not glial) cells in the lineages were eliminated by apoptosis before the formation of synaptic connectivity during pupal stages. Lineage-tracing experiments documented the extensive contribution of intermediate neural progenitor-containing DM lineages to all of the major modular substructures of the adult central complex. Moreover, blockage of apoptotic cell death specifically in these lineages led to prominent innervation defects of DM-derived neural progeny in the major neuropile substructures of the adult central complex. Our findings indicate that significant neural overproliferation occurs normally in type II DM lineage development, and that elimination of excess neurons in these lineages through programmed cell death is required for the formation of correct neuropile innervation in the developing central complex. Thus, amplification of neuronal proliferation through intermediate progenitors and reduction of neuronal number through programmed cell death operate in concert in type II neural stem-cell lineages during brain development.

  8. Apocynin attenuates cholesterol oxidation product-induced programmed cell death by suppressing NF-κB-mediated cell death process in differentiated PC12 cells.

    PubMed

    Lee, Da Hee; Nam, Yoon Jeong; Lee, Chung Soo

    2015-10-01

    Cholesterol oxidation products are suggested to be involved in neuronal degeneration. Apocynin has demonstrated to have anti-inflammatory and anti-oxidant effects. We assessed the effect of apocynin on the cholesterol oxidation product-induced programmed cell death in neuronal cells using differentiated PC12 cells in relation to NF-κB-mediated cell death process. 7-Ketocholesterol and 25-hydroxycholesterol decreased the levels of Bid and Bcl-2, increased the levels of Bax and p53, and induced loss of the mitochondrial transmembrane potential, release of cytochrome c and activation of caspases (-8, -9 and -3). 7-Ketocholesterol caused an increase in the levels of cytosolic and nuclear NF-κB p65, cytosolic NF-κB p50 and cytosolic phospho-IκB-α, which was inhibited by the addition of 0.5 μM Bay11-7085 (an inhibitor of NF-κB activation). Apocynin attenuated the cholesterol oxidation product-induced changes in the programmed cell death-related protein levels, NF-κB activation, production of reactive oxygen species, and depletion of GSH. The results show that apocynin appears to attenuate the cholesterol oxidation product-induced programmed cell death in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways that are mediated by NF-κB activation. The preventive effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Transcriptional adaptation of Mycosphaerella graminicola to programmed cell death (PCD) of its susceptible wheat host.

    PubMed

    Keon, John; Antoniw, John; Carzaniga, Raffaella; Deller, Siân; Ward, Jane L; Baker, John M; Beale, Michael H; Hammond-Kosack, Kim; Rudd, Jason J

    2007-02-01

    Many important fungal pathogens of plants spend long periods (days to weeks) of their infection cycle in symptomless association with living host tissue, followed by a sudden transition to necrotrophic feeding as host tissue death occurs. Little is known about either the host responses associated with this sudden transition or the specific adaptations made by the pathogen to invoke or tolerate it. We are studying a major host-specific fungal pathogen of cultivated wheat, Septoria tritici (teleomorph Mycosphaerella graminicola). Here, we describe the host responses of wheat leaves infected with M. graminicola during the development of disease symptoms and use microarray transcription profiling to identify adaptive responses of the fungus to its changing environment. We show that symptom development on a susceptible host genotype has features reminiscent of the hypersensitive response, a rapid and strictly localized form of host programmed cell death (PCD) more commonly associated with disease-resistance mechanisms. The initiation and advancement of this host response is associated with a loss of cell-membrane integrity and dramatic increases in apoplastic metabolites and the rate of fungal growth. Microarray analysis of the fungal genes differentially expressed before and after the onset of host PCD supports a transition to more rapid growth. Specific physiological adaptation of the fungus is also revealed with respect to membrane transport, chemical and oxidative stress mechanisms, and metabolism. Our data support the hypothesis that host plant PCD plays an important role in susceptibility towards fungal pathogens with necrotrophic lifestyles.

  10. Role of apoptosis-inducing factor (AIF) in programmed nuclear death during conjugation in Tetrahymena thermophila

    PubMed Central

    2010-01-01

    Background Programmed nuclear death (PND), which is also referred to as nuclear apoptosis, is a remarkable process that occurs in ciliates during sexual reproduction (conjugation). In Tetrahymena thermophila, when the new macronucleus differentiates, the parental macronucleus is selectively eliminated from the cytoplasm of the progeny, concomitant with apoptotic nuclear events. However, the molecular mechanisms underlying these events are not well understood. The parental macronucleus is engulfed by a large autophagosome, which contains numerous mitochondria that have lost their membrane potential. In animals, mitochondrial depolarization precedes apoptotic cell death, which involves DNA fragmentation and subsequent nuclear degradation. Results We focused on the role of mitochondrial apoptosis-inducing factor (AIF) during PND in Tetrahymena. The disruption of AIF delays the normal progression of PND, specifically, nuclear condensation and kilobase-size DNA fragmentation. AIF is localized in Tetrahymena mitochondria and is released into the macronucleus prior to nuclear condensation. In addition, AIF associates and co-operates with the mitochondrial DNase to facilitate the degradation of kilobase-size DNA, which is followed by oligonucleosome-size DNA laddering. Conclusions Our results suggest that Tetrahymena AIF plays an important role in the degradation of DNA at an early stage of PND, which supports the notion that the mitochondrion-initiated apoptotic DNA degradation pathway is widely conserved among eukaryotes. PMID:20146827

  11. Nuclear transfer with apoptotic bovine fibroblasts: can programmed cell death be reprogrammed?

    PubMed

    Miranda, Moyses dos Santos; Bressan, Fabiana Fernandes; De Bem, Tiago Henrique Camara; Merighe, Giovana Krempel Fonseca; Ohashi, Otávio Mitio; King, William Alan; Meirelles, Flavio Viera

    2012-06-01

    Cell death by apoptosis is considered to be irreversible. However, reports have indicated that its reversibility is possible if the cells have not yet reached the "point of no return." In order to add new information about this topic, we used cells at different moments of apoptotic process as nuclear donors in somatic cell nuclear transfer (SCNT) in order to test if programmed cell death can be reversed. Adult bovine fibroblasts were treated with 10 μM of staurosporine (STP) for 3 h and analyzed for phosphatidylserine externalization (Annexin assay) and presence of active caspase-9. Annexin-positive (Anx+) and Caspase-9-positive (Casp-9+) cells were isolated by FACS and immediately transferred into enucleated in vitro matured bovine oocytes. After STP treatment, 89.9% of cells were Anx+ (4.6% in control cells; p<0.01) and 24.9% were Casp-9+ (2.4% in control cells; p<0.01). Fusion and cleavage were not affected by the use apoptotic cells (p>0.05). Also, the use of Anx+ cells did not affect blastocyst production compared to control (26.4% vs. 22.9%, respectively; p>0.05). However, blastocyst formation was affected by the use of Casp-9+ cells (12.3%; p<0.05). These findings contribute to the idea of that apoptosis is reversible only at early stages. Additionally, we hypothesize that the "point of no return" for apoptosis may be located around activation of Caspase-9.

  12. The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis.

    PubMed

    Tsai, FuNien; Perlman, Harris; Cuda, Carla M

    2016-10-22

    Systemic lupus erythematosus (SLE) is a chronic multi-factorial autoimmune disease initiated by genetic and environmental factors, which in combination trigger disease onset in susceptible individuals. Damage to the kidney as a consequence of lupus nephritis (LN) is one of the most prevalent and severe outcomes, as LN affects up to 60% of SLE patients and accounts for much of SLE-associated morbidity and mortality. As remarkable strides have been made in unlocking new inflammatory mechanisms associated with signaling molecules of programmed cell death pathways, this review explores the available evidence implicating the action of these pathways specifically within dendritic cells and macrophages in the control of kidney disease. Although advancements into the underlying mechanisms responsible for inducing cell death inflammatory pathways have been made, there still exist areas of unmet need. By understanding the molecular mechanisms by which dendritic cells and macrophages contribute to LN pathogenesis, we can improve their viability as potential therapeutic targets to promote remission. Copyright © 2016. Published by Elsevier Inc.

  13. Acetic acid-induced programmed cell death and release of volatile organic compounds in Chlamydomonas reinhardtii.

    PubMed

    Zuo, Zhaojiang; Zhu, Yerong; Bai, Yanling; Wang, Yong

    2012-02-01

    Acetic acid widely spreads in atmosphere, aquatic ecosystems containing residues and anoxic soil. It can inhibit aquatic plant germination and growth, and even cause programmed cell death (PCD) of yeast. In the present study, biochemical and physiological responses of the model unicellular green algae Chlamydomonas reinhardtii were examined after acetic acid stress. H(2)O(2) burst was found in C. reinhardtii after acetic acid stress at pH 5.0 for 10 min. The photosynthetic pigments were degraded, gross photosynthesis and respiration were disappeared gradually, and DNA fragmentation was also detected. Those results indicated that C. reinhardtii cells underwent a PCD but not a necrotic, accidental cell death event. It was noticed that C. reinhardtii cells in PCD released abundant volatile organic compounds (VOCs) upon acetic acid stress. Therefore, we analyzed the VOCs and tested their effects on other normal cells. The treatment of C. reinhardtii cultures with VOCs reduced the cell density and increased antioxidant enzyme activity. Therefore, a function of VOCs as infochemicals involved in cell-to-cell communication at the conditions of applied stress is suggested.

  14. Involvement of Programmed Cell Death in Neurotoxicity of Metallic Nanoparticles: Recent Advances and Future Perspectives

    NASA Astrophysics Data System (ADS)

    Song, Bin; Zhou, Ting; Liu, Jia; Shao, LongQuan

    2016-11-01

    The widespread application of metallic nanoparticles (NPs) or NP-based products has increased the risk of exposure to NPs in humans. The brain is an important organ that is more susceptible to exogenous stimuli. Moreover, any impairment to the brain is irreversible. Recently, several in vivo studies have found that metallic NPs can be absorbed into the animal body and then translocated into the brain, mainly through the blood-brain barrier and olfactory pathway after systemic administration. Furthermore, metallic NPs can cross the placental barrier to accumulate in the fetal brain, causing developmental neurotoxicity on exposure during pregnancy. Therefore, metallic NPs become a big threat to the brain. However, the mechanisms underlying the neurotoxicity of metallic NPs remain unclear. Programmed cell death (PCD), which is different from necrosis, is defined as active cell death and is regulated by certain genes. PCD can be mainly classified into apoptosis, autophagy, necroptosis, and pyroptosis. It is involved in brain development, neurodegenerative disorders, psychiatric disorders, and brain injury. Given the pivotal role of PCD in neurological functions, we reviewed relevant articles and tried to summarize the recent advances and future perspectives of PCD involvement in the neurotoxicity of metallic NPs, with the purpose of comprehensively understanding the neurotoxic mechanisms of NPs.

  15. A tomato metacaspase gene is upregulated during programmed cell death in Botrytis cinerea-infected leaves.

    PubMed

    Hoeberichts, Frank A; ten Have, Arjen; Woltering, Ernst J

    2003-07-01

    Programmed cell death (PCD) in plant cells is often accompanied by biochemical and morphological hallmarks similar to those of animal apoptosis. However, orthologs of animal caspases, cysteinyl aspartate-specific proteases that constitute the core component of animal apoptosis, have not yet been identified in plants. Recent studies have revealed the presence of a family of genes encoding proteins with distant homology to mammalian caspases, designated metacaspases, in the Arabidopsis thaliana genome. Here, we describe the isolation of LeMCA1, a type-II metacaspase cDNA clone from tomato (Lycopersicon esculentum Mill.). BLAST analysis demonstrated that the LeMCA1 gene is located in close vicinity of several genes that have been linked with PCD. Southern analysis indicated the existence of at least one more metacaspase in the tomato genome. LeMCA1 mRNA levels rapidly increased upon infection of tomato leaves with Botrytis cinerea, a fungal pathogen that induces cell death in several plant species. LeMCA1 was not upregulated during chemical-induced PCD in suspension-cultured tomato cells.

  16. A comparison between nuclear dismantling during plant and animal programmed cell death.

    PubMed

    Domínguez, Fernando; Cejudo, Francisco Javier

    2012-12-01

    Programmed cell death (PCD) is a process of organized destruction of cells, essential for the development and maintenance of cellular homeostasis of multicellular organisms. Cells undergoing PCD begin a degenerative process in response to internal or external signals, whereby the nucleus becomes one of the targets. The process of nuclear dismantling includes events affecting the nuclear envelope, such as formation of lobes at the nuclear surface, selective proteolysis of nucleoporins and nuclear pore complex clustering. In addition, chromatin condensation increases in coordination with DNA fragmentation. These processes have been largely studied in animals, but remain poorly understood in plants. The overall process of cell death has different morphological and biochemical features in plants and animals. However, recent advances suggest that nuclear dismantling in plant cells progresses with morphological and biochemical characteristics similar to those in apoptotic animal cells. In this review, we summarize nuclear dismantling in plant PCD, focusing on the similarities and differences with their animal counterparts. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Reactive oxygen species do not contribute to ObgE*-mediated programmed cell death

    PubMed Central

    Dewachter, Liselot; Herpels, Pauline; Verstraeten, Natalie; Fauvart, Maarten; Michiels, Jan

    2016-01-01

    Programmed cell death (PCD) in bacteria is considered an important target for developing novel antimicrobials. Development of PCD-specific therapies requires a deeper understanding of what drives this process. We recently discovered a new mode of PCD in Escherichia coli that is triggered by expression of a mutant isoform of the essential ObgE protein, ObgE*. Our previous findings demonstrate that ObgE*-mediated cell death shares key characteristics with apoptosis in eukaryotic cells. It is well-known that reactive oxygen species (ROS) are formed during PCD in eukaryotes and play a pivotal role as signaling molecules in the progression of apoptosis. Therefore, we explored a possible role for ROS in bacterial killing by ObgE*. Using fluorescent probes and genetic reporters, we found that expression of ObgE* induces formation of ROS. Neutralizing ROS by chemical scavenging or by overproduction of ROS-neutralizing enzymes did not influence toxicity of ObgE*. Moreover, expression of ObgE* under anaerobic conditions proved to be as detrimental to bacterial viability as expression under aerobic conditions. In conclusion, ROS are byproducts of ObgE* expression that do not play a role in the execution or progression of ObgE*-mediated PCD. Targeted therapies should therefore look to exploit other aspects of ObgE*-mediated PCD. PMID:27641546

  18. The bacterial cell cycle checkpoint protein Obg and its role in programmed cell death

    PubMed Central

    Dewachter, Liselot; Verstraeten, Natalie; Fauvart, Maarten; Michiels, Jan

    2016-01-01

    The phenomenon of programmed cell death (PCD), in which cells initiate their own demise, is not restricted to multicellular organisms. Unicellular organisms, both eukaryotes and prokaryotes, also possess pathways that mediate PCD. We recently identified a PCD mechanism in Escherichia coli that is triggered by a mutant isoform of the essential GTPase ObgE (Obg of E. coli). Importantly, the PCD pathway mediated by mutant Obg (Obg*) differs fundamentally from other previously described bacterial PCD pathways and thus constitutes a new mode of PCD. ObgE was previously proposed to act as a cell cycle checkpoint protein able to halt cell division. The implication of ObgE in the regulation of PCD further increases the similarity between this protein and eukaryotic cell cycle regulators that are capable of doing both. Moreover, since Obg is conserved in eukaryotes, the elucidation of this cell death mechanism might contribute to the understanding of PCD in higher organisms. Additionally, if Obg*-mediated PCD is conserved among different bacterial species, it will be a prime target for the development of innovative antibacterials that artificially induce this pathway.

  19. Starch synthesis and programmed cell death during endosperm development in triticale (x Triticosecale Wittmack).

    PubMed

    Li, Chun-Yan; Li, Wei-Hua; Li, Cheng; Gaudet, Denis A; Laroche, André; Cao, Lian-Pu; Lu, Zhen-Xiang

    2010-07-01

    Triticale (x Triticosecale Wittmack) grains synthesize and accumulate starch as their main energy source. Starch accumulation rate and synthesis activities of ADP-glucose pyrophosphorylase, soluble starch synthases, granule-bound starch synthase and starch-branching enzyme showed similar pattern of unimodal curves during endosperm development. There was no significant difference in activity of the starch granule-bound protein isolated from total and separated starch granules at different developmental stages after anthesis in triticale. Evans Blue staining and analysis of DNA fragmentation indicated that cells of triticale endosperm undergo programmed cell death during its development. Dead cells within the endosperm were detected at 6 d post anthesis (DPA), and evidence of DNA fragmentation was first observed at 21 DPA. The period between initial detection of PCD to its rapid increase overlapped with the key stages of rapid starch accumulation during endosperm development. Cell death occurred stochastically throughout the whole endosperm, meanwhile, the activities of starch biosynthetic enzymes and the starch accumulation rate decreased in the late stages of grain filling. These results suggested that the timing and progression of PCD in triticale endosperm may interfere with starch synthesis and accumulation.

  20. Leaf-shape remodeling: programmed cell death in fistular leaves of Allium fistulosum.

    PubMed

    Ni, Xi-Lu; Su, Hui; Zhou, Ya-fu; Wang, Feng-Hua; Liu, Wen-Zhe

    2015-03-01

    Some species of Allium in Liliaceae have fistular leaves. The fistular lamina of Allium fistulosum undergoes a process from solid to hollow during development. The aims were to reveal the process of fistular leaf formation involved in programmed cell death (PCD) and to compare the cytological events in the execution of cell death to those in the unusual leaf perforations or plant aerenchyma formation. In this study, light and transmission electron microscopy were used to characterize the development of fistular leaves and cytological events. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays and gel electrophoresis were used to determine nuclear DNA cleavage during the PCD. The cavity arises in the leaf blade by degradation of specialized cells, the designated pre-cavity cells, in the center of the leaves. Nuclei of cells within the pre-cavity site become TUNEL-positive, indicating that DNA cleavage is an early event. Gel electrophoresis revealed that DNA internucleosomal cleavage occurred resulting in a characteristic DNA ladder. Ultrastructural analysis of cells at the different stages showed disrupted vacuoles, misshapen nuclei with condensed chromatin, degraded cytoplasm and organelles and emergence of secondary vacuoles. The cell walls degraded last, and residue of degraded cell walls aggregated together. These results revealed that PCD plays a critical role in the development of A. fistulosum fistular leaves. The continuous cavity in A. fistulosum leaves resemble the aerenchyma in the pith of some gramineous plants to improve gas exchange. © 2014 Scandinavian Plant Physiology Society.

  1. Donation after cardiac death: results of the SUMMA 112 - Hospital 12 de Octubre Program.

    PubMed

    Miranda-Utrera, Natalia; Medina-Polo, José; Pamplona, Manuel; de la Rosa, Federico; Rodríguez, Alfredo; Duarte, José M; Passas, Juan B; Mateos-Rodríguez, Alonso; Díaz, Rafael; Andrés, Amado

    2013-01-01

    In 2005, our center started a donation after cardiac death (DACD) program, by which patients who present an irreversible cardiac arrest outside hospital are brought to our center with the purpose of organ donation. We reviewed the outcomes of our program of kidney transplants from DACD. We conducted a retrospective study of the DACD, and we reviewed the procedures carried out in our institution between July 2005 and December 2010 and descriptively analyzed the results obtained for kidney donation. One hundred and fifty-two of 274 potential donors were transferred to our hospital. Of them, 126 (82.8%) were connected to cardiopulmonary bypass machine, and organs were procured in 113 donors (74.3%). The discarded grafts were mainly due to inadequate perfusion. One hundred and fifty-six kidneys were transplanted (51.3%). Over a median follow-up period of 18 ± 13.7 months, the median creatinine clearance was 78.2 ± 10.2 ml/min. 8.6% of the grafts had no primary function, and 85% had a delayed graft function. Recipient survival and graft survival were 98% and 87%, respectively. DACD is an adequate source of organs for kidney transplantation. Our functional and survival results are encouraged in the short term, although further work is required to increase the program's benefits. © 2013 John Wiley & Sons A/S.

  2. Predictors of Place of Death of Individuals in a Home-Based Primary and Palliative Care Program.

    PubMed

    Prioleau, Phoebe G; Soones, Tacara N; Ornstein, Katherine; Zhang, Meng; Smith, Cardinale B; Wajnberg, Ania

    2016-11-01

    To investigate factors associated with place of death of individuals in the Mount Sinai Visiting Doctors Program (MSVD). A retrospective chart review was performed of all MSVD participants who died in 2012 to assess predictors of place of death in the last month of life. MSVD, a home-based primary and palliative care program in New York. MSVD participants who were discharged from the program because of death between January 2012 and December 2012 and died at home, in inpatient hospice, or in the hospital (N = 183). Electronic medical records were reviewed to collect information on demographic characteristics, physician visits, and end-of-life conversations. Of 183 participants, 103 (56%) died at home, approximately twice the national average; 28 (15%) died in inpatient hospice; and 52 (28%) died in the hospital. Bivariate analyses showed that participants who were white, aged 90 and older, non-Medicaid, or had a recorded preference for place of death were more likely to die outside the hospital. Diagnoses and living situation were not significantly associated with place of death. Multivariate logistic regression analysis showed no statistical association between place of death and home visits in the last month of life (odds ratio = 1.21, 95% confidence interval = 0.52-2.77). Home-based primary and palliative care results in a high likelihood of nonhospital death, although certain demographic characteristics are strong predictors of death in the hospital. For MSVD participants, home visits in the last month of life were not associated with death outside the hospital. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

  3. The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program.

    PubMed

    Elliott, K; Ge, K; Du, W; Prendergast, G C

    2000-09-28

    Cell death processes are progressively inactivated during malignant development, in part by loss of tumor suppressors that can promote cell death. The Bin1 gene encodes a nucleocytosolic adaptor protein with tumor suppressor properties, initially identified through its ability to interact with and inhibit malignant transformation by c-Myc and other oncogenes. Bin1 is frequently missing or functionally inactivated in breast and prostate cancers and in melanoma. In this study, we show that Bin1 engages a caspase-independent cell death process similar to type II apoptosis, characterized by cell shrinkage, substratum detachment, vacuolated cytoplasm, and DNA degradation. Cell death induction was relieved by mutation of the BAR domain, a putative effector domain, or by a missplicing event that occurs in melanoma and inactivates suppressor activity. Cells in all phases of the cell cycle were susceptible to death and p53 and Rb were dispensable. Notably, Bin1 did not activate caspases and the broad spectrum caspase inhibitor ZVAD.fmk did not block cell death. Consistent with the lack of caspase involvement, dying cells lacked nucleosomal DNA cleavage and nuclear lamina degradation. Moreover, neither Bcl-2 or dominant inhibition of the Fas pathway had any effect. In previous work, we showed that Bin1 could not suppress cell transformation by SV40 large T antigen. Consistent with this finding, we observed that T antigen suppressed the death program engaged by Bin1. This observation was interesting in light of emerging evidence that T antigen has roles in cell immortalization and human cell transformation beyond Rb and p53 inactivation. In support of a link to c-Myc-induced death processes, AEBSF, a serine protease inhibitor that inhibits apoptosis by c-Myc, potently suppressed DNA degradation by Bin1. Our findings suggest that the tumor suppressor activity of Bin1 reflects engagement of a unique cell death program. We propose that loss of Bin1 may promote malignancy by

  4. Virus-host arms race at the joint origin of multicellularity and programmed cell death.

    PubMed

    Iranzo, Jaime; Lobkovsky, Alexander E; Wolf, Yuri I; Koonin, Eugene V

    2014-01-01

    Unicellular eukaryotes and most prokaryotes possess distinct mechanisms of programmed cell death (PCD). How an "altruistic" trait, such as PCD, could evolve in unicellular organisms? To address this question, we developed a mathematical model of the virus-host co-evolution that involves interaction between immunity, PCD and cellular aggregation. Analysis of the parameter space of this model shows that under high virus load and imperfect immunity, joint evolution of cell aggregation and PCD is the optimal evolutionary strategy. Given the abundance of viruses in diverse habitats and the wide spread of PCD in most organisms, these findings imply that multiple instances of the emergence of multicellularity and its essential attribute, PCD, could have been driven, at least in part, by the virus-host arms race.

  5. Oxidative damage and cell-programmed death induced in Zea mays L. by allelochemical stress.

    PubMed

    Ciniglia, Claudia; Mastrobuoni, Francesco; Scortichini, Marco; Petriccione, Milena

    2015-05-01

    The allelochemical stress on Zea mays was analyzed by using walnut husk washing waters (WHWW), a by-product of Juglans regia post-harvest process, which possesses strong allelopathic potential and phytotoxic effects. Oxidative damage and cell-programmed death were induced by WHWW in roots of maize seedlings. Treatment induced ROS burst, with excess of H2O2 content. Enzymatic activities of catalase were strongly increased during the first hours of exposure. The excess in malonildialdehyde following exposure to WHWW confirmed that oxidative stress severely damaged maize roots. Membrane alteration caused a decrease in NADPH oxidase activity along with DNA damage as confirmed by DNA laddering. The DNA instability was also assessed through sequence-related amplified polymorphism assay, thus suggesting the danger of walnut processing by-product and focusing the attention on the necessity of an efficient treatment of WHWW.

  6. A Bacterial Inhibitor of Host Programmed Cell Death Defenses is an E3 Ubiquitin Ligase

    SciTech Connect

    Janjusevic,R.; Abramovitch, R.; Martin, G.; Stebbins, C.

    2005-01-01

    The Pseudomonas syringae protein AvrPtoB is translocated into plant cells, where it inhibits immunity-associated programmed cell death (PCD). The structure of a C-terminal domain of AvrPtoB that is essential for anti-PCD activity reveals an unexpected homology to the U-box and RING-finger components of eukaryotic E3 ubiquitin ligases, and we show that AvrPtoB has ubiquitin ligase activity. Mutation of conserved residues involved in the binding of E2 ubiquitin-conjugating enzymes abolishes this activity in vitro, as well as anti-PCD activity in tomato leaves, which dramatically decreases virulence. These results show that Pseudomonas syringae uses a mimic of host E3 ubiquitin ligases to inactivate plant defenses.

  7. Role of peroxynitrite in programmed cell death induced in self-incompatible pollen.

    PubMed

    Serrano, Irene; Romero-Puertas, María C; Rodríguez Serrano, María; Sandalio, Luisa M; Olmedilla, Adela

    2012-07-01

    Reactive oxygen species and NO are involved in the signaling pathway of programmed cell death (PCD). Information concerning the role of these molecules in self-incompatible pollination is scarce especially in non-model species studied in vivo. We recently reported that in the olive tree, compatible and self-incompatible pollen have different levels of reactive oxygen and nitrogen species and that PCD is induced in self-incompatible pollen. Levels of O 2 (.-) and NO are higher in pollen after self-incompatible pollination than after compatible pollination. The presence of these reactive species was concomitant with the presence of peroxynitrite. Similar results were obtained on pollen-germination experiments both in vivo and in vitro. These data, together with observations made after treating pollinated flowers with scavengers, suggest that peroxynitrite plays a role in PCD induced after self-incompatible pollination and we propose here a model to describe the way in which it might work.

  8. Autophagy, programmed cell death and reactive oxygen species in sexual reproduction in plants.

    PubMed

    Kurusu, Takamitsu; Kuchitsu, Kazuyuki

    2017-05-01

    Autophagy is one of the major cellular processes of recycling of proteins, metabolites and intracellular organelles, and plays crucial roles in the regulation of innate immunity, stress responses and programmed cell death (PCD) in many eukaryotes. It is also essential in development and sexual reproduction in many animals. In plants, although autophagy-deficient mutants of Arabidopsis thaliana show phenotypes in abiotic and biotic stress responses, their life cycle seems normal and thus little had been known until recently about the roles of autophagy in development and reproduction. Rice mutants defective in autophagy show sporophytic male sterility and immature pollens, indicating crucial roles of autophagy during pollen maturation. Enzymatic production of reactive oxygen species (ROS) by respiratory burst oxidase homologues (Rbohs) play multiple roles in regulating anther development, pollen tube elongation and fertilization. Significance of autophagy and ROS in the regulation of PCD of transient cells during plant sexual reproduction is discussed in comparison with animals.

  9. Early events induced by the toxin deoxynivalenol lead to programmed cell death in Nicotiana tabacum cells.

    PubMed

    Yekkour, Amine; Tran, Daniel; Arbelet-Bonnin, Delphine; Briand, Joël; Mathieu, Florence; Lebrihi, Ahmed; Errakhi, Rafik; Sabaou, Nasserdine; Bouteau, François

    2015-09-01

    Deoxynivalenol (DON) is a mycotoxin affecting animals and plants. This toxin synthesized by Fusarium culmorum and Fusarium graminearum is currently believed to play a decisive role in the fungal phytopathogenesis as a virulence factor. Using cultured cells of Nicotiana tabacum BY2, we showed that DON-induced programmed cell death (PCD) could require transcription and translation processes, in contrast to what was observed in animal cells. DON could induce different cross-linked pathways involving (i) reactive oxygen species (ROS) generation linked, at least partly, to a mitochondrial dysfunction and a transcriptional down-regulation of the alternative oxidase (Aox1) gene and (ii) regulation of ion channel activities participating in cell shrinkage, to achieve PCD.

  10. Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice

    PubMed Central

    Huai, Jisen; Firat, Elke; Nil, Ahmed; Million, Daniele; Gaedicke, Simone; Kanzler, Benoit; Freudenberg, Marina; van Endert, Peter; Kohler, Gabriele; Pahl, Heike L.; Aichele, Peter; Eichmann, Klaus; Niedermann, Gabriele

    2008-01-01

    The giant cytosolic protease tripeptidyl peptidase II (TPPII) has been implicated in the regulation of proliferation and survival of malignant cells, particularly lymphoma cells. To address its functions in normal cellular and systemic physiology we have generated TPPII-deficient mice. TPPII deficiency activates cell type-specific death programs, including proliferative apoptosis in several T lineage subsets and premature cellular senescence in fibroblasts and CD8+ T cells. This coincides with up-regulation of p53 and dysregulation of NF-κB. Prominent degenerative alterations at the organismic level were a decreased lifespan and symptoms characteristic of immunohematopoietic senescence. These symptoms include accelerated thymic involution, lymphopenia, impaired proliferative T cell responses, extramedullary hematopoiesis, and inflammation. Thus, TPPII is important for maintaining normal cellular and systemic physiology, which may be relevant for potential therapeutic applications of TPPII inhibitors. PMID:18362329

  11. Discovery of peptide inhibitors targeting human programmed death 1 (PD-1) receptor

    PubMed Central

    Lyu, Jiankun; He, Zenghui; Wang, Xia; Meng, Jiajia; Zhao, Zhenjiang; Zhu, Lili; Liu, Xiaofeng; Li, Honglin

    2016-01-01

    Blocking the interaction of human programmed death 1 (hPD-1) and its ligand hPD-L1 has been a promising immunotherapy in cancer treatment. In this paper, using a computational de novo peptide design method, we designed several hPD-1 binding peptides. The most potent peptide Ar5Y_4 showed a KD value of 1.38 ± 0.39 μM, comparable to the binding affinity of the cognate hPD-L1. A Surface Plasmon Resonance (SPR) competitive binding assay result indicated that Ar5Y_4 could inhibit the interaction of hPD-1/hPD-L1. Moreover, Ar5Y_4 could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Peptides described in this paper provide promising biologic candidates for cancer immunotherapy or diagnostics. PMID:27533458

  12. Programmed cell death acts at different stages of Drosophila neurodevelopment to shape the central nervous system

    PubMed Central

    Desplan, Claude

    2016-01-01

    Nervous system development is a process that integrates cell proliferation, differentiation and programmed cell death (PCD). PCD is an evolutionary conserved mechanism and a fundamental developmental process by which the final cell number in a nervous system is established. In vertebrates and invertebrates, PCD can be determined intrinsically by cell lineage and age, as well as extrinsically by nutritional, metabolic and hormonal states. Drosophila has been an instrumental model for understanding how this mechanism is regulated. We review the role of PCD in Drosophila central nervous system development from neural progenitors to neurons, its molecular mechanism and function, how it is regulated and implemented, and how it ultimately shapes the fly central nervous system from the embryo to the adult. Finally, we discuss ideas that emerge while integrating this information. PMID:27404003

  13. Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers.

    PubMed

    Rajan, Arun; Kim, Chul; Heery, Christopher R; Guha, Udayan; Gulley, James L

    2016-09-01

    The development of immune checkpoint inhibitors has altered the landscape of treatment of advanced cancers. These drugs are well tolerated and have shown clinical activity against a wide variety of solid tumors and hematological malignancies. The durability of response is particularly impressive when compared to other forms of systemic therapy. Nivolumab (Opdivo) is an IgG4 antibody that causes immune checkpoint blockade by diminishing inhibitory signaling through the programmed death receptor-1 pathway. It is approved for treatment of recurrent non-small cell lung cancer, melanoma, and renal cell carcinoma. Efforts to identify biomarkers of response to nivolumab are ongoing. Clinical trials are also being conducted to determine the benefits of combining nivolumab with other forms of treatment including chemotherapy, molecular-targeted therapy, radiation therapy, and other forms of immune therapy. This review outlines the clinical trials that have led to the emergence of nivolumab as a treatment option for patients with advanced cancers.

  14. Myelin basic protein-specific T lymphocytes proliferation and programmed cell death in demyelinating diseases.

    PubMed

    Saresella, Marina; Marventano, Ivana; Guerini, Franca Rosa; Zanzottera, Milena; Delbue, Serena; Marchioni, Enrico; Maserati, Renato; Longhi, Renato; Ferrante, Pasquale; Clerici, Mario

    2008-12-01

    A dynamic equilibrium between proliferation and programmed cell death (PCD) of auto-reactive T lymphocytes plays a pivotal role in the prevention of autoimmune diseases. We analyzed T lymphocytes myelin basic protein (MBP)-specific PCD and proliferation in demyelinating diseases. Results showed that MBP-specific PCD was significantly decreased in CD4+ and CD8+ T lymphocytes of progressive multifocal leukoencephalopathy (PML), not determined leukoencephalopathy (NDLE), and acute MS (AMS) patients compared to patients with stable MS (SMS) and healthy controls. MBP-specific proliferation/PCD rates were high in CD4+ T lymphocytes of PML, NDLE, and AMS patients, and in CD8+ T cells of PML and AMS individuals alone. Alterations of the balance between MBP-specific proliferation and PCD are present in demyelinating diseases and could play a major role in the pathogenesis of these diseases.

  15. Programmed death ligand 1 expression in hepatocellular carcinoma: Relationship With clinical and pathological features.

    PubMed

    Calderaro, Julien; Rousseau, Benoît; Amaddeo, Giuliana; Mercey, Marion; Charpy, Cécile; Costentin, Charlotte; Luciani, Alain; Zafrani, Elie-Serge; Laurent, Alexis; Azoulay, Daniel; Lafdil, Fouad; Pawlotsky, Jean-Michel

    2016-12-01

    The prognosis of hepatocellular carcinoma (HCC) remains poor, with only one third of patients eligible for curative treatments and very limited survival benefits with the use of sorafenib, the current standard of care for advanced disease. Recently, agents targeting the programmed death ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) immune checkpoint were shown to display impressive antitumor activity in various solid or hematological malignancies, including HCC. PD-L1 immunohistochemical expression is thought to represent a biomarker predictive of drug sensitivity. Here, we investigated PD-L1 expression in a series of 217 HCCs and correlated our results with clinical and histological features and immunohistochemical markers (PD-1, cytokeratin 19, glutamine synthetase, and β-catenin expression). PD-L1 expression by neoplastic cells was significantly associated with common markers of tumor aggressiveness (high serum alpha-fetoprotein levels, P = 0.038; satellite nodules, P < 0.001; macrovascular invasion, P < 0.001; microvascular invasion, P < 0.001; poor differentiation, P < 0.001) and with the progenitor subtype of HCC (cytokeratin 19 expression, P = 0.031). High PD-L1 expression by inflammatory cells from the tumor microenvironment also correlated with high serum alpha-fetoprotein levels (P < 0.001), macrovascular invasion (P = 0.001), poor differentiation (P = 0.001), high PD-1 expression (P < 0.001), and the so-called lymphoepithelioma-like histological subtype of HCC (P = 0.003).

  16. Role of class III phosphatidylinositol 3-kinase during programmed nuclear death of Tetrahymena thermophila.

    PubMed

    Akematsu, Takahiko; Fukuda, Yasuhiro; Attiq, Rizwan; Pearlman, Ronald E

    2014-02-01

    Programmed nuclear death (PND) in the ciliate protozoan Tetrahymena thermophila is a novel type of autophagy that occurs during conjugation, in which only the parental somatic macronucleus is destined to die and is then eliminated from the progeny cytoplasm. Other coexisting nuclei, however, such as new micro- and macronuclei are unaffected. PND starts with condensation in the nucleus followed by apoptotic DNA fragmentation, lysosomal acidification, and final resorption. Because of the peculiarity in the process and the absence of some ATG genes in this organism, the mechanism of PND has remained unclear. In this study, we focus on the role of class III phosphatidylinositol 3-kinase (PtdIns3K, corresponding to yeast Vps34) in order to identify central regulators of PND. We identified the sole Tetrahymena thermophila ortholog (TtVPS34) to yeast Vps34 and human PIK3C3 (the catalytic subunit of PtdIns3K), through phylogenetic analysis, and generated the gene knockdown mutant for functional analysis. Loss of TtVPS34 activity prevents autophagosome formation on the parental macronucleus, and this nucleus escapes from the lysosomal pathway. In turn, DNA fragmentation and final resorption of the nucleus are drastically impaired. These phenotypes are similar to the situation in the ATG8Δ mutants of Tetrahymena, implying an inextricable link between TtVPS34 and TtATG8s in controlling PND as well as general macroautophagy. On the other hand, TtVPS34 does not appear responsible for the nuclear condensation and does not affect the progeny nuclear development. These results demonstrate that TtVPS34 is critically involved in the nuclear degradation events of PND in autophagosome formation rather than with an involvement in commitment to the death program.

  17. Role of class III phosphatidylinositol 3-kinase during programmed nuclear death of Tetrahymena thermophila

    PubMed Central

    Akematsu, Takahiko; Fukuda, Yasuhiro; Attiq, Rizwan; Pearlman, Ronald E

    2014-01-01

    Programmed nuclear death (PND) in the ciliate protozoan Tetrahymena thermophila is a novel type of autophagy that occurs during conjugation, in which only the parental somatic macronucleus is destined to die and is then eliminated from the progeny cytoplasm. Other coexisting nuclei, however, such as new micro- and macronuclei are unaffected. PND starts with condensation in the nucleus followed by apoptotic DNA fragmentation, lysosomal acidification, and final resorption. Because of the peculiarity in the process and the absence of some ATG genes in this organism, the mechanism of PND has remained unclear. In this study, we focus on the role of class III phosphatidylinositol 3-kinase (PtdIns3K, corresponding to yeast Vps34) in order to identify central regulators of PND. We identified the sole Tetrahymena thermophila ortholog (TtVPS34) to yeast Vps34 and human PIK3C3 (the catalytic subunit of PtdIns3K), through phylogenetic analysis, and generated the gene knockdown mutant for functional analysis. Loss of TtVPS34 activity prevents autophagosome formation on the parental macronucleus, and this nucleus escapes from the lysosomal pathway. In turn, DNA fragmentation and final resorption of the nucleus are drastically impaired. These phenotypes are similar to the situation in the ATG8Δ mutants of Tetrahymena, implying an inextricable link between TtVPS34 and TtATG8s in controlling PND as well as general macroautophagy. On the other hand, TtVPS34 does not appear responsible for the nuclear condensation and does not affect the progeny nuclear development. These results demonstrate that TtVPS34 is critically involved in the nuclear degradation events of PND in autophagosome formation rather than with an involvement in commitment to the death program. PMID:24280724

  18. Programmed necrosis - a new mechanism of steroidogenic luteal cell death and elimination during luteolysis in cows

    PubMed Central

    Hojo, Takuo; Siemieniuch, Marta J.; Lukasik, Karolina; Piotrowska-Tomala, Katarzyna K.; Jonczyk, Agnieszka W.; Okuda, Kiyoshi; Skarzynski, Dariusz J.

    2016-01-01

    Programmed necrosis (necroptosis) is an alternative form of programmed cell death that is regulated by receptor-interacting protein kinase (RIPK) 1 and 3-dependent, but is a caspase (CASP)-independent pathway. In the present study, to determine if necroptosis participates in bovine structural luteolysis, we investigated RIPK1 and RIPK3 expression throughout the estrous cycle, during prostaglandin F2α (PGF)-induced luteolysis in the bovine corpus luteum (CL), and in cultured luteal steroidogenic cells (LSCs) after treatment with selected luteolytic factors. In addition, effects of a RIPK1 inhibitor (necrostatin-1, Nec-1; 50 μM) on cell viability, progesterone secretion, apoptosis related factors and RIPKs expression, were evaluated. Expression of RIPK1 and RIPK3 increased in the CL tissue during both spontaneous and PGF-induced luteolysis (P < 0.05). In cultured LSCs, tumor necrosis factor α (TNF; 2.3 nM) in combination with interferon γ (IFNG; 2.5 nM) up-regulated RIPK1 mRNA and protein expression (P < 0.05). TNF + IFNG also up-regulated RIPK3 mRNA expression (P < 0.05), but not RIPK3 protein. Although Nec-1 prevented TNF + IFNG-induced cell death (P < 0.05), it did not affect CASP3 and CASP8 expression. Nec-1 decreased both RIPK1 and RIPK3 protein expression (P < 0.05). These findings suggest that RIPKs-dependent necroptosis is a potent mechanism responsible for bovine structural luteolysis induced by pro-inflammatory cytokines. PMID:27901113

  19. Engagement of SIRPα Inhibits Growth and Induces Programmed Cell Death in Acute Myeloid Leukemia Cells

    PubMed Central

    Hubeek, Isabelle; van Beek, Ellen M.; Schornagel, Karin; Broekhuizen, Aart J. F.; Akyuz, Mercan; van de Loosdrecht, Arjan A.; Delwel, Ruud; Valk, Peter J.; Sonneveld, Edwin; Kearns, Pamela; Creutzig, Ursula; Reinhardt, Dirk; de Bont, Eveline S. J. M.; Coenen, Eva A.; van den Heuvel-Eibrink, Marry M.; Zwaan, C. Michel; Kaspers, Gertjan J. L.; Cloos, Jacqueline; van den Berg, Timo K.

    2013-01-01

    Background Recent studies show the importance of interactions between CD47 expressed on acute myeloid leukemia (AML) cells and the inhibitory immunoreceptor, signal regulatory protein-alpha (SIRPα) on macrophages. Although AML cells express SIRPα, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRPα in acute myeloid leukemia. Design and Methods We analyzed the expression of SIRPα, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRPα on two low SIRPα expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRPα expression on tumor cell growth and programmed cell death by its triggering with an agonistic antibody in these cells. Moreover, we examined the efficacy of agonistic antibody in combination with established antileukemic drugs. Results By microarray analysis of an extensive cohort of primary AML samples, we demonstrated that SIRPα is differentially expressed in AML subgroups and its expression level is dependent on differentiation stage, with high levels in FAB M4/M5 AML and low levels in FAB M0–M3. Interestingly, AML patients with high SIRPα expression had a poor prognosis. Our results also showed that SIRPα is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRPα with an agonistic antibody in the cells stably expressing chimeric SIRPα, led to inhibition of growth and induction of programmed cell death. Finally, the SIRPα-derived signaling synergized with the activity of established antileukemic drugs. Conclusions Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML. PMID:23320069

  20. The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma.

    PubMed

    Wu, Shafei; Shi, Xiaohua; Sun, Jian; Liu, Yuanyuan; Luo, Yufeng; Liang, Zhiyong; Wang, Jinghui; Zeng, Xuan

    2017-03-07

    Lung adenocarcinoma (AD) is a common variant of non-small cell lung cancer (NSCLC). Programmed cell death protein 1/programmed cell death ligand 1 (PD1/PD-L1) are promising immunotherapy targets and its expression may be an important biomarker of predicting clinical response. In this study, we evaluated PD-L1 expression in conjunction with clinicopathological characteristics and outcomes in resected lung adenocarcinoma. This study included 133 cases of lung adenocarcinoma. PD-L1 expression rate in lung adenocarcinoma was 16.5% at the mRNA level and 13.5% at the protein level, and the kappa coefficient of the two examination methods was 0.824 (P = 0.219, highly correlated). PD-L1 was highly expressed in male patients and smokers with lung adenocarcinoma (P = 0.019 and 0.002, respectively), while no associations were identified between PD-L1 expression and age, tumor size, clinical stage, positive pleural invasion, lymph node metastasis, or therapy methods. Overexpression of PD-L1 was a significant indicator of shorter recurrence free survival time and overall survival (P = 0.000 and 0.000, respectively). Multivariate analysis revealed that PD-L1 expression was an independent risk factor for poor recurrence free survival and overall survival (P = 0.009 and 0.016, respectively). Expression of PD-L1 was examined with immunohistochemistry, using the VENTANA PD-L1 (SP263) rabbit monoclonal antibody. mRNA levels of PD-L1 were evaluated using in situ hybridization. PD-L1 overexpression is more frequently observed in male patients and smokers in lung adenocarcinoma. PD-L1 expression is an indicator of worse prognosis in surgically resected lung adenocarcinoma patients.

  1. Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies.

    PubMed

    Tsirigotis, Panagiotis; Savani, Bipin N; Nagler, Arnon

    2016-09-01

    The use of tumor-specific monoclonal antibodies (MAbs) has revolutionize the field of cancer immunotherapy. Although treatment of malignant diseases with MAbs is promising, many patients fail to respond or relapse after an initial response. Both solid tumors and hematological malignancies develop mechanisms that enable them to evade the host immune system by usurping immune checkpoint pathways such as PD-1, PD-2, PDL-1, or PDL-2 (programmed cell death protein-1 or 2 and PD-Ligand 1 or 2), which are expressed on activated T cells and on T-regulatory, B cells, natural killers, monocytes, and dendritic cells. One of the most exciting anticancer development in recent years has been the immune checkpoint blockade therapy by using MAbs against immune checkpoint receptor and/or ligands. Anti-PD1 antibodies have been tested in clinical studies that included patients with hematological malignancies and showed remarkable efficacy in Hodgkin lymphoma (HL). In our review, we will focus on the effect of PD-1 activation on hematological malignancies and its role as a therapeutic target. Key messages The programmed death 1 (PD1) immune checkpoint is an important homeostatic mechanism of the immune system that helps in preventing autoimmunity and uncontrolled inflammation in cases of chronic infections. However, PD1 pathway is also operated by a wide variety of malignancies and represents one of the most important mechanisms by which tumor cells escape from the surveillance of the immune system. Blocking of immune checkpoints by the use of monoclonal antibodies opened a new era in the field of cancer immunotherapy. Results from clinical trials are promising, and currently, this approach has been proven effective and safe in patients with solid tumors and hematological malignancies.

  2. Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1

    PubMed Central

    Joneja, Upasana; Vranic, Semir; Swensen, Jeffrey; Feldman, Rebecca; Chen, Wangjuh; Kimbrough, Jeffrey; Xiao, Nianqing; Reddy, Sandeep; Palazzo, Juan; Gatalica, Zoran

    2017-01-01

    Aims Metaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions. Methods We profiled 297 samples (MBC (n=75), TNBC (n=106), human epidermal growth factor receptor 2 (HER2)-positive breast cancers (n=32) and hormone-positive breast cancers (n=84)) by next-generation sequencing. Immunohistochemistry for PD-L1 and programmed cell death 1 (PD-1) expression was performed using automated procedures. Results The most commonly mutated genes in MBCs included TP53 (56%) and PIK3CA (23%). Pathogenic mutations in other genes, including HRAS, FBXW7, PTEN, AKT1 and SMAD4, were rare. PD-L1 expression was detected in a significantly higher proportion of MBCs (46%) than in other subtypes (6% each in hormone-positive and HER2-positive breast cancers, and 9% in TNBC, not otherwise specified, p<0.001). PD-1-positive tumour infiltrating lymphocytes (TILs) varied greatly in MBCs. Conclusions Comprehensive profiling of a large cohort of this rare subtype of breast carcinoma highlighted the predominance of TP53 mutation and increased PD-L1 expression in carcinoma cells. These results can be exploited in clinical trials using immune checkpoint inhibitors. PMID:27531819

  3. Untangling the Roles of Anti-Apoptosis in Regulating Programmed Cell Death using Humanized Yeast Cells.

    PubMed

    Clapp, Caitlin; Portt, Liam; Khoury, Chamel; Sheibani, Sara; Eid, Rawan; Greenwood, Matthew; Vali, Hojatollah; Mandato, Craig A; Greenwood, Michael T

    2012-01-01

    Genetically programmed cell death (PCD) mechanisms, including apoptosis, are important for the survival of metazoans since it allows, among things, the removal of damaged cells that interfere with normal function. Cell death due to PCD is observed in normal processes such as aging and in a number of pathophysiologies including hypoxia (common causes of heart attacks and strokes) and subsequent tissue reperfusion. Conversely, the loss of normal apoptotic responses is associated with the development of tumors. So far, limited success in preventing unwanted PCD has been reported with current therapeutic approaches despite the fact that inhibitors of key apoptotic inducers such as caspases have been developed. Alternative approaches have focused on mimicking anti-apoptotic processes observed in cells displaying increased resistance to apoptotic stimuli. Hormesis and pre-conditioning are commonly observed cellular strategies where sub-lethal levels of pro-apoptotic stimuli lead to increased resistance to higher or lethal levels of stress. Increased expression of anti-apoptotic sequences is a common mechanism mediating these protective effects. The relevance of the latter observation is exemplified by the observation that transgenic mice overexpressing anti-apoptotic genes show significant reductions in tissue damage following ischemia. Thus strategies aimed at increasing the levels of anti-apoptotic proteins, using gene therapy or cell penetrating recombinant proteins are being evaluated as novel therapeutics to decrease cell death following acute periods of cell death inducing stress. In spite of its functional and therapeutic importance, more is known regarding the processes involved in apoptosis than anti-apoptosis. The genetically tractable yeast Saccharomyces cerevisiae has emerged as an exceptional model to study multiple aspects of PCD including the mitochondrial mediated apoptosis observed in metazoans. To increase our knowledge of the process of anti

  4. Untangling the Roles of Anti-Apoptosis in Regulating Programmed Cell Death using Humanized Yeast Cells

    PubMed Central

    Clapp, Caitlin; Portt, Liam; Khoury, Chamel; Sheibani, Sara; Eid, Rawan; Greenwood, Matthew; Vali, Hojatollah; Mandato, Craig A.; Greenwood, Michael T.

    2012-01-01

    Genetically programmed cell death (PCD) mechanisms, including apoptosis, are important for the survival of metazoans since it allows, among things, the removal of damaged cells that interfere with normal function. Cell death due to PCD is observed in normal processes such as aging and in a number of pathophysiologies including hypoxia (common causes of heart attacks and strokes) and subsequent tissue reperfusion. Conversely, the loss of normal apoptotic responses is associated with the development of tumors. So far, limited success in preventing unwanted PCD has been reported with current therapeutic approaches despite the fact that inhibitors of key apoptotic inducers such as caspases have been developed. Alternative approaches have focused on mimicking anti-apoptotic processes observed in cells displaying increased resistance to apoptotic stimuli. Hormesis and pre-conditioning are commonly observed cellular strategies where sub-lethal levels of pro-apoptotic stimuli lead to increased resistance to higher or lethal levels of stress. Increased expression of anti-apoptotic sequences is a common mechanism mediating these protective effects. The relevance of the latter observation is exemplified by the observation that transgenic mice overexpressing anti-apoptotic genes show significant reductions in tissue damage following ischemia. Thus strategies aimed at increasing the levels of anti-apoptotic proteins, using gene therapy or cell penetrating recombinant proteins are being evaluated as novel therapeutics to decrease cell death following acute periods of cell death inducing stress. In spite of its functional and therapeutic importance, more is known regarding the processes involved in apoptosis than anti-apoptosis. The genetically tractable yeast Saccharomyces cerevisiae has emerged as an exceptional model to study multiple aspects of PCD including the mitochondrial mediated apoptosis observed in metazoans. To increase our knowledge of the process of anti

  5. Time course of programmed cell death, which included autophagic features, in hybrid tobacco cells expressing hybrid lethality.

    PubMed

    Ueno, Naoya; Nihei, Saori; Miyakawa, Naoto; Hirasawa, Tadashi; Kanekatsu, Motoki; Marubashi, Wataru; van Doorn, Wouter G; Yamada, Tetsuya

    2016-12-01

    PCD with features of vacuolar cell death including autophagy-related features were detected in hybrid tobacco cells, and detailed time course of features of vacuolar cell death were established. A type of interspecific Nicotiana hybrid, Nicotiana suaveolens × N. tabacum exhibits temperature-sensitive lethality. This lethality results from programmed cell death (PCD) in hybrid seedlings, but this PCD occurs only in seedlings and suspension-cultured cells grown at 28 °C, not those grown at 36 °C. Plant PCD can be classified as vacuolar cell death or necrotic cell death. Induction of autophagy, vacuolar membrane collapse and actin disorganization are each known features of vacuolar cell death, but observed cases of PCD showing all these features simultaneously are rare. In this study, these features of vacuolar cell death were evident in hybrid tobacco cells expressing hybrid lethality. Ion leakage, plasma membrane disruption, increased activity of vacuolar processing enzyme, vacuolar membrane collapse, and formation of punctate F-actin foci were each evident in these cells. Transmission electron microscopy revealed that macroautophagic structures formed and tonoplasts ruptured in these cells. The number of cells that contained monodansylcadaverine (MDC)-stained structures and the abundance of nine autophagy-related gene transcripts increased just before cell death at 28 °C; these features were not evident at 36 °C. We assessed whether an autophagic inhibitor, wortmannin (WM), influenced lethality in hybrid cells. After the hybrid cell began to die, WM suppressed increases in ion leakage and cell deaths, and it decreased the number of cells containing MDC-stained structures. These results showed that several features indicative of autophagy and vacuolar cell death were evident in the hybrid tobacco cells subject to lethality. In addition, we documented a detailed time course of these vacuolar cell death features.

  6. From AIDS to parasite infection: pathogen-mediated subversion of programmed cell death as a mechanism for immune dysregulation.

    PubMed

    Ameisen, J C; Estaquier, J; Idziorek, T

    1994-12-01

    Premature cell death can result either from cell injury or degeneration, leading to necrosis, or from the activation of a physiological cell-suicide process, termed programmed cell death or apoptosis, that is regulated by intercellular signalling. This process plays an essential role in the selection of developing lymphocytes, and is also involved in the function of the mature adaptative immune system. A growing number of experimental findings during the last 4 years has provided support to our hypothesis that inappropriate HIV-mediated dysregulation of programmed T-cell death is relevant to AIDS pathogenesis. A series of recent experimental results also supports the general concept that the persistence and pathogenesis of several infectious pathogens, ranging from retroviruses to parasites, may be related to their capacity to dysregulate programmed cell death in various cell populations including lymphocytes. Subversion by pathogens of the physiological control of programmed cell death provides a paradigm for the pathogenesis of a wide range of infectious diseases that involve immune dysregulation and suggests therapeutic potential for the in vivo modulation of cell signalling.

  7. ROS-mediated abiotic stress-induced programmed cell death in plants

    PubMed Central

    Petrov, Veselin; Hille, Jacques; Mueller-Roeber, Bernd; Gechev, Tsanko S.

    2015-01-01

    During the course of their ontogenesis plants are continuously exposed to a large variety of abiotic stress factors which can damage tissues and jeopardize the survival of the organism unless properly countered. While animals can simply escape and thus evade stressors, plants as sessile organisms have developed complex strategies to withstand them. When the intensity of a detrimental factor is high, one of the defense programs employed by plants is the induction of programmed cell death (PCD). This is an active, genetically controlled process which is initiated to isolate and remove damaged tissues thereby ensuring the survival of the organism. The mechanism of PCD induction usually includes an increase in the levels of reactive oxygen species (ROS) which are utilized as mediators of the stress signal. Abiotic stress-induced PCD is not only a process of fundamental biological importance, but also of considerable interest to agricultural practice as it has the potential to significantly influence crop yield. Therefore, numerous scientific enterprises have focused on elucidating the mechanisms leading to and controlling PCD in response to adverse conditions in plants. This knowledge may help develop novel strategies to obtain more resilient crop varieties with improved tolerance and enhanced productivity. The aim of the present review is to summarize the recent advances in research on ROS-induced PCD related to abiotic stress and the role of the organelles in the process. PMID:25741354

  8. Novel visible light activated type 1 photosensitizers

    NASA Astrophysics Data System (ADS)

    Rajagopalan, Raghavan; Karwa, Amolkumar; Poreddy, Amruta R.; Lusiak, Przemyslaw M.; Pandurangi, Raghoottama S.; Cantrell, Gary L.; Dorshow, Richard B.

    2010-02-01

    Photodynamic therapy of tumors involving Type 2 photosenstizers has been conspicuously successful, but the Type 1 process, in contrast, has not received much attention despite its considerable potential. Accordingly, several classes of molecules containing fragile bonds such as azido (-N=N=N), azo (-N=N-), and oxaza (-N-O-) functional groups that produce reactive intermediates such as radicals and nitrenes upon photoexcitation with visible light were prepared and tested for cell viability using U397 leukemia cell line. The cells were incubated with the photosensitizer at various concentrations, and were illuminated for 5, 10, and 20 minutes. The results show that all the photosensitizers caused cell death compared to the controls when exposed to both the photosensitizers and light.

  9. Direct regulation of egl-1 and of programmed cell death by the Hox protein MAB-5 and by CEH-20, a C. elegans homolog of Pbx1.

    PubMed

    Liu, Huarui; Strauss, Tamara J; Potts, Malia B; Cameron, Scott

    2006-02-01

    Hox genes are crucial determinants of cell fates and of body morphology of animals; mutations affecting these genes result in abnormal patterns of programmed cell death. How Hox genes regulate programmed cell death is an important and poorly understood aspect of normal development. In the nematode C. elegans, the Hox gene mab-5 is required for the programmed cell deaths of two lineally related cells generated in the P11 and P12 lineages. We show here that in the P11 lineage, a complex between MAB-5 and the Pbx homolog CEH-20 directly regulates transcription of the BH3 domain gene egl-1 to initiate programmed cell death; in the P12 lineage, mab-5 and ceh-20 apparently act indirectly to initiate programmed cell death. Direct regulation of programmed cell death may be an evolutionarily ancient and conserved function of Hox genes.

  10. Type 1 diabetes pathogenesis - Prevention???

    PubMed

    Krishna, C S Muralidhara; Srikanta, S

    2015-04-01

    Pathogenesis of type 1 diabetes is multi-faceted, including, autoimmunity, genetics and environment. Autoimmunity directed against pancreatic islet cells results in slowly progressive selective beta-cell destruction ("Primary autoimmune insulitis"), culminating over years in clinically manifested insulin-dependent diabetes mellitus (IDDM). Circulating serum autoantibodies directed against the endocrine cells of the islets of Langerhans (Islet cell autoantibodies - ICAb) are an important hallmark of this disease. Assays for islet cell autoantibodies have facilitated the investigation and understanding of several facets in the pathogenesis of autoimmune diabetes. Their applications have extended into clinical practice and have opened new avenues for early preclinical prediction and preventive prophylaxis in IDDM/type 1 DM. Recently, surprisingly, differences in insulin content between T1DM islets, as well as, 'patchy' or 'lobular' destruction of islets have been described. These unique pathobiological phenomena, suggest that beta cell destruction may not always be inexorable and inevitably complete/total, and thus raise hopes for possible therapeutic interruption of beta cell autoimmunity - destruction and cure of type 1 diabetes. "Recurrent or secondary autoimmune insulitis" refers to the rapid reappearance of islet cell autoantibodies post pancreas transplant, and selective islet beta cell destruction in the grafted pancreas [never forgetting or "anamnestic" beta cell destructive memory], in the absence of any graft pancreas rejection [monozygotic twin to twin transplantation]. The one definite environmental factor is congenital rubella, because of which a subset of children subsequently develop type 1 diabetes. The putative predisposing factors are viruses, gluten and cow's milk. The putative protective factors include gut flora, helminths, viral infections, and Vitamin D. Prevention of T1DM can include: Primary prevention strategies before the development of

  11. Myopia in neurofibromatosis type 1.

    PubMed

    Garty, B Z; Laor, A; Danon, Y L

    1996-05-01

    We studied the prevalence of myopia in 17-year-old Israeli military recruits with neurofibromatosis type 1 (NF1). Twenty-four percent of the youngsters with neurofibromatosis had myopia, compared to 19% of the controls; this difference was statistically significant (P < 0.03). The recruits with NF1 had a slightly lower IQ, fewer years of education, and lower height and weight than the controls. Thus, these factors, which have been reported to be associated with myopia, did not significantly influence the high prevalence of myopia in the neurofibromatosis subjects. A high prevalence of myopia seems to be an additional feature of NF1.

  12. Inflammation-associated autophagy-related programmed necrotic death of human neutrophils characterized by organelle fusion events.

    PubMed

    Mihalache, Cristina C; Yousefi, Shida; Conus, Sébastien; Villiger, Peter M; Schneider, E Marion; Simon, Hans-Uwe

    2011-06-01

    The most common form of neutrophil death, under both physiological and inflammatory conditions, is apoptosis. In this study, we report a novel form of programmed necrotic cell death, associated with cytoplasmic organelle fusion events, that occurs in neutrophils exposed to GM-CSF and other inflammatory cytokines upon ligation of CD44. Strikingly, this type of neutrophil death requires PI3K activation, a signaling event usually involved in cellular survival pathways. In the death pathway reported in this study, PI3K is required for the generation of reactive oxygen species, which somehow trigger the generation of large cytoplasmic vacuoles, generated by the fusion of CD44-containing endosomes with autophagosomes and secondary, but not primary, granules. Neutrophils demonstrating vacuolization undergo rapid cell death that depends on receptor-interacting protein 1 kinase activity and papain family protease(s), but not caspases, that are most likely activated and released, respectively, during or as a consequence of organelle fusion. Vacuolized neutrophils are present in infectious and autoimmune diseases under in vivo conditions. Moreover, isolated neutrophils from such patients are highly sensitive toward CD44-mediated PI3K activation, reactive oxygen species production, and cell death, suggesting that the newly described autophagy-related form of programmed neutrophil necrosis plays an important role in inflammatory responses.

  13. Involvement of Proline Oxidase (PutA) in Programmed Cell Death of Xanthomonas

    PubMed Central

    Wadhawan, Surbhi; Gautam, Satyendra; Sharma, Arun

    2014-01-01

    Xanthomonas campestris strains have been reported to undergo programmed cell death (PCD) in a protein rich medium. Protein hydrolysates used in media such as nutrient broth comprise of casein digest with abundance of proline and glutamate. In the current study, X. campestris pv. campestris (Xcc) cells displayed PCD when grown in PCD inducing medium (PIM) containing casein tryptic digest. This PCD was also observed in PCD non-inducing carbohydrate rich medium (PNIM) fortified with either proline or proline along with glutamate. Surprisingly, no PCD was noticed in PNIM fortified with glutamate alone. Differential role of proline or glutamate in inducing PCD in Xcc cells growing in PNIM was studied. It was found that an intermediate product of this oxidation was involved in initiation of PCD. Proline oxidase also called as proline utilization A (PutA), catalyzes the two step oxidation of proline to glutamate. Interestingly, higher PutA activity was noticed in cells growing in PIM, and PCD was found to be inhibited by tetrahydro-2-furoic acid, a competitive inhibitor of this enzyme. Further, PCD was abolished in Xcc ΔputA strain generated using a pKNOCK suicide plasmid, and restored in Xcc ΔputA strain carrying functional PutA in a plasmid vector. Xanthomonas cells growing in PIM also displayed increased generation of ROS, as well as cell filamentation (a probable indication of SOS response). These filamented cells also displayed enhanced caspase-3-like activity during in situ labeling using a fluorescent tagged caspase-3 inhibitor (FITC-DEVD-FMK). The extent of PCD associated markers such as DNA damage, phosphatidylserine externalization and membrane depolarization were found to be significantly enhanced in wild type cells, but drastically reduced in Xcc ΔputA cells. These findings thus establish the role of PutA mediated proline oxidation in regulating death in stressed Xanthomonas cells. PMID:24788936

  14. Mitochondrial calcium overload triggers complement-dependent superoxide-mediated programmed cell death in Trypanosoma cruzi.

    PubMed

    Irigoín, Florencia; Inada, Natalia M; Fernandes, Mariana P; Piacenza, Lucía; Gadelha, Fernanda R; Vercesi, Anibal E; Radi, Rafael

    2009-03-15

    The epimastigote stage of Trypanosoma cruzi undergoes PCD (programmed cell death) when exposed to FHS (fresh human serum). Although it has been known for over 30 years that complement is responsible for FHS-induced death, the link between complement activation and triggering of PCD has not been established. We have previously shown that the mitochondrion participates in the orchestration of PCD in this model. Several changes in mitochondrial function were described, and in particular it was shown that mitochondrion-derived O(2)(*-) (superoxide radical) is necessary for PCD. In the present study, we establish mitochondrial Ca(2+) overload as the link between complement deposition and the observed changes in mitochondrial physiology and the triggering of PCD. We show that complement activation ends with the assembly of the MAC (membrane attack complex), which allows influx of Ca(2+) and release of respiratory substrates to the medium. Direct consequences of these events are accumulation of Ca(2+) in the mitochondrion and decrease in cell respiration. Mitochondrial Ca(2+) causes partial dissipation of the inner membrane potential and consequent mitochondrial uncoupling. Moreover, we provide evidence that mitochondrial Ca(2+) overload is responsible for the increased O(2)(*-) production, and that if cytosolic Ca(2+) rise is not accompanied by the accumulation of the cation in the mitochondrion and consequent production of O(2)(*-), epimastigotes die by necrosis instead of PCD. Thus our results suggest a model in which MAC assembly on the parasite surface allows Ca(2+) entry and its accumulation in the mitochondrion, leading to O(2)(*-) production, which in turn constitutes a PCD signal.

  15. Live to die another way: modes of programmed cell death and the signals emanating from dying cells

    PubMed Central

    Fuchs, Yaron; Steller, Hermann

    2015-01-01

    Preface All life ends in death, but perhaps one of life’s grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was virtually synonymous with apoptosis, but recently, alternative PCD mechanisms have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals emanating from dying cells, which can either fuel regeneration or instruct additional killing. Further advances in understanding the physiological role of multiple cell death mechanisms and associated signals will be important to selectively manipulate PCD for therapeutic purposes. PMID:25991373

  16. Live to die another way: modes of programmed cell death and the signals emanating from dying cells.

    PubMed

    Fuchs, Yaron; Steller, Hermann

    2015-06-01

    All life ends in death, but perhaps one of life's grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was almost synonymous with apoptosis; recently, however, alternative mechanisms of PCD have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals that emanate from dying cells, which can either trigger regeneration or instruct additional killing. Further advances in understanding the physiological roles of the various mechanisms of cell death and their associated signals will be important to selectively manipulate PCD for therapeutic purposes.

  17. Macromitophagy, neutral lipids synthesis, and peroxisomal fatty acid oxidation protect yeast from "liponecrosis", a previously unknown form of programmed cell death.

    PubMed

    Sheibani, Sara; Richard, Vincent R; Beach, Adam; Leonov, Anna; Feldman, Rachel; Mattie, Sevan; Khelghatybana, Leila; Piano, Amanda; Greenwood, Michael; Vali, Hojatollah; Titorenko, Vladimir I

    2014-01-01

    We identified a form of cell death called "liponecrosis." It can be elicited by an exposure of the yeast Saccharomyces cerevisiae to exogenous palmitoleic acid (POA). Our data imply that liponecrosis is: (1) a programmed, regulated form of cell death rather than an accidental, unregulated cellular process and (2) an age-related form of cell death. Cells committed to liponecrotic death: (1) do not exhibit features characteristic of apoptotic cell death; (2) do not display plasma membrane rupture, a hallmark of programmed necrotic cell death; (3) akin to cells committed to necrotic cell death, exhibit an increased permeability of the plasma membrane for propidium iodide; (4) do not display excessive cytoplasmic vacuolization, a hallmark of autophagic cell death; (5) akin to cells committed to autophagic death, exhibit a non-selective en masse degradation of cellular organelles and require the cytosolic serine/threonine protein kinase Atg1p for executing the death program; and (6) display a hallmark feature that has not been reported for any of the currently known cell death modalities-namely, an excessive accumulation of lipid droplets where non-esterified fatty acids (including POA) are deposited in the form of neutral lipids. We therefore concluded that liponecrotic cell death subroutine differs from the currently known subroutines of programmed cell death. Our data suggest a hypothesis that liponecrosis is a cell death module dynamically integrated into a so-called programmed cell death network, which also includes the apoptotic, necrotic, and autophagic modules of programmed cell death. Based on our findings, we propose a mechanism underlying liponecrosis.

  18. A Quantitative Comparison of Antibodies to Programmed Cell Death 1 Ligand 1.

    PubMed

    Gaule, Patricia; Smithy, James W; Toki, Maria; Rehman, Jamaal; Patell-Socha, Farah; Cougot, Delphine; Collin, Philippe; Morrill, Paul; Neumeister, Veronique; Rimm, David L

    2016-08-18

    Assessment of PD-L1 (programmed cell death 1 ligand 1) expression by immunohistochemical analysis has been used as a predictive diagnostic test to identify responders and guide treatment in trials of the PD-1 (programmed cell death 1) axis inhibitors. The definition of PD-L1 positive lacks standardization, and prediction of response by immunohistochemical analysis is additionally limited by the subjective nature of this technique. To examine whether PD-L1 antibody reagents are interchangeable by quantitatively comparing the expression of the PD-L1 protein. In this immunohistochemistry standardization study, 30 randomly selected cases of lung cancer resected from January 1, 2008, through December 31, 2009, were obtained from Yale Pathology Archives with a range of expression of PD-L1. To test for protein measurement, rather than clinical utility, a PD-L1 index tissue microarray, including cell line and tissue controls, was used. The results were then validated on a commercially available, genetically defined PD-L1 engineered cell line array with a range of controlled protein-expressing cell lines using 6 monoclonal antibodies (SP142, E1L3N, 9A11, SP263, 22c3, and 28-8). Protein levels were measured by quantitative immunofluorescence and quantitative chromogenic assessment. Data analysis was performed from September 2015 through May 2016. Concordance between 4 antibodies revealed regression for tumor tissue cores (R2 = 0.42-0.91) and cell line cores (R2 = 0.83-0.97) by quantitative immunofluorescence in the PD-L1 index tissue microarray. All 6 antibodies had high levels of concordance (R2 = 0.76-0.99) when using chromogenic staining in isogenic cell lines. Because the antibodies are highly concordant, these results suggest that assays based on the use of these antibodies could yield concordant results. They further suggest that previously described differences in PD-L1 expression in tissue are independent of the antibody used and likely attributable to

  19. A dynamic mathematical model to clarify signaling circuitry underlying programmed cell death control in Arabidopsis disease resistance.

    PubMed

    Agrawal, Vikas; Zhang, Chu; Shapiro, Allan D; Dhurjati, Prasad S

    2004-01-01

    Plant cells undergo programmed cell death in response to invading pathogens. This cell death limits the spread of the infection and triggers whole plant antimicrobial and immune responses. The signaling network connecting molecular recognition of pathogens to these responses is a prime target for manipulation in genetic engineering strategies designed to improve crop plant disease resistance. Moreover, as alterations to metabolism can be misinterpreted as pathogen infection, successful plant metabolic engineering will ultimately depend on controlling these signaling pathways to avoid inadvertent activation of cell death. Programmed cell death resulting from infection of Arabidopsis thaliana with Pseudomonas syringae bacterial pathogens was chosen as a model system. Signaling circuitry hypotheses in this model system were tested by construction of a differential-equations-based mathematical model. Model-based simulations of time evolution of signaling components matched experimental measurements of programmed cell death and associated signaling components obtained in a companion study. Simulation of systems-level consequences of mutations used in laboratory studies led to two major improvements in understanding of signaling circuitry: (1) Simulations supported experimental evidence that a negative feedback loop in salicylic acid biosynthesis postulated by others does not exist. (2) Simulations showed that a second negative regulatory circuit for which there was strong experimental support did not affect one of two pathways leading to programmed cell death. Simulations also generated testable predictions to guide future experiments. Additional testable hypotheses were generated by results of individually varying each model parameter over 2 orders of magnitude that predicted biologically important changes to system dynamics. These predictions will be tested in future laboratory studies designed to further elucidate the signaling network control structure.

  20. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): the ATL Prevention Program Nagasaki

    PubMed Central

    HINO, Shigeo

    2011-01-01

    In late 2010, the nation-wide screening of pregnant women for human T-lymphotropic virus type 1 (HTLV-1) infection was implemented in Japan to prevent milk-borne transmission of HTLV-1. In the late 1970s, recognition of the adult T-cell leukemia (ATL) cluster in Kyushu, Japan, led to the discovery of the first human retrovirus, HTLV-1. In 1980, we started to investigate mother-to-child transmission (MTCT) for explaining the peculiar endemicity of HTLV-1. Retrospective and prospective epidemiological data revealed the MTCT rate at ∼20%. Cell-mediated transmission of HTLV-1 without prenatal infection suggested a possibility of milk-borne transmission. Common marmosets were successfully infected by oral inoculation of HTLV-1 harboring cells. A prefecture-wide intervention study to refrain from breast-feeding by carrier mothers, the ATL Prevention Program Nagasaki, was commenced in July 1987. It revealed a marked reduction of HTLV-1 MTCT by complete bottle-feeding from 20.3% to 2.5%, and a significantly higher risk of short-term breast-feeding (<6 months) than bottle-feeding (7.4% vs. 2.5%, P < 0.001). PMID:21558754

  1. Ethylene signaling in salt stress- and salicylic acid-induced programmed cell death in tomato suspension cells.

    PubMed

    Poór, Péter; Kovács, Judit; Szopkó, Dóra; Tari, Irma

    2013-02-01

    Salt stress- and salicylic acid (SA)-induced cell death can be activated by various signaling pathways including ethylene (ET) signaling in intact tomato plants. In tomato suspension cultures, a treatment with 250 mM NaCl increased the production of reactive oxygen species (ROS), nitric oxide (NO), and ET. The 10(-3) M SA-induced cell death was also accompanied by ROS and NO production, but ET emanation, the most characteristic difference between the two cell death programs, did not change. ET synthesis was enhanced by addition of ET precursor 1-aminocyclopropane-1-carboxylic acid, which, after 2 h, increased the ROS production in the case of both stressors and accelerated cell death under salt stress. However, it did not change the viability and NO levels in SA-treated samples. The effect of ET induced by salt stress could be blocked with silver thiosulfate (STS), an inhibitor of ET action. STS reduced the death of cells which is in accordance with the decrease in ROS production of cells exposed to high salinity. Unexpectedly, application of STS together with SA resulted in increasing ROS and reduced NO accumulation which led to a faster cell death. NaCl- and SA-induced cell death was blocked by Ca(2+) chelator EGTA and calmodulin inhibitor W-7, or with the inhibitors of ROS. The inhibitor of MAPKs, PD98059, and the cysteine protease inhibitor E-64 reduced cell death in both cases. These results show that NaCl induces cell death mainly by ET-induced ROS production, but ROS generated by SA was not controlled by ET in tomato cell suspension.

  2. Short-term impact of a stress management and health promotion program on perceived stress, parental stress, health locus of control, and cortisol levels in parents of children and adolescents with diabetes type 1: a pilot randomized controlled trial.

    PubMed

    Tsiouli, Eleni; Pavlopoulos, Vassilis; Alexopoulos, Evangelos C; Chrousos, George; Darviri, Christina

    2014-01-01

    Parents of children and adolescents with diabetes type 1 (DT1) usually experience high stress levels, as they have to cope with multiple demands in their everyday life. Different complex interventions have been implemented, which sometimes have led to opposite results. The purpose of this study was to assess stress levels in parents of children and adolescents with DT1 and to evaluate the effectiveness of a stress management program (progressive muscle relaxation combined with diaphragmatic breathing) in reducing perceived and parenting stress, increasing internal locus of control, promoting healthy lifestyle, and normalizing cortisol levels. Randomized controlled trial. A total of 44 parents were randomly assigned to the intervention group (performing relaxation for eight weeks, n = 19) and control group (n = 25). Pre-post measurements included cortisol levels, lifestyle characteristics, perceived stress, perception of health, and parenting stress. A statistically significant decrease in perceived stress (from 27.21 to 19.00, P = .001), as well as in parenting stress (from 85.79 to 73.68, P = .003), was observed in the intervention group. A statistically significant difference was found in perceived stress between the two groups after the intervention (Dmean = 6.64, P = .010). No significant difference was revealed between or within the groups in cortisol levels. Significant improvement was reported by the subjects of the intervention group in various lifestyle parameters. Relaxation techniques seem to have a positive impact on stress and on various lifestyle factors in parents of children and adolescents with DT1. Future research on long-term benefits of an intervention program comprising of various relaxation schemes is warranted. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Prevention of type 1 diabetes

    PubMed Central

    Wherrett, Diane K.; Daneman, Denis

    2009-01-01

    SYNOPSIS Prevention of loss of β cells in type 1 diabetes is a major goal of current research. Knowledge of the genetic susceptibility, the increasing ability to predict who may be at risk, the recognition of the potential clinical impact of residual insulin secretion after diagnosis and the development of new immunomodulatory agents have supported an increasing number of clinical trials to prevent β cell loss. Interventions can be targeted at three stages: prior to the development of autoimmunity – primary prevention, after autoimmunity is recognized – secondary prevention or after diagnosis when significant numbers of β cells remain- tertiary prevention. Thus far a number of agents show promise when given shortly after diagnosis but no interventions prior to diagnosis have shown benefit. Knowledge in this area has grown quickly in recent years and will continue to grow rapidly with a number of international collaborative efforts underway. PMID:19944292

  4. Involvement of TatD nuclease during programmed cell death in the protozoan parasite Trypanosoma brucei.

    PubMed

    Gannavaram, Sreenivas; Debrabant, Alain

    2012-03-01

    In this report, we describe the involvement of TatD nuclease during programmed cell death (PCD) in the human protozoan parasite Trypanosoma brucei. T. brucei TatD nuclease showed intrinsic DNase activity, was localized in the cytoplasm and translocated to the nucleus when cells were treated with inducers previously demonstrated to cause PCD in T. brucei. Overexpression of TatD nuclease resulted in elevated PCD and conversely, loss of TatD expression by RNAi conferred significant resistance to the induction of PCD in T. brucei. Co-immunoprecipitation studies revealed that TatD nuclease interacts with endonucleaseG suggesting that these two nucleases could form a DNA degradation complex in the nucleus. Together, biochemical activity, RNAi and subcellular localization results demonstrate the role of TatD nuclease activity in DNA degradation during PCD in these evolutionarily ancient eukaryotic organisms. Further, in conjunction with endonucleaseG, TatD may represent a critical nuclease in a caspase-independent PCD pathway in trypanosomatid parasites since caspases have not been identified in these organisms. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

  5. Enhanced expression of Programmed cell death 1 (PD-1) protein in benign vascular anomalies.

    PubMed

    Amaya, Clarissa N; Wians, Frank H; Bryan, Brad A; Torabi, Alireza

    2017-04-01

    Programmed cell death 1 (PD-1) and its ligands have been shown to play a significant role in evasion of malignant tumour cells from the immune system. Last year, the United States Food and Drug Administration (FDA) approved anti-PD-1 inhibitors for treatment of non-small cell lung carcinoma and recently has approved anti-PD-L1 blocker for treatment of metastatic urothelial cell carcinoma. However, the role that the immune system might have on benign tumours including vascular anomalies has received less attention. In this study, we evaluated PD-1 and PD-L1 expression on two benign vascular anomalies: infantile haemangiomas and venous malformations. Tissue microarrays (TMAs) from these two entities were stained for PD-1 and PD-L1 antibodies. Blood vessels from normal tissue were used as control. The endothelial cells in both infantile haemangioma and venous malformation showed high expression of PD-1 but were negative for PD-L1. Endothelial cells within the blood vessels in normal tissues were negative for both PD-1 and PD-L1. Our results showed over-expression of PD-1 in subsets of vascular anomalies, while PD-L1 was negative. This would raise the possibility of immunotherapy in benign vascular tumour when other options are exhausted.

  6. Expression and biological function of programmed death ligands in human placenta mesenchymal stem cells.

    PubMed

    Wang, Guoyan; Zhang, Siying; Wang, Feifei; Li, Guangyun; Zhang, Lixia; Luan, Xiying

    2013-02-01

    Mesenchymal stem cells (MSCs) play important roles in tissue regeneration due to their self-renewal, multilineage differentiation and immunosuppression abilities. MSCs can be isolated from various kinds of tissue, such as umbilical cord, cord blood and placenta. Human placenta mesenchymal stem cells (hPMSCs) possess stronger immunosuppressive properties, such as the ability to inhibit T-cell activation and proliferation, than human bone marrow MSCs. We have investigated that the roles of the programmed death ligands 1 and 2 (PDL1 and PDL2) in hPMSC adhesion, migration and immunosuppression were investigated. PDL1 and PDL2 were highly expressed by hPMSCs. Knockdown of PDL1 and/or PDL2 by siRNA increased hPMSC adhesion, but greatly decreasing migration. PDL1 and PDL2 expressed on hPMSCs inhibited T-cell proliferation by arresting the cell cycle. Knockdown of PDL1 and/or PDL2 in hPMSCs, however, had no effect on the expression of CD69, a T-cell early activation marker found on both CD4(+) and CD8(+) T-cell subsets. In summary, the roles of the negative co-stimulators PDL1 and PDL2 is on the adhesion, migration and immunosuppression of hPMSCs. These findings may be useful regarding the potential use of hPMSCs in clinical cell.

  7. Induction of metamorphosis in the marine gastropod Ilyanassa obsoleta: 5HT, NO and programmed cell death.

    PubMed

    Leise, Esther M; Kempf, S C; Durham, N R; Gifondorwa, D J

    2004-01-01

    The central nervous system (CNS) of a metamorphically competent larva of the caenogastropod Ilyanassa obsoleta contains a medial, unpaired apical ganglion (AG) of approximately 25 neurons that lies above the commissure connecting the paired cerebral ganglia. The AG, also known as the cephalic or apical sensory organ (ASO), contains numerous sensory neurons and innervates the ciliated velar lobes, the larval swimming and feeding structures. Before metamorphosis, the AG contains 5 serotonergic neurons and exogenous serotonin can induce metamorphosis in competent larvae. The AG appears to be a purely larval structure as it disappears within 3 days of metamorphic induction. In competent larvae, most neurons of the AG display nitric oxide synthase (NOS)-like immunoreactivity and inhibition of NOS activity can induce larval metamorphose. Because nitric oxide (NO) can prevent cells from undergoing apoptosis, a form of programmed cell death (PCD), we hypothesize that inhibition of NOS activity triggers the loss of the AG at the beginning of the metamorphic process. Within 24 hours of metamorphic induction, cellular changes that are typical of the early stages of PCD are visible in histological sections and results of a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in metamorphosing larvae show AG nuclei containing fragmented DNA, supporting our hypothesis.

  8. Extracellular calcium triggers unique transcriptional programs and modulates staurosporine-induced cell death in Neurospora crassa

    PubMed Central

    Gonçalves, A. P.; Monteiro, João; Lucchi, Chiara; Kowbel, David J.; Cordeiro, J. M.; Correia-de-Sá, Paulo; Rigden, Daniel J.; Glass, N. L.; Videira, Arnaldo

    2014-01-01

    Alterations in the intracellular levels of calcium are a common response to cell death stimuli in animals and fungi and, particularly, in the Neurospora crassa response to staurosporine. We highlight the importance of the extracellular availability of Ca2+ for this response. Limitation of the ion in the culture medium further sensitizes cells to the drug and results in increased accumulation of reactive oxygen species (ROS). Conversely, an approximately 30-fold excess of external Ca2+ leads to increased drug tolerance and lower ROS generation. In line with this, distinct staurosporine-induced cytosolic Ca2+ signaling profiles were observed in the absence or presence of excessive external Ca2+. High-throughput RNA sequencing revealed that different concentrations of extracellular Ca2+ define distinct transcriptional programs. Our transcriptional profiling also pointed to two putative novel Ca2+-binding proteins, encoded by the NCU08524 and NCU06607 genes, and provides a reference dataset for future investigations on the role of Ca2+ in fungal biology. PMID:28357255

  9. Laticiferous canal formation in fruits of Decaisnea fargesii: a programmed cell death process?

    PubMed

    Zhou, Ya-Fu; Liu, Wen-Zhe

    2011-10-01

    Programmed cell death (PCD), a topic of abiding interest, remodels plants at the cell, tissue, and organ levels involving various developmental processes of plants. The aim of this study is to provide a morphological characterization of evidence of PCD involvement in the laticiferous canal formation in fruit of Decaisnea fargesii. Several ultrastructural features of PCD have been observed including disintegration of vacuole and plasma membranes, cell wall degeneration, degenerated cytoplasm, abundant membrane structures and flocculent material, mitochondria and misshapen nuclei coupled with degraded plastids in vacuoles, and nuclei enveloped by rubber granule. In D. fargesii, the nuclei of the secretory epidermal cells become TUNEL-positive from the sunken stage to the late expanding stage, then DAPI-negative during the mature stage, indicating an early event of deoxyribonucleic acid (DNA) cleavage and a late event of complete DNA degeneration. Gel electrophoresis indicates that DNA cleavage is random and does not result in the laddering pattern indicating multiples of internucleosomal units. During the PCD of secretory epidermal cells, the rubber granules continue to be synthesized and accumulated in the secretory epidermal cells despite nuclear degradation. The PCD's role in laticiferous canal formation suggests that PCD may play important roles in gland development of plants.

  10. Expression of programmed death 1 is correlated with progression of osteosarcoma.

    PubMed

    Zheng, Wenjie; Xiao, Hong; Liu, Huan; Zhou, Yue

    2015-02-01

    Accumulating bodies of evidence indicate that immune dysregulation plays a key role in the development of osteosarcoma (OS). Programmed death 1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T-cell inhibition upon binding with its ligand. Researches on PD-1 and OS remain extremely limited. Here, we investigated whether PD-1 could be involved in the development of OS. Expression of PD-1 was measured by flow cytometry on peripheral CD4+ and CD8+ T cells from 56 OS cases and 42 healthy controls. Data revealed that percentages of PD-1 were significantly upregulated on both peripheral CD4+ and CD8+ T cells from OS patients (p < 0.001 and p < 0.001, respectively). Patients with different tumor locations did not present obvious variations in PD-1 level. However, patients with metastasis showed significantly higher level of PD-1 on CD4+ T cells than those without metastasis (p < 0.001). Furthermore, PD-1 expression on CD4+ T cells started to increase in stage III, whereas PD-1 expression on CD8+ T cells started to increase in stage II. In addition, patients with pathological fracture were observed to have elevated PD-1 on both CD4+ and CD8+ T cells. These data suggest that PD-1 is involved in the pathogenesis of OS, especially in the progression of disease.

  11. Effects of zinc on programmed cell death of Musca domestica and Drosophila melanogaster blood cells.

    PubMed

    Filipiak, Marta; Bilska, Ewelina; Tylko, Grzegorz; Pyza, Elzbieta

    2010-04-01

    Programmed cell death (PCD) and phagocytotic activity of immune cells play a pivotal role in insect development. We examined the influence of Zn(2+), an important element to fundamental biological processes, on phagocytosis and apoptosis of hemocytes in two fly species: Musca domestica and Drosophila melanogaster. Hemocytes were isolated from the third instar larvae of both species and treated for 3h with zinc chloride solutions, containing 0.35 mM or 1.7 mM of Zn(2+), and untreated as control. Phagocytotic activity of hemocytes was examined by flow cytometry after adding latex fluorescent beads to the medium, while apoptosis was evaluated by application of annexinV-FITC and pan-caspase-FITC inhibitor. Mitochondrial viability was determined by measuring resazurin absorbancy in the cell medium. The obtained results showed that Zn(2+) increases phagocytosis and affects PCD of both species hemocytes but each in a different way. Zinc decreases fraction of annexin-positive hemocytes in M. domestica but increases it in D. melanogaster. The pan-caspase analysis revealed low and high activity of caspases in hemocytes of M. domestica and D. melanogaster, respectively. Zn(2+) also decreased the viability of hemocyte mitochondria but only in D. melanogaster. It suggests that flies use different pathways of PCD, or that Zn plays a different role in this process in M. domestica than in D. melanogaster. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  12. YihE kinase is a central regulator of programmed cell death in bacteria

    PubMed Central

    Dorsey-Oresto, Angella; Lu, Tao; Mosel, Michael; Wang, Xiuhong; Salz, Tal; Drlica, Karl; Zhao, Xilin

    2013-01-01

    Stress-mediated programmed cell death (PCD) in bacteria has recently attracted attention, largely because it raises novel possibilities for controlling pathogens. How PCD in bacteria is regulated to avoid population extinction from transient, moderate stress remains a central question. We report that the YihE protein kinase is a key regulator that protects Escherichia coli from antimicrobial and environmental stressors by antagonizing the MazEF toxin-antitoxin module. YihE was linked to a reactive oxygen species (ROS) cascade, and a deficiency of yihE stimulated stress-induced PCD even after stress dissipated. YihE was partially regulated by the Cpx envelope stress-response system, which, along with MazF toxin and superoxide, has both protective and destructive roles that help bacteria make a live-or-die decision in response to stress. YihE probably acts early in the stress response to limit self-sustaining ROS production and PCD. Inhibition of YihE may provide a new way to enhance antimicrobial lethality and attenuate virulence. PMID:23416055

  13. Nonparametric functional mapping of quantitative trait loci underlying programmed cell death.

    PubMed

    Cui, Yuehua; Wu, Rongling; Casella, George; Zhu, Jun

    2008-01-01

    The development of an organism represents a complex dynamic process, which is controlled by a network of genes and multiple environmental factors. Programmed cell death (PCD), a physiological cell suicide process, occurs during the development of most organisms and is, typically, a complex dynamic trait. Understanding how genes control this complex developmental process has been a long-standing topic in PCD studies. In this article, we propose a nonparametric model, based on orthogonal Legendre polynomials, to map genes or quantitative trait loci (QTLs) that govern the dynamic features of the PCD process. The model is built under the maximum likelihood-based functional mapping framework and is implemented with the EM algorithm. A general information criterion is proposed for selecting the optimal Legendre order that best fits the dynamic pattern of the PCD process. The consistency of the order selection criterion is established. A nonstationary structured antedependence model (SAD) is applied to model the covariance structure among the phenotypes measured at different time points. The developed model generates a number of hypothesis tests regarding the genetic control mechanism of the PCD process. Extensive simulation studies are conducted to investigate the statistical behavior of the model. Finally, we apply the model to a rice tiller number data set in which several QTLs are identified. The developed model provides a quantitative and testable framework for assessing the interplay between genes and the developmental PCD process, and will have great implications for elucidating the genetic architecture of the PCD process.

  14. Global patent landscape of programmed cell death 1: implications of the rapid expansion.

    PubMed

    Kong, Xiangjun; Zhang, Qianru; Lai, Yunfeng; Hu, Hao; Chen, Xin; Hu, Yuanjia

    2017-09-19

    Inhibitors of programmed cell death 1 (PD-1) and its ligands are producing a paradigm shift in cancer treatment. The promising clinical outcomes and a multi-billion dollar market have prompted active research and development and resulted in relentless patent protection. However, the global patent landscape in this field remains unclear. Areas covered: The patent landscape encompassing global patenting activities and developing trends in the field is discussed based on a data set of 1287 patent families. Patenting activities have expanded rapidly in the past three years. Specific trends in relevant aspects are presented, including patent filing countries, patent ownership, co-patents, technical areas, and technological connections in terms of patent citation relationships. Expert opinion: Together with patenting momentum in recent years, fragmented ownership and dense technological connections of PD-1-related inventions raise the possibility of a patent thicket. The explosion of patent applications and complex citation relationships could also lead to considerable patent conflicts and disputes on overlapping intellectual property rights, in addition to existing legal uncertainties. Patent applicants in this field are encouraged to be aware of these concerns when developing valid patent strategies.

  15. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy.

    PubMed

    Okamoto, Masahide; Okamoto, Mitsuhiro; Gotoh, Koro; Masaki, Takayuki; Ozeki, Yoshinori; Ando, Hisae; Anai, Manabu; Sato, Asami; Yoshida, Yuichi; Ueda, So; Kakuma, Tetsuya; Shibata, Hirotaka

    2016-11-01

    Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for insulin-dependent diabetes mellitus as a side-effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy. A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti-PD-1 therapy.

  16. Programmed Cell Death Occurs Asymmetrically during Abscission in Tomato[C][W][OA

    PubMed Central

    Bar-Dror, Tal; Dermastia, Marina; Kladnik, Aleš; Žnidarič, Magda Tušek; Novak, Maruša Pompe; Meir, Shimon; Burd, Shaul; Philosoph-Hadas, Sonia; Ori, Naomi; Sonego, Lilian; Dickman, Martin B.; Lers, Amnon

    2011-01-01

    Abscission occurs specifically in the abscission zone (AZ) tissue as a natural stage of plant development. Previously, we observed delay of tomato (Solanum lycopersicum) leaf abscission when the LX ribonuclease (LX) was inhibited. The known association between LX expression and programmed cell death (PCD) suggested involvement of PCD in abscission. In this study, hallmarks of PCD were identified in the tomato leaf and flower AZs during the late stage of abscission. These included loss of cell viability, altered nuclear morphology, DNA fragmentation, elevated levels of reactive oxygen species and enzymatic activities, and expression of PCD-associated genes. Overexpression of antiapoptotic proteins resulted in retarded abscission, indicating PCD requirement. PCD, LX, and nuclease gene expression were visualized primarily in the AZ distal tissue, demonstrating an asymmetry between the two AZ sides. Asymmetric expression was observed for genes associated with cell wall hydrolysis, leading to AZ, or associated with ethylene biosynthesis, which induces abscission. These results suggest that different abscission-related processes occur asymmetrically between the AZ proximal and distal sides. Taken together, our findings identify PCD as a key mechanism that occurs asymmetrically during normal progression of abscission and suggest an important role for LX in this PCD process. PMID:22128123

  17. Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity

    PubMed Central

    Kerzerho, Jerome; Maazi, Hadi; Speak, Anneliese O.; Szely, Natacha; Lombardi, Vincent; Khoo, Bryant; Geryak, Stacey; Lam, Jonathan; Soroosh, Pejman; Van Snick, Jacques; Akbari, Omid

    2013-01-01

    Background Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiologic and immunologic processes are not fully understood. Objective The aim of this study was to determine whether TH9 cells develop in vivo in a model of chronic airway hyperreactivity (AHR) and what factors control this development. Method We have developed a novel chronic allergen exposure model using the clinically relevant antigen Aspergillus fumigatus to determine the time kinetics of TH9 development in vivo. Results TH9 cells were detectable in the lungs after chronic allergen exposure. The number of TH9 cells directly correlated with the severity of AHR, and anti–IL-9 treatment decreased airway inflammation. Moreover, we have identified programmed cell death ligand (PD-L) 2 as a negative regulator of TH9 cell differentiation. Lack of PD-L2 was associated with significantly increased TGF-β and IL-1α levels in the lungs, enhanced pulmonary TH9 differentiation, and higher morbidity in the sensitized mice. Conclusion Our findings suggest that PD-L2 plays a pivotal role in the regulation of TH9 cell development in chronic AHR, providing novel strategies for modulating adaptive immunity during chronic allergic responses. PMID:23174661

  18. Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis.

    PubMed

    Lee, Y H; Woo, J H; Choi, S J; Ji, J D; Song, G G

    2009-01-01

    Programmed cell death 1 (PDCD1 or PD1) polymorphisms have been inconsistently reported to be associated with systemic lupus erythematosus (SLE). The aim of this study was to explore whether the PDCD1 polymorphisms confer a susceptibility to SLE and lupus nephritis (LN). We conducted a meta-analysis on the association of PDCD1 polymorphisms with SLE in overall and specific ethnic populations. A total of 15 separate comparisons were included in this meta-analysis consisting of nine Europeans, two Latin Americans, two Africans, one Asian and one unknown participant. In subgroup analysis, the PD1.3A allele was significantly associated with SLE in Latin Americans (OR = 3.073, 95% CI = 1.416-6.461, P = 0.003), but not in patients of European and African decent. The PD1.3A allele was a risk factor for LN in European descendants (OR = 2.207, 95% CI = 1.488-3.467, P < 0.001). The PD1.5C allele was a risk factor for SLE in Europeans (OR = 1.297, 95% CI = 1.024-1.643, P = 0.031). In conclusion, this meta-analysis demonstrated an association of the PD1.3A allele with LN in European and SLE in Latin-American populations. Furthermore, the PD1.5C allele was associated with SLE susceptibility in Europeans.

  19. Programmed cell death 4 (PDCD4) suppresses metastastic potential of human hepatocellular carcinoma cells

    PubMed Central

    Zhang, Shuhong; Li, Jianfeng; Jiang, Ying; Xu, Yijun; Qin, Chengyong

    2009-01-01

    Background Hepatocellular carcinoma (HCC) is a lethal malignancy with high rate of metastasis and poor prognosis. There are no effective managements to block metastasis of HCC. Programmed cell death 4 (PDCD4) is found to be a tumor transformation suppressor. Among investigations on effects of PDCD4, little is about the metastatic potentials of HCC cells. This study was to investigate the role of PDCD4 on metastatic potential of human HCC cells. Methods We examined the expression of PDCD4 in three HCC cell lines with different metastatic potentials, MHCC-97H (high metastatic potential), MHCC-97L (low metastatic potential) and Hep3B (no metastatic potential). A plasmid encoding PDCD4 gene was constructed and then transfected into HCC cells with the lowest PDCD4 expression level. Effects of PDCD4 on cell proliferation, cell apoptosis, gene expression of metastasis tumor antigen 1 (MTA1) and in vitro migration and invasion capacity were assessed after transfection. Results Our results showed that the expression level of PDCD4 was inversely correlated to the metastatic potential of HCC cells. After transfection with the PDCD4 gene, HCC cell proliferation rate was significantly decreased, cell apoptosis rate was significantly increased, the expression of MTA1 gene, HCC cell migration and Matrigel invasion were also remarkably inhibited. Conclusion PDCD4 expression is inversely correlated to the metastatic potential of HCC cells. PDCD4 can effectively suppress the metastatic potential of HCC cells. PMID:19480673

  20. Mod(mdg4) participates in hormonally regulated midgut programmed cell death during metamorphosis.

    PubMed

    Cai, Mei-Juan; Liu, Wen; He, Hong-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2012-12-01

    The insect midgut undergoes programmed cell death (PCD) during metamorphosis, but the molecular basis for this phenomenon has not been demonstrated. We report a mod(mdg4) protein [designated as mod(mdg4)1A] that is involved in hormonally regulated insect midgut PCD, from the lepidopteran Helicoverpa armigera. Mod(mdg4)1A is localized in the larval midgut and is highly expressed during metamorphosis. Knockdown of mod(mdg4)1a by feeding dsRNA to the larvae suppressed midgut PCD and delayed metamorphosis. The mechanism is that mod(mdg4)1a knockdown decreased the transcript levels of genes involved in PCD and metamorphosis, but increased the transcript level of inhibitor of apoptosis survivin. The transcript level of mod(mdg4)1a is independently upregulated by 20-hydroxyecdysone (20E) or juvenile hormone (JH) analog methoprene. Overlapped 20E and methoprene counteractively regulate the transcript level of mod(mdg4)1a. 20E upregulates the mod(mdg4)1a transcript level not through its nuclear receptor EcRB1. Methoprene upregulates the mod(mdg4)1a transcript level through the juvenile hormone candidate receptor Met. These findings indicate that mod(mdg4)1a participates in midgut PCD and metamorphosis by regulating the transcript levels of a network of genes via different pathways under 20E and JH regulation.

  1. Vacuolar processing enzyme activates programmed cell death in the apical meristem inducing loss of apical dominance.

    PubMed

    Teper-Bamnolker, Paula; Buskila, Yossi; Belausov, Eduard; Wolf, Dalia; Doron-Faigenboim, Adi; Ben-Dor, Shifra; Van der Hoorn, Renier A L; Lers, Amnon; Eshel, Dani

    2017-10-01

    The potato (Solanum tuberosum L.) tuber is a swollen underground stem that can sprout in an apical dominance (AD) pattern. Bromoethane (BE) induces loss of AD and the accumulation of vegetative vacuolar processing enzyme (S. tuberosum vacuolar processing enzyme [StVPE]) in the tuber apical meristem (TAM). Vacuolar processing enzyme activity, induced by BE, is followed by programmed cell death in the TAM. In this study, we found that the mature StVPE1 (mVPE) protein exhibits specific activity for caspase 1, but not caspase 3 substrates. Optimal activity of mVPE was achieved at acidic pH, consistent with localization of StVPE1 to the vacuole, at the edge of the TAM. Downregulation of StVPE1 by RNA interference resulted in reduced stem branching and retained AD in tubers treated with BE. Overexpression of StVPE1 fused to green fluorescent protein showed enhanced stem branching after BE treatment. Our data suggest that, following stress, induction of StVPE1 in the TAM induces AD loss and stem branching. © 2017 John Wiley & Sons Ltd.

  2. Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients.

    PubMed

    Shirali, Anushree C; Perazella, Mark A; Gettinger, Scott

    2016-08-01

    Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling pathway have recently been approved for use in advanced pretreated non-small cell lung cancer and melanoma. Clinical trial data suggest that these drugs may have adverse effects on the kidney, but these effects have not been well described. We present 6 cases of acute kidney injury in patients with lung cancer who received anti-PD-1 antibodies, with each case displaying evidence of acute interstitial nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN, but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The association of AIN with these drugs in our patients raises the possibility that PD-1 inhibitor therapy may release suppression of T-cell immunity that normally permits renal tolerance of drugs known to be associated with AIN. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  3. Amoebicidal activity of caffeine and maslinic acid by the induction of Programmed Cell Death in Acanthamoeba.

    PubMed

    Martín-Navarro, Carmen M; López-Arencibia, Atteneri; Sifaoui, Ines; Reyes-Battle, María; Fouque, Emilie; Osuna, Antonio; Valladares, Basilio; Piñero, José E; Héchard, Yann; Maciver, Sutherland K; Lorenzo-Morales, Jacob

    2017-03-20

    Free living amoebae of the genus Acanthamoeba are the causal agents of a sight threatening ulceration of the cornea called Acanthamoeba keratitis, and the rare but usually fatal granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba infections, they are generally lengthy and/or have limited efficacy. For the best clinical outcome, the treatments should target both the trophozoite and the cyst stages as the later are known to confer resistance to treatment. In this study we document the activity of caffeine and maslinic acid against both the trophozoite and the cyst stages of three clinical strains of Acanthamoeba These drugs were chosen because they are reported to inhibit glycogen phosphorylase which is required for encystation. Maslinic acid is also reported to be an inhibitor of extracellular proteases which may be relevant since the protease activity of Acanthamoeba is correlated with their pathogenicity. We also provide evidence or the first time that both drugs exert their anti-amoebal effects through programmed cell death.

  4. Inhibition of cathepsin B by caspase-3 inhibitors blocks programmed cell death in Arabidopsis

    PubMed Central

    Ge, Y; Cai, Y-M; Bonneau, L; Rotari, V; Danon, A; McKenzie, E A; McLellan, H; Mach, L; Gallois, P

    2016-01-01

    Programmed cell death (PCD) is used by plants for development and survival to biotic and abiotic stresses. The role of caspases in PCD is well established in animal cells. Over the past 15 years, the importance of caspase-3-like enzymatic activity for plant PCD completion has been widely documented despite the absence of caspase orthologues. In particular, caspase-3 inhibitors blocked nearly all plant PCD tested. Here, we affinity-purified a plant caspase-3-like activity using a biotin-labelled caspase-3 inhibitor and identified Arabidopsis thaliana cathepsin B3 (AtCathB3) by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Consistent with this, recombinant AtCathB3 was found to have caspase-3-like activity and to be inhibited by caspase-3 inhibitors. AtCathepsin B triple-mutant lines showed reduced caspase-3-like enzymatic activity and reduced labelling with activity-based caspase-3 probes. Importantly, AtCathepsin B triple mutants showed a strong reduction in the PCD induced by ultraviolet (UV), oxidative stress (H2O2, methyl viologen) or endoplasmic reticulum stress. Our observations contribute to explain why caspase-3 inhibitors inhibit plant PCD and provide new tools to further plant PCD research. The fact that cathepsin B does regulate PCD in both animal and plant cells suggests that this protease may be part of an ancestral PCD pathway pre-existing the plant/animal divergence that needs further characterisation. PMID:27058316

  5. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation

    PubMed Central

    1992-01-01

    Programmed cell death (PCD) plays a key role in developmental biology and in maintenance of the steady state in continuously renewing tissues. Currently, its existence is inferred mainly from gel electrophoresis of a pooled DNA extract as PCD was shown to be associated with DNA fragmentation. Based on this observation, we describe here the development of a method for the in situ visualization of PCD at the single-cell level, while preserving tissue architecture. Conventional histological sections, pretreated with protease, were nick end labeled with biotinylated poly dU, introduced by terminal deoxy- transferase, and then stained using avidin-conjugated peroxidase. The reaction is specific, only nuclei located at positions where PCD is expected are stained. The initial screening includes: small and large intestine, epidermis, lymphoid tissues, ovary, and other organs. A detailed analysis revealed that the process is initiated at the nuclear periphery, it is relatively short (1-3 h from initiation to cell elimination) and that PCD appears in tissues in clusters. The extent of tissue-PCD revealed by this method is considerably greater than apoptosis detected by nuclear morphology, and thus opens the way for a variety of studies. PMID:1400587

  6. Program Death-1 Suppresses Autoimmune Arthritis by Inhibiting Th17 Response.

    PubMed

    Yang, Lifen; Qiao, Guilin; Hassan, Yassir; Li, Zhenping; Zhang, Xiaoqing; Kong, Huimin; Zeng, Weimin; Yin, Fei; Zhang, Jian

    2016-10-01

    Program death-1 (PD-1) is a co-inhibitory receptor inducibly expressed on activated T cells. PD-1 has been reported to be associated with the development of several autoimmune diseases including rheumatoid arthritis, but the precise cellular and molecular mechanisms have not been fully elucidated. To study the role of PD-1 in the pathogenesis of rheumatoid arthritis and the possible underlying mechanisms, we performed collagen-induced arthritis (CIA) in C57BL/6 mice. Here, we show that PD-1 deficiency leads to the development of severe CIA in mice. When analyzing T cells from CIA mice ex vivo, we noticed aberrant antigen-specific Th17 responses in mice lacking PD-1. This is possibly due to deregulated activation of PKC-θ and Akt. In support of this notion, treating Pdcd1 (-/-) mice with an inhibitor of PI3-kinase that is upstream of PKC-θ and Akt significantly suppressed the disease severity. Therefore, our data indicate that PD-1 dampens antigen-specific Th17 response, thus inhibiting the disease.

  7. Programmed cell death in plants: protective effect of mitochondrial-targeted quinones.

    PubMed

    Vasil'ev, L A; Dzyubinskaya, E V; Kiselevsky, D B; Shestak, A A; Samuilov, V D

    2011-10-01

    Ubiquinone or plastoquinone covalently linked to synthetic decyltriphenylphosphonium (DTPP(+)) or rhodamine cations prevent programmed cell death (PCD) in pea leaf epidermis induced by chitosan or CN(-). PCD was monitored by recording the destruction of cell nuclei. CN(-) induced the destruction of nuclei in both epidermal cells (EC) and guard cells (GC), whereas chitosan destroyed nuclei in EC not in GC. The half-maximum concentrations for the protective effects of the quinone derivatives were within the pico- and nanomolar range. The protective effect of the quinones was removed by a protonophoric uncoupler and reduced by tetraphenylphosphonium cations. CN(-)-Induced PCD was accelerated by the tested quinone derivatives at concentrations above 10(-8)-10(-7) M. Unlike plastoquinone linked to the rhodamine cation (SkQR1), DTPP(+) derivatives of quinones suppressed menadione-induced H(2)O(2) generation in the cells. The CN(-)-induced destruction of GC nuclei was prevented by DTPP(+) derivatives in the dark not in the light. SkQR1 inhibited this process both in the dark and in the light, and its effect in the light was similar to that of rhodamine 6G. The data on the protective effect of cationic quinone derivatives indicate that mitochondria are involved in PCD in plants.

  8. Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development.

    PubMed

    Aizawa, Ryo; Yamada, Atsushi; Suzuki, Dai; Iimura, Tadahiro; Kassai, Hidetoshi; Harada, Takeshi; Tsukasaki, Masayuki; Yamamoto, Gou; Tachikawa, Tetsuhiko; Nakao, Kazuki; Yamamoto, Matsuo; Yamaguchi, Akira; Aiba, Atsu; Kamijo, Ryutaro

    2012-01-01

    Cdc42, a member of the Rho subfamily of small GTPases, is known to be a regulator of multiple cellular functions, including cytoskeletal organization, cell migration, proliferation, and apoptosis. However, its tissue-specific roles, especially in mammalian limb development, remain unclear. To investigate the physiological function of Cdc42 during limb development, we generated limb bud mesenchyme-specific inactivated Cdc42 (Cdc42(fl/fl); Prx1-Cre) mice. Cdc42(fl/fl); Prx1-Cre mice demonstrated short limbs and body, abnormal calcification of the cranium, cleft palate, disruption of the xiphoid process, and syndactyly. Severe defects were also found in long bone growth plate cartilage, characterized by loss of columnar organization of chondrocytes, and thickening and massive accumulation of hypertrophic chondrocytes, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed that expressions of Col10 and Mmp13 were reduced in non-resorbed hypertrophic cartilage, indicating that deletion of Cdc42 inhibited their terminal differentiation. Syndactyly in Cdc42(fl/fl); Prx1-Cre mice was caused by fusion of metacarpals and a failure of interdigital programmed cell death (ID-PCD). Whole mount in situ hybridization analysis of limb buds showed that the expression patterns of Sox9 were ectopic, while those of Bmp2, Msx1, and Msx2, known to promote apoptosis in the interdigital mesenchyme, were down-regulated. These results demonstrate that Cdc42 is essential for chondrogenesis and ID-PCD during limb development.

  9. Localization of Barley yellow dwarf virus Movement Protein Modulating Programmed Cell Death in Nicotiana benthamiana

    PubMed Central

    Ju, Jiwon; Kim, Kangmin; Lee, Kui-Jae; Lee, Wang Hu; Ju, Ho-Jong

    2017-01-01

    Barley yellow dwarf virus (BYDV) belongs to Luteovirus and is limited only at phloem related tissues. An open reading frame (ORF) 4 of BYDV codes for the movement protein (MP) of BYDV gating plasmodesmata (PD) to facilitate virus movement. Like other Luteoviruses, ORF 4 of BYDV is embedded in the ORF3 but expressed from the different reading frame in leaky scanning manner. Although MP is a very important protein for systemic infection of BYDV, there was a little information. In this study, MP was characterized in terms of subcellular localization and programmed cell death (PCD). Gene of MP or its mutant (ΔMP) was expressed by Agroinfiltration method. MP was clearly localized at the nucleus and the PD, but ΔMP which was deleted distal N-terminus of MP showed no localization to PD exhibited the different target with original MP. In addition to PD localization, MP appeared associated with small granules in cytoplasm whereas ΔMP did not. MP associated with PD and small granules induced PCD, but ΔMP showed no association with PD and small granules did not exhibit PCD. Based on this study, the distal N-terminal region within MP is seemingly responsible for the localization of PD and the induction small granules and PCD induction. These results suggest that subcellular localization of BYDV MP may modulate the PCD in Nicotiana benthamiana. PMID:28167888

  10. A novel ligand of calcitonin receptor reveals a potential new sensor that modulates programmed cell death

    PubMed Central

    Furness, SGB; Hare, DL; Kourakis, A; Turnley, AM; Wookey, PJ

    2016-01-01

    We have discovered that the accumulation of an anti-calcitonin receptor (anti-CTR) antibody conjugated to a fluorophore (mAb2C4:AF568) provides a robust signal for cells undergoing apoptotic programmed cell death (PCD). PCD is an absolute requirement for normal development of metazoan organisms. PCD is a hallmark of common diseases such as cardiovascular disease and tissue rejection in graft versus host pathologies, and chemotherapeutics work by increasing PCD. This robust signal or high fluorescent events were verified by confocal microscopy and flow cytometry in several cell lines and a primary culture in which PCD had been induced. In Jurkat cells, GBM-L2 and MG63 cells, the percentage undergoing PCD that were positive for both mAb2C4:AF568 and annexin V ranged between 70 and >90%. In MG63 cells induced for the preapoptotic cell stress response (PACSR), the normal expression of α-tubulin, a key structural component of the cytoskeleton, and accumulation of mAb2C4:AF568 were mutually exclusive. Our data support a model in which CTR is upregulated during PACSR and recycles to the plasma membrane with apoptosis. In cells committed to apoptosis (α-tubulin negative), there is accumulation of the CTR-ligand mAb2C4:AF568 generating a high fluorescent event. The reagent mAb2C4:AF568 effectively identifies a novel event linked to apoptosis. PMID:27777788

  11. Relationship between programmed cell death-1 polymorphisms and clearance of hepatitis B virus.

    PubMed

    Ülger, Y; Bayram, S; Sandıkçı, M Ü; Akgöllü, E; Bekar, A

    2015-06-01

    Programmed cell death-1 (PD-1) plays a critical role in regulating T-cell function during hepatitis B virus (HBV) infection. This study investigated the relationship between the polymorphisms of PD-1 gene and the susceptibility to HBV infection. Single nucleotide polymorphisms (SNPs) in PD-1 gene at positions +7146 G>A (guanine to adenine substitution) and +7209 C>T (cytosine to thymine substitution) were analysed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 220 subjects with chronic hepatitis B infection and 165 spontaneous clearance of HBV subjects. However, no statistically significant differences were found in the genotype distributions of the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms among chronic hepatitis B and spontaneous clearance subjects. According to stratified analyses, borderline significance was observed between PD-1 +7146 GA genotype and risk of HBV chronicity in the subgroup of male gender (OR = 1.88, 95% 0.95-3.71; P = 0.07). Our findings demonstrate for the first time that the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms have not been any major role in genetic susceptibility to chronicity of HBV infection, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.

  12. Ageratum enation virus Infection Induces Programmed Cell Death and Alters Metabolite Biosynthesis in Papaver somniferum.

    PubMed

    Srivastava, Ashish; Agrawal, Lalit; Raj, Rashmi; Jaidi, Meraj; Raj, Shri K; Gupta, Swati; Dixit, Ritu; Singh, Poonam C; Tripathi, Tusha; Sidhu, Om P; Singh, Brahma N; Shukla, Sudhir; Chauhan, Puneet S; Kumar, Susheel

    2017-01-01

    A previously unknown disease which causes severe vein thickening and inward leaf curl was observed in a number of opium poppy (Papaver somniferum L.) plants. The sequence analysis of full-length viral genome and associated betasatellite reveals the occurrence of Ageratum enation virus (AEV) and Ageratum leaf curl betasatellite (ALCB), respectively. Co-infiltration of cloned agroinfectious DNAs of AEV and ALCB induces the leaf curl and vein thickening symptoms as were observed naturally. Infectivity assay confirmed this complex as the cause of disease and also satisfied the Koch's postulates. Comprehensive microscopic analysis of infiltrated plants reveals severe structural anomalies in leaf and stem tissues represented by unorganized cell architecture and vascular bundles. Moreover, the characteristic blebs and membranous vesicles formed due to the virus-induced disintegration of the plasma membrane and intracellular organelles were also present. An accelerated nuclear DNA fragmentation was observed by Comet assay and confirmed by TUNEL and Hoechst dye staining assays suggesting virus-induced programmed cell death. Virus-infection altered the biosynthesis of several important metabolites. The biosynthesis potential of morphine, thebaine, codeine, and papaverine alkaloids reduced significantly in infected plants except for noscapine whose biosynthesis was comparatively enhanced. The expression analysis of corresponding alkaloid pathway genes by real time-PCR corroborated well with the results of HPLC analysis for alkaloid perturbations. The changes in the metabolite and alkaloid contents affect the commercial value of the poppy plants.

  13. Programmed cell death in the marine cyanobacterium Trichodesmium mediates carbon and nitrogen export

    PubMed Central

    Bar-Zeev, Edo; Avishay, Itamar; Bidle, Kay D; Berman-Frank, Ilana

    2013-01-01

    The extent of carbon (C) and nitrogen (N) export to the deep ocean depends upon the efficacy of the biological pump that transports primary production to depth, thereby preventing its recycling in the upper photic zone. The dinitrogen-fixing (diazotrophic) Trichodesmium spp. contributes significantly to oceanic C and N cycling by forming extensive blooms in nutrient-poor tropical and subtropical regions. These massive blooms generally collapse several days after forming, but the cellular mechanism responsible, along with the magnitude of associated C and N export processes, are as yet unknown. Here, we used a custom-made, 2-m high water column to simulate a natural bloom and to specifically test and quantify whether the programmed cell death (PCD) of Trichodesmium mechanistically regulates increased vertical flux of C and N. Our findings demonstrate that extremely rapid development and abrupt, PCD-induced demise (within 2–3 days) of Trichodesmium blooms lead to greatly elevated excretions of transparent exopolymers and a massive downward pulse of particulate organic matter. Our results mechanistically link autocatalytic PCD and bloom collapse to quantitative C and N export fluxes, suggesting that PCD may have an impact on the biological pump efficiency in the oceans. PMID:23887173

  14. In Vitro Brucella suis Infection Prevents the Programmed Cell Death of Human Monocytic Cells

    PubMed Central

    Gross, Antoine; Terraza, Annie; Ouahrani-Bettache, Safia; Liautard, Jean-Pierre; Dornand, Jacques

    2000-01-01

    During the complex interaction between an infectious agent and a host organism, the pathogen can interfere with the host cell's programmed death to its own benefit. Induction or prevention of host cell apoptosis appears to be a critical step for determining the infection outcome. Members of the gram-negative bacterial genus Brucella are intracellular pathogens which preferentially invade monocytic cells and develop within these cells. We investigated the effect of Brucella suis infection on apoptosis of human monocytic phagocytes. The present study provides evidence that Brucella infection inhibited spontaneously occurring apoptosis in human monocytes. Prevention of monocyte apoptosis was not mediated by Brucella lipopolysaccharide and required bacterial survival within infected cells. Both invaded and noninvaded cells were protected, indicating that soluble mediators released during infection were involved in the phenomenon. Analysis of Brucella-infected monocytes revealed specific overexpression of the A1 gene, a member of the bcl-2 family implicated in the survival of hematopoietic cells. Brucella infection also rendered macrophage-like cells resistant to Fas ligand- or gamma interferon-induced apoptosis, suggesting that Brucella infection protected host cells from several cytotoxic processes occurring at different steps of the immune response. The present data clearly show that Brucella suis modulated the monocyte/macrophage's apoptotic response to the advantage of the pathogen, thus preventing host cell elimination. This might represent a strategy for Brucella development in infected hosts. PMID:10603407

  15. Over-expression of mitochondrial heat shock protein 70 suppresses programmed cell death in rice.

    PubMed

    Qi, Yaocheng; Wang, Hongjuan; Zou, Yu; Liu, Cheng; Liu, Yanqi; Wang, Ying; Zhang, Wei

    2011-01-03

    In this study, we identified and functionally characterized the mitochondrial heat shock protein 70 (mtHsp70). Over-expression of mtHsp70 suppressed heat- and H(2)O(2)-induced programmed cell death (PCD) in rice protoplasts, as reflected by higher cell viability, decreased DNA laddering and chromatin condensation. Mitochondrial membrane potential (Δψ(m)) after heat shock was destroyed gradually in protoplasts, but mtHsp70 over-expression showed higher Δψ(m) relative to the vector control cells, and partially inhibited cytochrome c release from mitochondria to cytosol. Heat treatment also significantly increased reactive oxygen species (ROS) generation, a phenomenon not observed in protoplasts over-expressing mtHsp70. Together, these results suggest that mtHsp70 may suppress PCD in rice protoplasts by maintaining mitochondrial Δψ(m) and inhibiting the amplification of ROS. Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  16. Intracellular energy depletion triggers programmed cell death during petal senescence in tulip.

    PubMed

    Azad, A K; Ishikawa, Takayuki; Ishikawa, Takahiro; Sawa, Y; Shibata, H

    2008-01-01

    Programmed cell death (PCD) in petals provides a model system to study the molecular aspects of organ senescence. In this study, the very early triggering signal for PCD during the senescence process from young green buds to 14-d-old petals of Tulipa gesneriana was determined. The opening and closing movement of petals of intact plants increased for the first 3 d and then gradually decreased. DNA degradation and cytochrome c (Cyt c) release were clearly observed in 6-d-old flowers. Oxidative stress or ethylene production can be excluded as the early signal for petal PCD. In contrast, ATP was dramatically depleted after the first day of flower opening. Sucrose supplementation to cut flowers maintained their ATP levels and the movement ability for a longer time than in those kept in water. The onset of DNA degradation, Cyt c release, and petal senescence was also delayed by sucrose supplementation to cut flowers. These results suggest that intracellular energy depletion, rather than oxidative stress or ethylene production, may be the very early signal to trigger PCD in tulip petals.

  17. Intracellular energy depletion triggers programmed cell death during petal senescence in tulip

    PubMed Central

    Azad, A. K.; Ishikawa, Takayuki; Ishikawa, Takahiro; Shibata, H.

    2008-01-01

    Programmed cell death (PCD) in petals provides a model system to study the molecular aspects of organ senescence. In this study, the very early triggering signal for PCD during the senescence process from young green buds to 14-d-old petals of Tulipa gesneriana was determined. The opening and closing movement of petals of intact plants increased for the first 3 d and then gradually decreased. DNA degradation and cytochrome c (Cyt c) release were clearly observed in 6-d-old flowers. Oxidative stress or ethylene production can be excluded as the early signal for petal PCD. In contrast, ATP was dramatically depleted after the first day of flower opening. Sucrose supplementation to cut flowers maintained their ATP levels and the movement ability for a longer time than in those kept in water. The onset of DNA degradation, Cyt c release, and petal senescence was also delayed by sucrose supplementation to cut flowers. These results suggest that intracellular energy depletion, rather than oxidative stress or ethylene production, may be the very early signal to trigger PCD in tulip petals. PMID:18515833

  18. Programmed death-1 controls T cell survival by regulating oxidative metabolism.

    PubMed

    Tkachev, Victor; Goodell, Stefanie; Opipari, Anthony W; Hao, Ling-Yang; Franchi, Luigi; Glick, Gary D; Ferrara, James L M; Byersdorfer, Craig A

    2015-06-15

    The coinhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly upregulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1(Hi)ROS(Hi) phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels, and PD-1-driven increases in ROS were dependent upon the oxidation of fatty acids, because treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by antioxidants. Furthermore, PD-1-driven changes in ROS were fundamental to establishing a cell's susceptibility to subsequent metabolic inhibition, because blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing ROS in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.

  19. Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response

    PubMed Central

    Choi, Hyo-Kyoung; Choi, Youngsok; Park, Eun Sung; Park, Soo-Yeon; Lee, Seung-Hyun; Seo, Jaesung; Jeong, Mi-Hyeon; Jeong, Jae-Wook; Jeong, Jae-Ho; Lee, Peter C. W.; Choi, Kyung-Chul; Yoon, Ho-Geun

    2015-01-01

    The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5WT in PDCD5−/− MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions. PMID:26077467

  20. Streptomyces natalensis programmed cell death and morphological differentiation are dependent on oxidative stress

    PubMed Central

    Beites, Tiago; Oliveira, Paulo; Rioseras, Beatriz; Pires, Sílvia D. S.; Oliveira, Rute; Tamagnini, Paula; Moradas-Ferreira, Pedro; Manteca, Ángel; Mendes, Marta V.

    2015-01-01

    Streptomyces are aerobic Gram-positive bacteria characterized by a complex life cycle that includes hyphae differentiation and spore formation. Morphological differentiation is triggered by stressful conditions and takes place in a pro-oxidant environment, which sets the basis for an involvement of the oxidative stress response in this cellular process. Characterization of the phenotypic traits of Streptomyces natalensis ΔkatA1 (mono-functional catalase) and ΔcatR (Fur-like repressor of katA1 expression) strains in solid medium revealed that both mutants had an impaired morphological development process. The sub-lethal oxidative stress caused by the absence of KatA1 resulted in the formation of a highly proliferative and undifferentiated vegetative mycelium, whereas de-repression of CatR regulon, from which KatA1 is the only known representative, resulted in the formation of scarce aerial mycelium. Both mutant strains had the transcription of genes associated with aerial mycelium formation and biosynthesis of the hyphae hydrophobic layer down-regulated. The first round of the programmed cell death (PCD) was inhibited in both strains which caused the prevalence of the transient primary mycelium (MI) over secondary mycelium (MII). Our data shows that the first round of PCD and morphological differentiation in S. natalensis is dependent on oxidative stress in the right amount at the right time. PMID:26256439

  1. Initiation of programmed cell death in the suspensor is predominantly regulated maternally in a tobacco hybrid.

    PubMed

    Luo, An; Zhao, Peng; Zhang, Li-Yao; Sun, Meng-Xiang

    2016-07-19

    Maternal gene products deposited in the egg regulate early embryogenesis before activation of the embryonic genome in animals. While in higher plants, it is believed that genes of parental origin contribute to early embryogenesis. However, little is known regarding the particular processes in which genes of parental origin are involved during early embryogenesis. Previously, we found that the initiation of programmed cell death (PCD) in the suspensor of the embryo is regulated by the cystatin, NtCYS. Here, we confirmed that both parental transcripts contribute to PCD, but the relative expression level of the maternal NtCYS allele was much higher than that of the paternal allele in early embryos of tobacco interspecific hybrids. The expression level of the maternal NtCYS allele was decreased markedly, which was necessary for the initiation of PCD, while the paternal allele didn't change. Interestingly, the pattern of PCD in the hybrid suspensor and the morphology of the hybrid suspensor were similar to those of the maternal parent. Our results suggest that NtCYS-mediated PCD initiation in the hybrid suspensor is likely controlled in a maternal dominant manner. This finding represents an example of the involvement of parental transcripts in a specific developmental event during early embryogenesis.

  2. Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis.

    PubMed

    Lauenborg, Britt; Kopp, Katharina; Krejsgaard, Thorbjørn; Eriksen, Karsten W; Geisler, Carsten; Dabelsteen, Sally; Gniadecki, Robert; Zhang, Qian; Wasik, Mariusz A; Woetmann, Anders; Odum, Niels

    2010-10-01

    The programmed cell death-10 (PDCD10; also known as cerebral cavernous malformation-3 or CCM3) gene encodes an evolutionarily conserved protein associated with cell apoptosis. Mutations in PDCD10 result in cerebral cavernous malformations, an important cause of cerebral hemorrhage. PDCD10 is associated with serine/threonine kinases and phosphatases and modulates the extracellular signal-regulated kinase pathway suggesting a role in the regulation of cellular growth. Here we provide evidence of a constitutive expression of PDCD10 in malignant T cells and cell lines from peripheral blood of cutaneous T-cell lymphoma (Sezary syndrome) patients. PDCD10 is associated with protein phosphatase-2A, a regulator of mitogenesis and apoptosis in malignant T cells. Inhibition of oncogenic signal pathways [Jak3, Notch1, and nuclear factor-κB (NF-κB)] partly inhibits the constitutive PDCD10 expression, whereas an activator of Jak3 and NF-κB, interleukin-2 (IL-2), enhances PDCD10 expression. Functional data show that PDCD10 depletion by small interfering RNA induces apoptosis and decreases proliferation of the sensitive cells. To our knowledge, these data provide the first functional link between PDCD10 and cancer.

  3. Ageratum enation virus Infection Induces Programmed Cell Death and Alters Metabolite Biosynthesis in Papaver somniferum

    PubMed Central

    Srivastava, Ashish; Agrawal, Lalit; Raj, Rashmi; Jaidi, Meraj; Raj, Shri K.; Gupta, Swati; Dixit, Ritu; Singh, Poonam C.; Tripathi, Tusha; Sidhu, Om P.; Singh, Brahma N.; Shukla, Sudhir; Chauhan, Puneet S.; Kumar, Susheel

    2017-01-01

    A previously unknown disease which causes severe vein thickening and inward leaf curl was observed in a number of opium poppy (Papaver somniferum L.) plants. The sequence analysis of full-length viral genome and associated betasatellite reveals the occurrence of Ageratum enation virus (AEV) and Ageratum leaf curl betasatellite (ALCB), respectively. Co-infiltration of cloned agroinfectious DNAs of AEV and ALCB induces the leaf curl and vein thickening symptoms as were observed naturally. Infectivity assay confirmed this complex as the cause of disease and also satisfied the Koch’s postulates. Comprehensive microscopic analysis of infiltrated plants reveals severe structural anomalies in leaf and stem tissues represented by unorganized cell architecture and vascular bundles. Moreover, the characteristic blebs and membranous vesicles formed due to the virus-induced disintegration of the plasma membrane and intracellular organelles were also present. An accelerated nuclear DNA fragmentation was observed by Comet assay and confirmed by TUNEL and Hoechst dye staining assays suggesting virus-induced programmed cell death. Virus-infection altered the biosynthesis of several important metabolites. The biosynthesis potential of morphine, thebaine, codeine, and papaverine alkaloids reduced significantly in infected plants except for noscapine whose biosynthesis was comparatively enhanced. The expression analysis of corresponding alkaloid pathway genes by real time-PCR corroborated well with the results of HPLC analysis for alkaloid perturbations. The changes in the metabolite and alkaloid contents affect the commercial value of the poppy plants. PMID:28729873

  4. Structure-function correlation of human programmed cell death 5 protein.

    PubMed

    Yao, Hongwei; Xu, Lanjun; Feng, Yingang; Liu, Dongsheng; Chen, Yingyu; Wang, Jinfeng

    2009-06-15

    Human programmed cell death 5 (PDCD5) is a translocatory protein playing an important role in the apoptotic process of cells. Although there are accumulated data about PDCD5 function, the correlation of the structure with the function of PDCD5 has not been investigated. Here, we report the studies of structure-function relationship of PDCD5 by multidimensional NMR methods and by FACScan flow cytometer and fluorescence microscope. The 3D structure of intact PDCD5 and the internal motions of PDCD5 have been determined. PDCD5 has a compact core structure of low flexibility with two mobile alpha-helices at N-terminal region and a flexible unstructured C-terminal region. The flow cytometry and internalization measurements of different PDCD5 fragments indicate that the charged residues are crucial for the ability of apoptosis-promoting and cell translocation of the protein. Combined analyses reveal a fact that the regions that seem to be most involved in the function also are more flexible in PDCD5.

  5. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate.

    PubMed

    Cuvillier, O; Pirianov, G; Kleuser, B; Vanek, P G; Coso, O A; Gutkind, S; Spiegel, S

    1996-06-27

    Ceramide is an important regulatory participant of programmed cell death (apoptosis) induced by tumour-necrosis factor (TNF)-alpha and Fas ligand, members of the TNF superfamily. Conversely, sphingosine and sphingosine-1-phosphate, which are metabolites of ceramide, induce mitogenesis and have been implicated as second messengers in cellular proliferation induced by platelet-derived growth factor and serum. Here we report that sphingosine-1-phosphate prevents the appearance of the key features of apoptosis, namely intranucleosomal DNA fragmentation and morphological changes, which result from increased concentrations of ceramide. Furthermore, inhibition of ceramide-mediated apoptosis by activation of protein kinase C results from stimulation of sphingosine kinase and the concomitant increase in intracellular sphingosine-1-phosphate. Finally sphingosine-1-phosphate not only stimulates the extracellular signal-regulated kinase (ERK) pathway, it counteracts the ceramide-induced activation of stress-activated protein kinase (SAPK/JNK). Thus, the balance between the intracellular levels of ceramide and sphingosine-1-phosphate and their regulatory effects on different family members of mitogen-activated protein kinases determines the fate of the cell.

  6. Localization of Barley yellow dwarf virus Movement Protein Modulating Programmed Cell Death in Nicotiana benthamiana.

    PubMed

    Ju, Jiwon; Kim, Kangmin; Lee, Kui-Jae; Lee, Wang Hu; Ju, Ho-Jong

    2017-02-01

    Barley yellow dwarf virus (BYDV) belongs to Luteovirus and is limited only at phloem related tissues. An open reading frame (ORF) 4 of BYDV codes for the movement protein (MP) of BYDV gating plasmodesmata (PD) to facilitate virus movement. Like other Luteoviruses, ORF 4 of BYDV is embedded in the ORF3 but expressed from the different reading frame in leaky scanning manner. Although MP is a very important protein for systemic infection of BYDV, there was a little information. In this study, MP was characterized in terms of subcellular localization and programmed cell death (PCD). Gene of MP or its mutant (ΔMP) was expressed by Agroinfiltration method. MP was clearly localized at the nucleus and the PD, but ΔMP which was deleted distal N-terminus of MP showed no localization to PD exhibited the different target with original MP. In addition to PD localization, MP appeared associated with small granules in cytoplasm whereas ΔMP did not. MP associated with PD and small granules induced PCD, but ΔMP showed no association with PD and small granules did not exhibit PCD. Based on this study, the distal N-terminal region within MP is seemingly responsible for the localization of PD and the induction small granules and PCD induction. These results suggest that subcellular localization of BYDV MP may modulate the PCD in Nicotiana benthamiana.

  7. Reduction in natural death and renal failure from a systematic screening and treatment program in an Australian Aboriginal community.

    PubMed

    Hoy, Wendy E; Wang, Zhiqiang; Baker, Philip R A; Kelly, Angela M

    2003-02-01

    Australian Aborigines in remote areas are experiencing an epidemic of renal and cardiovascular disease. In November 1995, we introduced a renal and cardiovascular treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated end-stage renal disease (ESRD) of 2760 per million. Our previous study described an estimated 50% reduction in renal failure and all-cause natural deaths in the treatment group through December 31, 1998. We now describe a reduction in these events through mid 2000. People eligible for treatment were those with confirmed hypertension, diabetics with microalbuminuria or overt albuminuria, and people with overt albuminuria, regardless of blood pressure and diabetes. Treatment centered around the use of perindopril (Coversyl, Servier), with additional agents as needed to reach defined blood pressure goals, attempts at control of glucose and lipid levels, and health education. Two hundred and sixty-seven people, or 30% of the adult population, have been enrolled, with mean follow up of 3.39 years. Rates of terminal endpoints were compared on an intention-to-treat basis with those of 327 historical controls matched for baseline disease severity, who were followed for a mean of 3.18 years in the pre-treatment program era, against a background of no treatment or inconsistent changing treatment. Terminal events occurred in 38 controls and 23 people in the treatment group. The estimated rate of natural deaths in the treatment group was 50% that of the controls, (P=0.012); the rate of renal deaths was 47% (P=0.038) and the rate of non-renal deaths was 54% that of controls (P=0.085). Survival benefit in the treatment group was observed at all levels of overt albuminuria, in non-diabetics and diabetics, in normotensive as well as hypertensive people, and in people who had been taking angiotensin converting enzyme-inhibitors (ACEi) in the pre-program era, as well as those who had

  8. AtPDCD5 Plays a Role in Programmed Cell Death after UV-B Exposure in Arabidopsis1[OPEN

    PubMed Central

    Falcone Ferreyra, María Lorena; D’Andrea, Lucio; AbdElgawad, Hamada

    2016-01-01

    DNA damage responses have evolved to sense and react to DNA damage; the induction of DNA repair mechanisms can lead to genomic restoration or, if the damaged DNA cannot be adequately repaired, to the execution of a cell death program. In this work, we investigated the role of an Arabidopsis (Arabidopsis thaliana) protein, AtPDCD5, which is highly similar to the human PDCD5 protein; it is induced by ultraviolet (UV)-B radiation and participates in programmed cell death in the UV-B DNA damage response. Transgenic plants expressing AtPDCD5 fused to GREEN FLUORESCENT PROTEIN indicate that AtPDCD5 is localized both in the nucleus and the cytosol. By use of pdcd5 mutants, we here demonstrate that these plants have an altered antioxidant metabolism and accumulate higher levels of DNA damage after UV-B exposure, similar to levels in ham1ham2 RNA interference transgenic lines with decreased expression of acetyltransferases from the MYST family. By coimmunoprecipitation and pull-down assays, we provide evidence that AtPDCD5 interacts with HAM proteins, suggesting that both proteins participate in the same pathway of DNA damage responses. Plants overexpressing AtPDCD5 show less DNA damage but more cell death in root tips upon UV-B exposure. Finally, we here show that AtPDCD5 also participates in age-induced programmed cell death. Together, the data presented here demonstrate that AtPDCD5 plays an important role during DNA damage responses induced by UV-B radiation in Arabidopsis and also participates in programmed cell death programs. PMID:26884483

  9. AtPDCD5 Plays a Role in Programmed Cell Death after UV-B Exposure in Arabidopsis.

    PubMed

    Falcone Ferreyra, María Lorena; Casadevall, Romina; D'Andrea, Lucio; AbdElgawad, Hamada; Beemster, Gerrit T S; Casati, Paula

    2016-04-01

    DNA damage responses have evolved to sense and react to DNA damage; the induction of DNA repair mechanisms can lead to genomic restoration or, if the damaged DNA cannot be adequately repaired, to the execution of a cell death program. In this work, we investigated the role of an Arabidopsis (Arabidopsis thaliana) protein, AtPDCD5, which is highly similar to the human PDCD5 protein; it is induced by ultraviolet (UV)-B radiation and participates in programmed cell death in the UV-B DNA damage response. Transgenic plants expressing AtPDCD5 fused to GREEN FLUORESCENT PROTEIN indicate that AtPDCD5 is localized both in the nucleus and the cytosol. By use of pdcd5 mutants, we here demonstrate that these plants have an altered antioxidant metabolism and accumulate higher levels of DNA damage after UV-B exposure, similar to levels in ham1ham2 RNA interference transgenic lines with decreased expression of acetyltransferases from the MYST family. By coimmunoprecipitation and pull-down assays, we provide evidence that AtPDCD5 interacts with HAM proteins, suggesting that both proteins participate in the same pathway of DNA damage responses. Plants overexpressing AtPDCD5 show less DNA damage but more cell death in root tips upon UV-B exposure. Finally, we here show that AtPDCD5 also participates in age-induced programmed cell death. Together, the data presented here demonstrate that AtPDCD5 plays an important role during DNA damage responses induced by UV-B radiation in Arabidopsis and also participates in programmed cell death programs. © 2016 American Society of Plant Biologists. All Rights Reserved.

  10. Ethylene-Mediated Programmed Cell Death during Maize Endosperm Development of Wild-Type and shrunken2 Genotypes.

    PubMed Central

    Young, T. E.; Gallie, D. R.; DeMason, D. A.

    1997-01-01

    We characterized the progression of programmed cell death during maize (Zea mays L.) endosperm development of starchy (Su; wild-type) and shrunken2 (sh2) genotypes and tested the involve ment of ethylene in mediating this process. Histological and viability staining demonstrated that endosperm cell death was initiated earlier and progressed more rapidly in sh2 endosperm compared with Su endosperm. Internucleosomal DNA fragmentation accompanied endosperm cell death and occurred more extensively in sh2 endosperm. 1-Aminocyclopropane-1-carboxylic acid levels peaked approximately 16 d after pollination (dap) in Su endosperm and gradually decreased during subsequent development, whereas two large 1-aminocyclopropane-1-carboxylic acid peaks were observed in sh2 endosperm, the first between 16 and 20 dap and the second at 36 dap. Ethylene levels were elevated in sh2 kernels compared with Su kernels, with an initial peak 20 dap approximately 3-fold higher than in Su kernels and a second peak 36 dap approximately 5-fold higher than that in Su kernels. Ethylene treatment of Su kernels resulted in earlier and more extensive endosperm cell death and DNA fragmentation. Aminoethoxyvinylglycine treatment of sh2 kernels reduced the extent of DNA fragmentation. We conclude that ethylene is involved in triggering programmed cell death in developing maize endosperm and is responsible for the aberrant phenotype of sh2 kernels. PMID:12223841

  11. Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death.

    PubMed

    Tian, Wei; Deng, Yongchuan; Li, Ling; He, Haifei; Sun, Jie; Xu, Dong

    2013-02-01

    Multidrug resistance (MDR) is a major challenge in cancer therapy. Apoptosis tolerance is one of the key mechanisms of MDR. Honokiol, a small-molecule pharmacologically active component, exhibits competent cytotoxicity in a variety of human cancer cells through apoptosis and other forms of programmed cell death (such as programmed necrosis). Although much work has been done on its antitumor effects, little attention has been paid on systemic evaluation of efficacy of honokiol combined with other chemotherapeutic agents, especially in drug‑resistant cell lines. Here, we systematically and quantitatively assess its combinational effect with different chemotherapeutic agents using the combination index (CI) equation. We found that honokiol synergized with chemotherapeutic agents both in sensitive and resistant, solid and non-solid (MCF-7, HL-60, MCF-7/ADR and HL-60/ADR) cell lines. Honokiol (40 µg/ml) induced necrotic cell death in MCF-7/ADR cells with characterized morphological and biochemical features. Co-incubation with honokiol and etoposide (VP-16) activated a complex death modality, which was composed of necrotic cell death and apoptosis. This dual-death pathway was shut down when pretreated with pan-caspase inhibitor (z-VAD-fmk) and cyclophilin D inhibitor (cyclosporin A). Western blot analysis results proved that honokiol also enhanced VP-16-induced apoptosis potentially via blocking nuclear factor‑κB (NF-κB) activation. Our data for the first time quantitatively demonstrate that honokiol synergizes frequently-used chemotherapeutic agents via enhanced apoptosis and additional programmed necrotic death. These findings indicate a promising way to circumvent MDR and apoptosis tolerance.

  12. Do mitochondria play a role in remodelling lace plant leaves during programmed cell death?

    PubMed

    Lord, Christina E N; Wertman, Jaime N; Lane, Stephanie; Gunawardena, Arunika H L A N

    2011-06-06

    Programmed cell death (PCD) is the regulated death of cells within an organism. The lace plant (Aponogeton madagascariensis) produces perforations in its leaves through PCD. The leaves of the plant consist of a latticework of longitudinal and transverse veins enclosing areoles. PCD occurs in the cells at the center of these areoles and progresses outwards, stopping approximately five cells from the vasculature. The role of mitochondria during PCD has been recognized in animals; however, it has been less studied during PCD in plants. The following paper elucidates the role of mitochondrial dynamics during developmentally regulated PCD in vivo in A. madagascariensis. A single areole within a window stage leaf (PCD is occurring) was divided into three areas based on the progression of PCD; cells that will not undergo PCD (NPCD), cells in early stages of PCD (EPCD), and cells in late stages of PCD (LPCD). Window stage leaves were stained with the mitochondrial dye MitoTracker Red CMXRos and examined. Mitochondrial dynamics were delineated into four categories (M1-M4) based on characteristics including distribution, motility, and membrane potential (ΔΨm). A TUNEL assay showed fragmented nDNA in a gradient over these mitochondrial stages. Chloroplasts and transvacuolar strands were also examined using live cell imaging. The possible importance of mitochondrial permeability transition pore (PTP) formation during PCD was indirectly examined via in vivo cyclosporine A (CsA) treatment. This treatment resulted in lace plant leaves with a significantly lower number of perforations compared to controls, and that displayed mitochondrial dynamics similar to that of non-PCD cells. Results depicted mitochondrial dynamics in vivo as PCD progresses within the lace plant, and highlight the correlation of this organelle with other organelles during developmental PCD. To the best of our knowledge, this is the first report of mitochondria and chloroplasts moving on transvacuolar

  13. Do mitochondria play a role in remodelling lace plant leaves during programmed cell death?

    PubMed Central

    2011-01-01

    Background Programmed cell death (PCD) is the regulated death of cells within an organism. The lace plant (Aponogeton madagascariensis) produces perforations in its leaves through PCD. The leaves of the plant consist of a latticework of longitudinal and transverse veins enclosing areoles. PCD occurs in the cells at the center of these areoles and progresses outwards, stopping approximately five cells from the vasculature. The role of mitochondria during PCD has been recognized in animals; however, it has been less studied during PCD in plants. Results The following paper elucidates the role of mitochondrial dynamics during developmentally regulated PCD in vivo in A. madagascariensis. A single areole within a window stage leaf (PCD is occurring) was divided into three areas based on the progression of PCD; cells that will not undergo PCD (NPCD), cells in early stages of PCD (EPCD), and cells in late stages of PCD (LPCD). Window stage leaves were stained with the mitochondrial dye MitoTracker Red CMXRos and examined. Mitochondrial dynamics were delineated into four categories (M1-M4) based on characteristics including distribution, motility, and membrane potential (ΔΨm). A TUNEL assay showed fragmented nDNA in a gradient over these mitochondrial stages. Chloroplasts and transvacuolar strands were also examined using live cell imaging. The possible importance of mitochondrial permeability transition pore (PTP) formation during PCD was indirectly examined via in vivo cyclosporine A (CsA) treatment. This treatment resulted in lace plant leaves with a significantly lower number of perforations compared to controls, and that displayed mitochondrial dynamics similar to that of non-PCD cells. Conclusions Results depicted mitochondrial dynamics in vivo as PCD progresses within the lace plant, and highlight the correlation of this organelle with other organelles during developmental PCD. To the best of our knowledge, this is the first report of mitochondria and chloroplasts

  14. Heart rate variability in neonates of type 1 diabetic pregnancy.

    PubMed

    Russell, Noirin E; Higgins, Mary F; Kinsley, Brendan F; Foley, Michael E; McAuliffe, Fionnuala M

    2016-01-01

    Cardiomyopathy is a common finding in offspring of pre-gestational type 1 diabetic pregnancy. Echocardiographic and biochemical evidence of fetal cardiac dysfunction have also been reported. Studies suggest that offspring of diabetic mothers (ODM) undergo a fetal programming effect due to the hyperglycaemic intrauterine milieu which increases their risk of cardiovascular morbidity in adult life. Decreased neonatal heart rate variability (HRV) has been described in association with in-utero growth restriction, prematurity, sudden infant death syndrome and congenital heart disease. The effect of in-utero exposure to hyperglycaemia in diabetic pregnancy on neonatal HRV is unknown. Our aim was to determine if neonatal HRV differs between normal and diabetic pregnancy. This was a prospective observational study of 38 patients with pregestational type 1 diabetes and 26 controls. HRV assessment was performed using Powerlab (ADI Instruments Ltd). Heart rate variability assessment and cord blood sampling for pH and glucose were performed for all neonates. Maternal glycaemic control was assessed via measurement of glycosylated haemoglobin in each trimester in the diabetic cohort. Neonates of diabetic mothers had evidence of altered heart rate variability, with increased low frequency to high frequency ratio (LF: HF), suggestive of a shift towards sympathetic predominance (p<0.05). This altered HRV was significantly related to fetal acidaemia, cord blood glucose values and maternal glycaemic control during pregnancy (p<0.05). Neonates of pregestational diabetic pregnancy have altered HRV which is related to maternal hyperglycaemia, fetal acidaemia and fetal glycaemia. Exposure of the developing heart to fluctuations in maternal glycaemia with subsequent alterations in HRV may explain why infants of diabetic mothers are at greater risk of cardiovascular disease in later life. Copyright © 2015. Published by Elsevier Ireland Ltd.

  15. A critical role for ethylene in hydrogen peroxide release during programmed cell death in tomato suspension cells.

    PubMed

    de, JongAnkeJ; Yakimova, Elena T; Kapchina, Veneta M; Woltering, Ernst J

    2002-02-01

    Camptothecin, a topo isomerase-I inhibitor used in cancer therapy, induces apoptosis in animal cells. In tomato (Lycopersicon esculentum Mill.) suspension cells, camptothecin induces cell death that is accompanied by the characteristic nuclear morphological changes such as chromatin condensation and nuclear and DNA fragmentation that are commonly associated with apoptosis in animal systems. These effects of camptothecin can effectively be blocked by inhibitors of animal caspases, indicating that, in tomato suspension cells, camptothecin induces a form of programmed cell death (PCD) with similarities to animal apoptosis (A.J. De Jong et al. (2000) Planta 211:656-662). Camptothecin induced cell death was employed to study processes involved in plant PCD. Camptothecin induced a transient increase in H2O2 production starting within 2 h of application. Both camptothecin-induced cell death and the release of H2O2 were effectively blocked by application of the calcium-channel blocker lanthanum chloride, the caspase-specific inhibitor Z-Asp-CH2-DCB, or the NADPH oxidase inhibitor diphenyl iodonium, indicating that camptothecin exerts its effect on cell death through a calcium- and caspase-dependent stimulation of NADPH oxidase activity. In addition, we show that ethylene is an essential factor in camptothecin-induced PCD. Inhibition of either ethylene synthesis or ethylene perception by L-alpha-(2-aminoethoxyvinyl)glycine or silver thiosulphate, respectively, blocked camptothecin-induced H2O2 production and PCD. Although, in itself, insufficient to trigger H2O2 production and cell death, exogenous ethylene greatly stimulated camptothecin-induced H2O2 production and cell death. These results show that ethylene is a potentiator of the camptothecin-induced oxidative burst and subsequent PCD in tomato cells. The possible mechanisms by which ethylene stimulates cell death are discussed.

  16. Type 1 diabetes associated autoimmunity.

    PubMed

    Kahaly, George J; Hansen, Martin P

    2016-07-01

    Diabetes mellitus is increasing in prevalence worldwide. The economic costs are considerable given the cardiovascular complications and co-morbidities that it may entail. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. Genetic background may affect the risk for autoimmune disease and patients with T1D exhibit an increased risk of other autoimmune disorders such as autoimmune thyroid disease, Addison's disease, autoimmune gastritis, coeliac disease and vitiligo. Approximately 20%-25% of patients with T1D have thyroid antibodies, and up to 50% of such patients progress to clinical autoimmune thyroid disease. Approximately 0.5% of diabetic patients have concomitant Addison's disease and 4% have coeliac disease. The prevalence of autoimmune gastritis and pernicious anemia is 5% to 10% and 2.6% to 4%, respectively. Early detection of antibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown disease. Patients and family members should be educated to be able to recognize signs and symptoms of underlying disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Immunogenetics of type 1 diabetes.

    PubMed

    Kim, Mimi S; Polychronakos, Constantin

    2005-01-01

    The T-cell mediated autoimmune process that destroys pancreatic beta cells in type 1 diabetes (T1D) is a complex phenotype influenced by multiple genetic and environmental factors. Human leukocyte antigen (HLA) accounts for about half of the genetic susceptibility, through a large variety of protective and predisposing haplotypes. Other important loci associated with T1D, with much smaller effects than HLA, include the insulin variable number of tandem repeats, PTPN22, and CTLA-4. Detecting the association and confirming it beyond doubt is only the first step. Identifying the functional variant from among a block of polymorphisms in tight linkage disequilibrium and determining its biological consequences can be an even more challenging task. It is hoped that the identification of additional loci and functional analysis of known ones, no matter how small each individual effect is, will provide: (1) pathophysiological insights necessary for the development of preventive interventions; (2) risk prediction to identify individuals that can benefit from them, and (3) potentially, identification of distinct subgenotypes, with different immune dysregulation pathways leading to the common disease phenotype that may respond to different preventive interventions. (c) 2005 S. Karger AG, Basel.

  18. Role of a Transcriptional Regulator in Programmed Cell Death and Plant Development

    SciTech Connect

    Julie M. Stone

    2008-09-13

    The long-term goal of this research is to understand the role(s) and molecular mechanisms of programmed cell death (PCD) in the controlling plant growth, development and responses to biotic and abiotic stress. We developed a genetic selection scheme to identify A. thaliana FB1-resistant (fbr) mutants as a way to find genes involved in PCD (Stone et al., 2000; Stone et al., 2005; Khan and Stone, 2008). The disrupted gene in fbr6 (AtSPL14) responsible for the FB1-insensitivity and plant architecture phenotypes encodes a plant-specific SBP DNA-binding domain transcriptional regulator (Stone et al., 2005; Liang et al., 2008). This research plan is designed to fill gaps in the knowledge about the role of SPL14 in plant growth and development. The work is being guided by three objectives aimed at determining the pathways in which SPL14 functions to modulate PCD and/or plant development: (1) determine how SPL14 functions in plant development, (2) identify target genes that are directly regulated by SPL14, and (3) identify SPL14 modifications and interacting proteins. We made significant progress during the funding period. Briefly, some major accomplishments are highlighted below: (1) To identify potential AtSPL14 target genes, we identified a consensus DNA binding site for the AtSPL14 SBP DNA-binding domain using systematic evolution of ligands by exponential selection (SELEX) and site-directed mutagenesis (Liang et al., 2008). This consensus binding site was used to analyze Affymetrix microarray gene expression data obtained from wild-type and fbr6 mutant plants to find possible AtSPL14-regulated genes. These candidate AtSPL14-regulated genes are providing new information on the molecular mechanisms linking plant PCD and plant development through modulation of the 26S proteasome. (2) Transgenic plants expressing epitope-tagged versions of AtSPL14 are being used to confirm the AtSPL14 targets (by ChIP-PCR) and further dissect the molecular interactions (Nazarenus, Liang

  19. Ceramide synthase-dependent ceramide generation and programmed cell death: involvement of salvage pathway in regulating postmitochondrial events.

    PubMed

    Mullen, Thomas D; Jenkins, Russell W; Clarke, Christopher J; Bielawski, Jacek; Hannun, Yusuf A; Obeid, Lina M

    2011-05-06

    The sphingolipid ceramide has been widely implicated in the regulation of programmed cell death or apoptosis. The accumulation of ceramide has been demonstrated in a wide variety of experimental models of apoptosis and in response to a myriad of stimuli and cellular stresses. However, the detailed mechanisms of its generation and regulatory role during apoptosis are poorly understood. We sought to determine the regulation and roles of ceramide production in a model of ultraviolet light-C (UV-C)-induced programmed cell death. We found that UV-C irradiation induces the accumulation of multiple sphingolipid species including ceramide, dihydroceramide, sphingomyelin, and hexosylceramide. Late ceramide generation was also found to be regulated by Bcl-xL, Bak, and caspases. Surprisingly, inhibition of de novo synthesis using myriocin or fumonisin B1 resulted in decreased overall cellular ceramide levels basally and in response to UV-C, but only fumonisin B1 inhibited cell death, suggesting the presence of a ceramide synthase (CerS)-dependent, sphingosine-derived pool of ceramide in regulating programmed cell death. We found that this pool did not regulate the mitochondrial pathway, but it did partially regulate activation of caspase-7 and, more importantly, was necessary for late plasma membrane permeabilization. Attempting to identify the CerS responsible for this effect, we found that combined knockdown of CerS5 and CerS6 was able to decrease long-chain ceramide accumulation and plasma membrane permeabilization. These data identify a novel role for CerS and the sphingosine salvage pathway in regulating membrane permeability in the execution phase of programmed cell death.

  20. Bcl-2 proteins and autophagy regulate mitochondrial dynamics during programmed cell death in the Drosophila ovary

    PubMed Central

    Tanner, Elizabeth A.; Blute, Todd A.; Brachmann, Carrie Baker; McCall, Kimberly

    2011-01-01

    The Bcl-2 family has been shown to regulate mitochondrial dynamics during cell death in mammals and C. elegans, but evidence for this in Drosophila has been elusive. Here, we investigate the regulation of mitochondrial dynamics during germline cell death in the Drosophila melanogaster ovary. We find that mitochondria undergo a series of events during the progression of cell death, with remodeling, cluster formation and uptake of clusters by somatic follicle cells. These mitochondrial dynamics are dependent on caspases, the Bcl-2 family, the mitochondrial fission and fusion machinery, and the autophagy machinery. Furthermore, Bcl-2 family mutants show a striking defect in cell death in the ovary. These data indicate that a mitochondrial pathway is a major mechanism for activation of cell death in Drosophila oogenesis. PMID:21177345

  1. Programmed neuronal cell death induced by HIV-1 tat and methamphetamine.

    PubMed

    Qi, Li; Gang, Lu; Hang, Kwong Wing; Ling, Choi Heung; Xiaofeng, Zeng; Zhen, Li; Wai, Yew David; Sang, Poon Wai

    2011-12-01

    Apoptosis and autophagy are the two major types of programmed cell death (PCD) in neurons. Homeostatic autophagy often precedes apoptosis, and when apoptosis is blocked, the failure to keep homeostasis will lead to necrosis instead. It has been reported that human immunodeficiency virus (HIV) infected methamphetamine (Meth) abusers represent greater neuropathological abnormalities than Meth abusers or HIV-positive non-Meth users. Recent publications suggest that Tat and Meth when administered together result in greater neuronal damage than when administered separately. However, the cellular events of the combined Tat-Meth effect have not yet been fully characterized. Therefore, we investigated the effects of Tat and/or Meth on apoptosis and autophagy to elucidate whether PCD was involved in Tat and/or Meth-induced neuronal damage. Annexin-V-FITC/PI staining assay was used to detect cellular apoptosis using a neuroblastoma cell line SH-SY5Y. Cellular ultrastructural changes were observed under transmission electron microscopy (TEM). Flow-cytometric data showed apoptosis following Meth treatment, and more extensive apoptosis with Tat + Meth treatment. The most important finding was that the autophagosome and/or multilamellar bodies (MLBs) were most pronounced with Tat + Meth treatment, were less so with Meth treatment, and infrequent with Tat treatment. This suggests the involvement of autophagy and apoptosis in Tat with Meth-elicited cell damage. However, the relation between apoptosis and autophagy remains unknown in this experiment. Further research is needed to analyze the relation among related molecules. A thorough understanding of this multifaceted relationship will be critical for the assessment of therapeutic modalities for patients with HIV with drug abuse. Copyright © 2011 Wiley Periodicals, Inc.

  2. Photoacoustic spectral analysis to sense programmed erythrocyte cell death (eryptosis) for monitoring cancer response to treatment

    NASA Astrophysics Data System (ADS)

    Fadhel, Muhannad N.; Kibria, Fayruz; Kolios, Michael C.

    2016-03-01

    Many types of cancer therapies target the tumor microenvironment, causing biochemical and morphological changes in tissues. In therapies using ultrasound activated microbubbles, vascular collapse is typically reported. Red blood cells (RBCs) that leak out of the vasculature become exposed to the ceramide that is released from damaged endothelial cells. Ceramide can induce programmed cell death in RBCs (eryptosis), and is characterized by cell shrinkage, membrane blebbing and scrambling. Since the effect of eryptotic cells on generated photoacoustics (PA) signals has not been reported, we investigated the potential PA may have for cancer treatment monitoring by using PA spectral analysis to sense eryptosis. To induce eryptosis, C2-ceramide was added to RBC suspensions and that were incubated for 24 hours at 37°C. A control and ceramide-induced sample was imaged in a vessel phantom using a high frequency PA system (VevoLAZR, 10 - 45 MHz bandwidth) irradiated with multiple wavelengths ranging from 680 to 900 nm. PA spectral parameters were measured and linked to changes in RBCs as it underwent eryptosis. These samples were examined using optical microscopy, a blood gas analyzer and an integrating sphere setup to measure optical properties (wavelengths 600 - 900 nm). The results of the experiment demonstrate how PA spectral analysis can be used to identify eryptosis at a depth of more than 1 cm into the phantom using ultrasound derived the y-intercept and mid bandfit (MBF) parameters at optical wavelengths of 800 - 900 nm. These parameters were correlated to the morphological and biochemical changes that eryptotic RBCs display. The results establish the potential of PA in cancer treatment monitoring through sensing treatment induced eryptosis.

  3. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

    PubMed Central

    O’Connor, Roddy S.; Thangavelu, Govindarajan; Lovitch, Scott B.; Dandamudi, Durga Bhavani; Vincent, Benjamin G.; Tkachev, Victor; Pawlicki, Jan M.; Furlan, Scott N.; Kean, Leslie S.; Aoyama, Kazutoshi; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Foncea, Rocio; Ranganathan, Parvathi; Devine, Steven M.; Burrill, Joel S.; Guo, Lili; Sacristan, Catarina; Snyder, Nathaniel W.; Blair, Ian A.; Milone, Michael C.; Dustin, Michael L.; Riley, James L.; Bernlohr, David A.; Murphy, William J.; Fife, Brian T.; Munn, David H.; Miller, Jeffrey S.; Serody, Jonathan S.; Freeman, Gordon J.; Sharpe, Arlene H.; Turka, Laurence A.

    2016-01-01

    Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD. PMID:27294527

  4. Cancer-secreted AGR2 induces programmed cell death in normal cells

    PubMed Central

    Vitello, Elizabeth A.; Quek, Sue-Ing; Kincaid, Heather; Fuchs, Thomas; Crichton, Daniel J.; Troisch, Pamela; Liu, Alvin Y.

    2016-01-01

    Anterior Gradient 2 (AGR2) is a protein expressed in many solid tumor types including prostate, pancreatic, breast and lung. AGR2 functions as a protein disulfide isomerase in the endoplasmic reticulum. However, AGR2 is secreted by cancer cells that overexpress this molecule. Secretion of AGR2 was also found in salamander limb regeneration. Due to its ubiquity, tumor secretion of AGR2 must serve an important role in cancer, yet its molecular function is largely unknown. This study examined the effect of cancer-secreted AGR2 on normal cells. Prostate stromal cells were cultured, and tissue digestion media containing AGR2 prepared from prostate primary cancer 10-076 CP and adenocarcinoma LuCaP 70CR xenograft were added. The control were tissue digestion media containing no AGR2 prepared from benign prostate 10-076 NP and small cell carcinoma LuCaP 145.1 xenograft. In the presence of tumor-secreted AGR2, the stromal cells were found to undergo programmed cell death (PCD) characterized by formation of cellular blebs, cell shrinkage, and DNA fragmentation as seen when the stromal cells were UV irradiated or treated by a pro-apoptotic drug. PCD could be prevented with the addition of the monoclonal AGR2-neutralizing antibody P3A5. DNA microarray analysis of LuCaP 70CR media-treated vs. LuCaP 145.1 media-treated cells showed downregulation of the gene SAT1 as a major change in cells exposed to AGR2. RT-PCR analysis confirmed the array result. SAT1 encodes spermidine/spermine N1-acetyltransferase, which maintains intracellular polyamine levels. Abnormal polyamine metabolism as a result of altered SAT1 activity has an adverse effect on cells through the induction of PCD. PMID:27283903

  5. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.

    PubMed

    Saha, Asim; O'Connor, Roddy S; Thangavelu, Govindarajan; Lovitch, Scott B; Dandamudi, Durga Bhavani; Wilson, Caleph B; Vincent, Benjamin G; Tkachev, Victor; Pawlicki, Jan M; Furlan, Scott N; Kean, Leslie S; Aoyama, Kazutoshi; Taylor, Patricia A; Panoskaltsis-Mortari, Angela; Foncea, Rocio; Ranganathan, Parvathi; Devine, Steven M; Burrill, Joel S; Guo, Lili; Sacristan, Catarina; Snyder, Nathaniel W; Blair, Ian A; Milone, Michael C; Dustin, Michael L; Riley, James L; Bernlohr, David A; Murphy, William J; Fife, Brian T; Munn, David H; Miller, Jeffrey S; Serody, Jonathan S; Freeman, Gordon J; Sharpe, Arlene H; Turka, Laurence A; Blazar, Bruce R

    2016-07-01

    Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.

  6. Programmed cell death promotes male sterility in the functional dioecious Opuntia stenopetala (Cactaceae)

    PubMed Central

    Flores-Rentería, Lluvia; Orozco-Arroyo, Gregorio; Cruz-García, Felipe; García-Campusano, Florencia; Alfaro, Isabel; Vázquez-Santana, Sonia

    2013-01-01

    Background and Aims The sexual separation in dioecious species has interested biologists for decades; however, the cellular mechanism leading to unisexuality has been poorly understood. In this study, the cellular changes that lead to male sterility in the functionally dioecious cactus, Opuntia stenopetala, are described. Methods The spatial and temporal patterns of programmed cell death (PCD) were determined in the anthers of male and female flowers using scanning electron microscopy analysis and histological observations, focusing attention on the transition from bisexual to unisexual development. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assays were used as an indicator of DNA fragmentation to corroborate PCD. Key results PCD was detected in anthers of both female and male flowers, but their patterns differed in time and space. Functionally male individuals developed viable pollen, and normal development involved PCD on each layer of the anther wall, which occurred progressively from the inner (tapetum) to the outer layer (epidermis). Conversely, functional female individuals aborted anthers by premature and displaced PCD. In anthers of female flowers, the first signs of PCD, such as a nucleus with irregular shape, fragmented and condensed chromatin, high vacuolization and condensed cytoplasm, occurred at the microspore mother cell stage. Later these features were observed simultaneously in all anther wall layers, connective tissue and filament. Neither pollen formation nor anther dehiscence was detected in female flowers of O. stenopetala due to total anther disruption. Conclusions Temporal and spatial changes in the patterns of PCD are responsible for male sterility of female flowers in O. stenopetala. Male fertility requires the co-ordination of different events, which, when altered, can lead to male sterility and to functionally unisexual individuals. PCD could be a widespread mechanism in the determination of

  7. Programmed cell death promotes male sterility in the functional dioecious Opuntia stenopetala (Cactaceae).

    PubMed

    Flores-Rentería, Lluvia; Orozco-Arroyo, Gregorio; Cruz-García, Felipe; García-Campusano, Florencia; Alfaro, Isabel; Vázquez-Santana, Sonia

    2013-09-01

    The sexual separation in dioecious species has interested biologists for decades; however, the cellular mechanism leading to unisexuality has been poorly understood. In this study, the cellular changes that lead to male sterility in the functionally dioecious cactus, Opuntia stenopetala, are described. The spatial and temporal patterns of programmed cell death (PCD) were determined in the anthers of male and female flowers using scanning electron microscopy analysis and histological observations, focusing attention on the transition from bisexual to unisexual development. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assays were used as an indicator of DNA fragmentation to corroborate PCD. PCD was detected in anthers of both female and male flowers, but their patterns differed in time and space. Functionally male individuals developed viable pollen, and normal development involved PCD on each layer of the anther wall, which occurred progressively from the inner (tapetum) to the outer layer (epidermis). Conversely, functional female individuals aborted anthers by premature and displaced PCD. In anthers of female flowers, the first signs of PCD, such as a nucleus with irregular shape, fragmented and condensed chromatin, high vacuolization and condensed cytoplasm, occurred at the microspore mother cell stage. Later these features were observed simultaneously in all anther wall layers, connective tissue and filament. Neither pollen formation nor anther dehiscence was detected in female flowers of O. stenopetala due to total anther disruption. Temporal and spatial changes in the patterns of PCD are responsible for male sterility of female flowers in O. stenopetala. Male fertility requires the co-ordination of different events, which, when altered, can lead to male sterility and to functionally unisexual individuals. PCD could be a widespread mechanism in the determination of functionally dioecious species.

  8. Reactive Carbonyl Species Activate Caspase-3-Like Protease to Initiate Programmed Cell Death in Plants.

    PubMed

    Biswas, Md Sanaullah; Mano, Jun'ichi

    2016-07-01

    Reactive oxygen species (ROS)-triggered programmed cell death (PCD) is a typical plant response to biotic and abiotic stressors. We have recently shown that lipid peroxide-derived reactive carbonyl species (RCS), downstream products of ROS, mediate oxidative signal to initiate PCD. Here we investigated the mechanism by which RCS initiate PCD. Tobacco Bright Yellow-2 cultured cells were treated with acrolein, one of the most potent RCS. Acrolein at 0.2 mM caused PCD in 5 h (i.e. lethal), but at 0.1 mM it did not (sublethal). Specifically, these two doses caused critically different effects on the cells. Both lethal and sublethal doses of acrolein exhausted the cellular glutathione pool in 30 min, while the lethal dose only caused a significant ascorbate decrease and ROS increase in 1-2 h. Prior to such redox changes, we found that acrolein caused significant increases in the activities of caspase-1-like protease (C1LP) and caspase-3-like protease (C3LP), the proteases which trigger PCD. The lethal dose of acrolein increased the C3LP activity 2-fold more than did the sublethal dose. In contrast, C1LP activity increments caused by the two doses were not different. Acrolein and 4-hydroxy-(E)-2-nonenal, another RCS, activated both proteases in a cell-free extract from untreated cells. H2O2 at 1 mM added to the cells increased C1LP and C3LP activities and caused PCD, and the RCS scavenger carnosine suppressed their activation and PCD. However, H2O2 did not activate the proteases in a cell-free extract. Thus the activation of caspase-like proteases, particularly C3LP, by RCS is an initial biochemical event in oxidative signal-stimulated PCD in plants.

  9. Relationship between petal abscission and programmed cell death in Prunus yedoensis and Delphinium belladonna

    PubMed Central

    Yamada, Tetsuya; Ichimura, Kazuo

    2007-01-01

    Depending on the species, the end of flower life span is characterized by petal wilting or by abscission of petals that are still fully turgid. Wilting at the end of petal life is due to programmed cell death (PCD). It is not known whether the abscission of turgid petals is preceded by PCD. We studied some parameters that indicate PCD: chromatin condensation, a decrease in nuclear diameter, DNA fragmentation, and DNA content per nucleus, using Prunus yedoensis and Delphiniumbelladonna which both show abscission of turgid petals at the end of floral life. No DNA degradation, no chromatin condensation, and no change in nuclear volume was observed in P. yedoensis petals, prior to abscission. In abscising D.belladonna petals, in contrast, considerable DNA degradation was found, chromatin was condensed and the nuclear volume considerably reduced. Following abscission, the nuclear area in both species drastically increased, and the chromatin became unevenly distributed. Similar chromatin changes were observed after dehydration (24 h at 60°C) of petals severed at the time of flower opening, and in dehydrated petals of Ipomoea nil and Petunia hybrida, severed at the time of flower opening. In these flowers the petal life span is terminated by wilting rather than abscission. It is concluded that the abscission of turgid petals in D. belladonna was preceded by a number of PCD indicators, whereas no such evidence for PCD was found at the time of P. yedoensis petal abscission. Dehydration of the petal cells, after abscission, was associated with a remarkable nuclear morphology which was also found in younger petals subjected to dehydration. This nuclear morphology has apparently not been described previously, for any organism. PMID:17618454

  10. Programmed Cell Death Progresses Differentially in Epidermal and Mesophyll Cells of Lily Petals

    PubMed Central

    Mochizuki-Kawai, Hiroko; Niki, Tomoko; Shibuya, Kenichi; Ichimura, Kazuo

    2015-01-01

    In the petals of some species of flowers, programmed cell death (PCD) begins earlier in mesophyll cells than in epidermal cells. However, PCD progression in each cell type has not been characterized in detail. We separately constructed a time course of biochemical signs and expression patterns of PCD-associated genes in epidermal and mesophyll cells in Lilium cv. Yelloween petals. Before visible signs of senescence could be observed, we found signs of PCD, including DNA degradation and decreased protein content in mesophyll cells only. In these cells, the total proteinase activity increased on the day after anthesis. Within 3 days after anthesis, the protein content decreased by 61.8%, and 22.8% of mesophyll cells was lost. A second peak of proteinase activity was observed on day 6, and the number of mesophyll cells decreased again from days 4 to 7. These biochemical and morphological results suggest that PCD progressed in steps during flower life in the mesophyll cells. PCD began in epidermal cells on day 5, in temporal synchrony with the time course of visible senescence. In the mesophyll cells, the KDEL-tailed cysteine proteinase (LoCYP) and S1/P1 nuclease (LoNUC) genes were upregulated before petal wilting, earlier than in epidermal cells. In contrast, relative to that in the mesophyll cells, the expression of the SAG12 cysteine proteinase homolog (LoSAG12) drastically increased in epidermal cells in the final stage of senescence. These results suggest that multiple PCD-associated genes differentially contribute to the time lag of PCD progression between epidermal and mesophyll cells of lily petals. PMID:26605547

  11. Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas.

    PubMed

    Chong, Lauren C; Twa, David D W; Mottok, Anja; Ben-Neriah, Susana; Woolcock, Bruce W; Zhao, Yongjun; Savage, Kerry J; Marra, Marco A; Scott, David W; Gascoyne, Randy D; Morin, Ryan D; Mungall, Andrew J; Steidl, Christian

    2016-09-01

    Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24.1; harboring PDL1/CD274 and PDL2/PDCD1LG2). We describe 36 novel PDL SRs, including 17 intrachromosomal events (inversions, duplications, deletions) and 19 translocations involving BZRAP-AS1, CD44, GET4, IL4R, KIAA0226L, MID1, RCC1, PTPN1 and segments of the immunoglobulin loci. Moreover, analysis of the precise chromosomal breakpoints reveals 2 distinct cluster breakpoint regions (CBRs) within either CD274 (CBR1) or PDCD1LG2 (CBR2). To determine the phenotypic consequences of these SRs, we performed immunohistochemistry for CD274 and PDCD1LG2 on primary pretreatment biopsies and found that PDL SRs are significantly associated with PDL protein expression. Finally, stable ectopic expression of wild-type PDCD1LG2 and the PDCD1LG2-IGHV7-81 fusion showed, in coculture, significantly reduced T-cell activation. Taken together, our data demonstrate the complementary utility of fluorescence in situ hybridization and capture sequencing approaches and provide a classification scheme for PDL SRs with implications for future studies using PDL immune-checkpoint inhibitors in B-cell lymphomas.

  12. Salicylic acid induced cysteine protease activity during programmed cell death in tomato plants.

    PubMed

    Kovács, Judit; Poór, Péter; Szepesi, Ágnes; Tari, Irma

    2016-06-01

    The hypersensitive response (HR), a type of programmed cell death (PCD) during biotic stress is mediated by salicylic acid (SA). The aim of this work was to reveal the role of proteolysis and cysteine proteases in the execution of PCD in response of SA. Tomato plants were treated with sublethal (0.1 mM) and lethal (1 mM) SA concentrations through the root system. Treatment with 1 mM SA increased the electrolyte leakage and proteolytic activity and reduced the total protein content of roots after 6 h, while the proteolytic activity did not change in the leaves and in plants exposed to 0.1 mM SA. The expression of the papain-type cysteine protease SlCYP1, the vacuolar processing enzyme SlVPE1 and the tomato metacaspase SlMCA1 was induced within the first three hours in the leaves and after 0.5 h in the roots in the presence of 1 mM SA but the transcript levels did not increase significantly at sublethal SA. The Bax inhibitor-1 (SlBI-1), an antiapoptotic gene was over-expressed in the roots after SA treatments and it proved to be transient in the presence of sublethal SA. Protease inhibitors, SlPI2 and SlLTC were upregulated in the roots by sublethal SA but their expression remained low at 1 mM SA concentration. It is concluded that in contrast to leaves the SA-induced PCD is associated with increased proteolytic activity in the root tissues resulting from a fast up-regulation of specific cysteine proteases and down-regulation of protease inhibitors.

  13. Ricinosomes: an organelle for developmentally regulated programmed cell death in senescing plant tissues

    NASA Astrophysics Data System (ADS)

    Gietl, C.; Schmid, M.

    2001-02-01

    This review describes aspects of programmed cell death (PCD). Present research maps the enzymes involved and explores the signal transduction pathways involved in their synthesis. A special organelle (the ricinosome) has been discovered in the senescing endosperm of germinating castor beans (Ricinus communis) that develops at the beginning of PCD and delivers large amounts of a papain-type cysteine endopeptidase (CysEP) in the final stages of cellular disintegration. Castor beans store oil and proteins in a living endosperm surrounding the cotyledons. These stores are mobilized during germination and transferred into the cotyledons. PCD is initiated after this transfer is complete. The CysEP is synthesized in the lumen of the endoplasmic reticulum (ER) where it is retained by its C-terminal KDEL peptide as a rather inactive pro-enzyme. Large number of ricinosomes bud from the ER at the same time as the nuclear DNA is characteristically fragmented during PCD. The mitochondria, glyoxysomes and ribosomes are degraded in autophagic vacuoles, while the endopeptidase is activated by removal of the propeptide and the KDEL tail and enters the cytosol. The endosperm dries and detaches from the cotyledons. A homologous KDEL-tailed cysteine endopeptidase has been found in several senescing tissues; it has been localized in ricinosomes of withering day-lily petals and dying seed coats. Three genes for a KDEL-tailed cysteine endopeptidase have been identified in Arabidopsis. One is expressed in senescing ovules, the second in the vascular vessels and the third in maturing siliques. These genes open the way to exploring PCD in plants.

  14. Programmed Cell Death Progresses Differentially in Epidermal and Mesophyll Cells of Lily Petals.

    PubMed

    Mochizuki-Kawai, Hiroko; Niki, Tomoko; Shibuya, Kenichi; Ichimura, Kazuo

    2015-01-01

    In the petals of some species of flowers, programmed cell death (PCD) begins earlier in mesophyll cells than in epidermal cells. However, PCD progression in each cell type has not been characterized in detail. We separately constructed a time course of biochemical signs and expression patterns of PCD-associated genes in epidermal and mesophyll cells in Lilium cv. Yelloween petals. Before visible signs of senescence could be observed, we found signs of PCD, including DNA degradation and decreased protein content in mesophyll cells only. In these cells, the total proteinase activity increased on the day after anthesis. Within 3 days after anthesis, the protein content decreased by 61.8%, and 22.8% of mesophyll cells was lost. A second peak of proteinase activity was observed on day 6, and the number of mesophyll cells decreased again from days 4 to 7. These biochemical and morphological results suggest that PCD progressed in steps during flower life in the mesophyll cells. PCD began in epidermal cells on day 5, in temporal synchrony with the time course of visible senescence. In the mesophyll cells, the KDEL-tailed cysteine proteinase (LoCYP) and S1/P1 nuclease (LoNUC) genes were upregulated before petal wilting, earlier than in epidermal cells. In contrast, relative to that in the mesophyll cells, the expression of the SAG12 cysteine proteinase homolog (LoSAG12) drastically increased in epidermal cells in the final stage of senescence. These results suggest that multiple PCD-associated genes differentially contribute to the time lag of PCD progression between epidermal and mesophyll cells of lily petals.

  15. Relationship between petal abscission and programmed cell death in Prunus yedoensis and Delphinium belladonna.

    PubMed

    Yamada, Tetsuya; Ichimura, Kazuo; van Doorn, Wouter G

    2007-10-01

    Depending on the species, the end of flower life span is characterized by petal wilting or by abscission of petals that are still fully turgid. Wilting at the end of petal life is due to programmed cell death (PCD). It is not known whether the abscission of turgid petals is preceded by PCD. We studied some parameters that indicate PCD: chromatin condensation, a decrease in nuclear diameter, DNA fragmentation, and DNA content per nucleus, using Prunus yedoensis and Delphinium belladonna which both show abscission of turgid petals at the end of floral life. No DNA degradation, no chromatin condensation, and no change in nuclear volume was observed in P. yedoensis petals, prior to abscission. In abscising D. belladonna petals, in contrast, considerable DNA degradation was found, chromatin was condensed and the nuclear volume considerably reduced. Following abscission, the nuclear area in both species drastically increased, and the chromatin became unevenly distributed. Similar chromatin changes were observed after dehydration (24 h at 60 degrees C) of petals severed at the time of flower opening, and in dehydrated petals of Ipomoea nil and Petunia hybrida, severed at the time of flower opening. In these flowers the petal life span is terminated by wilting rather than abscission. It is concluded that the abscission of turgid petals in D. belladonna was preceded by a number of PCD indicators, whereas no such evidence for PCD was found at the time of P. yedoensis petal abscission. Dehydration of the petal cells, after abscission, was associated with a remarkable nuclear morphology which was also found in younger petals subjected to dehydration. This nuclear morphology has apparently not been described previously, for any organism.

  16. Programmed cell death activated by Rose Bengal in Arabidopsis thaliana cell suspension cultures requires functional chloroplasts

    PubMed Central

    Gutiérrez, Jorge; González-Pérez, Sergio; García-García, Francisco; Daly, Cara T.; Lorenzo, Óscar; Revuelta, José L.; McCabe, Paul F.; Arellano, Juan B.

    2014-01-01

    Light-grown Arabidopsis thaliana cell suspension culture (ACSC) were subjected to mild photooxidative damage with Rose Bengal (RB) with the aim of gaining a better understanding of singlet oxygen-mediated defence responses in plants. Additionally, ACSC were treated with H2O2 at concentrations that induced comparable levels of protein oxidation damage. Under low to medium light conditions, both RB and H2O2 treatments activated transcriptional defence responses and inhibited photosynthetic activity, but they differed in that programmed cell death (PCD) was only observed in cells treated with RB. When dark-grown ACSC were subjected to RB in the light, PCD was suppressed, indicating that the singlet oxygen-mediated signalling pathway in ACSC requires functional chloroplasts. Analysis of up-regulated transcripts in light-grown ACSC, treated with RB in the light, showed that both singlet oxygen-responsive transcripts and transcripts with a key role in hormone-activated PCD (i.e. ethylene and jasmonic acid) were present. A co-regulation analysis proved that ACSC treated with RB exhibited higher correlation with the conditional fluorescence (flu) mutant than with other singlet oxygen-producing mutants or wild-type plants subjected to high light. However, there was no evidence for the up-regulation of EDS1, suggesting that activation of PCD was not associated with the EXECUTER- and EDS1-dependent signalling pathway described in the flu mutant. Indigo Carmine and Methylene Violet, two photosensitizers unable to enter chloroplasts, did not activate transcriptional defence responses in ACSC; however, whether this was due to their location or to their inherently low singlet oxygen quantum efficiencies was not determined. PMID:24723397

  17. Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

    PubMed Central

    Greenwald, Noah F.; Du, Ziming; Agar, Nathalie Y. R.; Kaiser, Ursula B.; Woodmansee, Whitney W.; Reardon, David A.; Freeman, Gordon J.; Fecci, Peter E.; Laws, Edward R.; Santagata, Sandro; Dunn, Gavin P.; Dunn, Ian F.

    2016-01-01

    Purpose Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. Methods PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. Results Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. Conclusions Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management. PMID:27655724

  18. The function of donor versus recipient programmed death-ligand 1 in corneal allograft survival.

    PubMed

    Shen, Linling; Jin, Yiping; Freeman, Gordon J; Sharpe, Arlene H; Dana, M Reza

    2007-09-15

    Programmed death-ligand (PD-L)1 and PD-L2, newer B7 superfamily members, are implicated in the negative regulation of immune responses and peripheral tolerance. To examine their function in alloimmunity, we used the murine model of orthotopic corneal transplantation. We demonstrate that PD-L1, but not PD-L2, is constitutively expressed at high levels by the corneal epithelial cells, and at low levels by corneal CD45+ cells in the stroma, whereas it is undetectable on stromal fibroblasts and corneal endothelial cells. Inflammation induces PD-L1 up-regulation by corneal epithelial cells, and infiltration of significant numbers of PD-L1+CD45+CD11b+ cells. Blockade with anti-PD-L1 mAb dramatically enhances rejection of C57BL/6 corneal allografts by BALB/c recipients. To examine the selective contribution of donor vs host PD-L1 in modulating allorejection, we used PD-L1-/- mice as hosts or donors of combined MHC and minor H-mismatched corneal grafts. BALB/c grafts placed in PD-L1-/- C57BL/6 hosts resulted in pronounced T cell priming in the draining lymph nodes, and universally underwent rapid rejection. Allografts from PD-L1-/- C57BL/6 donors were also significantly more susceptible to rejection than wild-type C57BL/6 grafts placed into BALB/c hosts, primarily as a result of increased T cell infiltration rather than enhanced priming. Taken together, our results identify differential roles for recipient vs donor PD-L1 in regulating induction vs effector of alloimmunity in corneal grafts, the most common form of tissue transplantation, and highlight the importance of peripheral tissue-derived PD-L1 in down-regulating local immune responses.

  19. Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis.

    PubMed

    Soleimanifar, Narjes; Amirzargar, Ali Akbar; Mahmoudi, Mahdi; Pourfathollah, Ali Akbar; Azizi, Esfandiar; Jamshidi, Ahmad Reza; Rezaei, Nima; Tahoori, Mohammad Taher; Bidad, Katayoon; Nikbin, Behrouz; Nicknam, Mohammad Hossein

    2011-12-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disease, characterized by axial arthritis in which the genetic-environmental factors seem to be involved in the pathogenesis of the disease. This study was performed to investigate the role of polymorphisms of the programmed cell death 1 (PDCD1) gene on susceptibility to AS. In this study, 161 Iranian patients with AS and 208 normal controls were enrolled; two single-nucleotide polymorphisms (SNPs) of the PDCD1 gene PD-1.3 (G, A) in nucleotide position +7146 of intron 4 and PD-1.9 (C, T) in nucleotide +7625 of exon 5 were studied. Analysis of PD-1.3 revealed that 82% of patients and 79% of controls had GG genotype, while GA and AA genotypes were detected in 17% and 0.6% of patients, respectively, and 20% and 1.4% of controls, respectively. Moreover, the genotype CC (PD-1.9) was present in 92% of patients and 97% of controls. Although these differences were not statistically significant between patients and controls, comparisons of genotypes frequencies in the AS patients, based on human leukocyte antigen (HLA)-B27, revealed that all patients who had CT genotype (PD-1.9) were HLA-B27 positive, whereas 30% of patients with CC genotype were HLA-B27 negative. There was no evidence of association for PDCD1 SNPs with AS in our study, but CT genotype (PD-1.9) seems to be associated with HLA-B27 positivity in the patients with AS.

  20. Programmed cell death in Ricinus and Arabidopsis: the function of KDEL cysteine peptidases in development.

    PubMed

    Hierl, Georg; Vothknecht, Ute; Gietl, Christine

    2012-05-01

    Programmed cell death (PCD) in plants is a prerequisite for development as well as seed and fruit production. It also plays a significant role in pathogen defense. A unique group of papain-type cysteine endopeptidases, characterized by a C-terminal endoplasmic reticulum (ER) retention signal (KDEL CysEP), is involved in plant PCD. Genes for these endopeptidases have been sequenced and analyzed from 25 angiosperms and gymnosperms. They have no structural relationship to caspases involved in mammalian PCD and homologs to this group of plant cysteine endopeptidases have not been found in mammals or yeast. In castor beans (Ricinus communis), the CysEP is synthesized as pre-pro-enzyme. The pro-enzyme is transported to the cytosol of cells undergoing PCD in ER-derived vesicles called ricinosomes. These vesicles release the mature CysEP in the final stages of organelle disintegration triggered by acidification of the cytoplasm resulting from the disruption of the vacuole. Mature CysEP digests the hydroxyproline (Hyp)-rich proteins (extensins) that form the basic scaffold of the plant cell wall. The KDEL CysEPs accept a wide variety of amino acids at the active site, including the glycosylated Hyp residues of the extensins. In Arabidopsis, three KDEL CysEPs (AtCEP1, AtCEP2 and AtCEP3) are expressed in tissues undergoing PCD. In transgenic Arabidopsis plants expressing β-glucuronidase under the control of the promoters for these three genes, cell- and tissue-specific activities were mapped during seedling, flower and seed development. KDEL CysEPs participate in the collapse of tissues in the final stage of PCD and in tissue re-modeling such as lateral root formation.

  1. Ricinosomes: an organelle for developmentally regulated programmed cell death in senescing plant tissues.

    PubMed

    Gietl, C; Schmid, M

    2001-02-01

    This review describes aspects of programmed cell death (PCD). Present research maps the enzymes involved and explores the signal transduction pathways involved in their synthesis. A special organelle (the ricinosome) has been discovered in the senescing endosperm of germinating castor beans (Ricinus communis) that develops at the beginning of PCD and delivers large amounts of a papain-type cysteine endopeptidase (CysEP) in the final stages of cellular disintegration. Castor beans store oil and proteins in a living endosperm surrounding the cotyledons. These stores are mobilized during germination and transferred into the cotyledons. PCD is initiated after this transfer is complete. The CysEP is synthesized in the lumen of the endoplasmic reticulum (ER) where it is retained by its C-terminal KDEL peptide as a rather inactive pro-enzyme. Large number of ricinosomes bud from the ER at the same time as the nuclear DNA is characteristically fragmented during PCD. The mitochondria, glyoxysomes and ribosomes are degraded in autophagic vacuoles, while the endopeptidase is activated by removal of the propeptide and the KDEL tail and enters the cytosol. The endosperm dries and detaches from the cotyledons. A homologous KDEL-tailed cysteine endopeptidase has been found in several senescing tissues; it has been localized in ricinosomes of withering day-lily petals and dying seed coats. Three genes for a KDEL-tailed cysteine endopeptidase have been identified in Arabidopsis. One is expressed in senescing ovules, the second in the vascular vessels and the third in maturing siliques. These genes open the way to exploring PCD in plants.

  2. Programmed death-ligand 1, 2 expressions are decreased in the psoriatic epidermis.

    PubMed

    Kim, Dae Suk; Je, Jung Hwan; Kim, Sung Hee; Shin, Dongyun; Kim, Tae-Gyun; Kim, Do Young; Kim, Soo Min; Lee, Min-Geol

    2015-08-01

    Psoriatic keratinocytes are one of the key components that amplify and maintain chronic inflammation. We hypothesized that lack of proper regulatory functions of keratinocytes can be responsible for chronic inflammation in psoriasis. Programmed death-ligands (PD-L) 1, 2 are expressed on keratinocytes, and expressions by nonlymphoid cells are important for mediating peripheral T cell tolerance. In our study, we investigated whether PD-L1, 2 expressions are altered in keratinocytes of psoriatic epidermis compared to normal epidermis. Epidermis was separated and analyzed for PD-L1, 2 expressions in mRNA and protein levels. Immunohistochemical stainings were done in skin biopsy samples from psoriasis, normal skin, allergic contact dermatitis (ACD), pityriasis rosea (PR) and lichen planus (LP). Expressions of PD-L1, 2 mRNA levels were significantly decreased in psoriatic epidermis compared to normal epidermis. In protein levels, PD-L1 expression was significantly decreased in psoriatic epidermis. However, PD-L2 expression was not detected in both normal and psoriatic epidermis. Immunohistochemical stainings revealed significantly less PD-L1 expression in psoriatic epidermis compared to normal epidermis. Even compared to other cutaneous inflammatory diseases, psoriatic epidermis showed less expression than ACD, PR and LP. PD-L2 expression was minimally detected in normal epidermis and not in psoriatic epidermis, but its expression was increased in ACD, PR and LP. In conclusion, we demonstrated that PD-L1, 2 are decreased in psoriatic epidermis in mRNA and protein levels. In addition, we showed that their expression was significantly lower than other inflammatory skin diseases. We suggest that decreased expression of PD-L1, 2 on psoriatic epidermis can contribute to its chronic unregulated inflammatory characteristics.

  3. Programmed cell death genes are linked to elevated creatine kinase levels in unhealthy male nonagenarians

    PubMed Central

    Kim, Sangkyu; Simon, Eric; Myers, Leann; Hamm, L. Lee; Jazwinski, S. Michal

    2016-01-01

    Declining health in the oldest-old takes an energy toll for simple maintenance of body functions. The underlying mechanisms, however, differ in males and females. In females, the declines are explained by loss of muscle mass, but this is not the case in males in whom they are associated with increased levels of circulating creatine kinase. This relationship raises the possibility that muscle damage rather than muscle loss is the cause of the increased energy demands of unhealthy aging in males. We have now examined factors that contribute to the increase in creatine kinase. Much of it (60%) can be explained by a history of cardiac problems and lower kidney function, while being mitigated by moderate physical activity, reinforcing the notion that tissue damage is a likely source. In a search for genetic risk factors associated with elevated creatine kinase, the Ku70 gene XRCC6 and the ceramide synthase gene LASS1 were investigated because of their roles in telomere length and longevity and healthy aging, respectively. Single-nucleotide polymorphisms in these two genes were independently associated with creatine kinase levels. The XRCC6 variant was epistatic to one of the LASS1 variants but not to the other. These gene variants have potential regulatory activity. Ku70 is an inhibitor of the pro-apoptotic Bax, while the product of Lass1, ceramide, operates in both caspase-dependent and independent pathways of programmed cell death, providing a potential cellular mechanism for the effects of these genes on tissue damage and circulating creatine kinase. PMID:26913518

  4. Program death 1 (PD1) haplotyping in patients with breast carcinoma.

    PubMed

    Haghshenas, Mohammad Reza; Naeimi, Sirous; Talei, Abdolrasoul; Ghaderi, Abbas; Erfani, Nasrollah

    2011-08-01

    Located on chromosome 2q37.3, the programmed death 1 (PD1) gene encodes for PD-1 (also known as CD279), a negative co-stimulator in the immune system. PD-1 renders potent inhibitory effects on T and B lymphocytes as well as monocyte responses. Expression of PD-1 ligands by tumor cells has been reported to contribute in immune system evasion. We aimed, in current study, to investigate the association of two single nucleotide polymorphisms in PD1 gene, +7146 G to A (PD-1.3) and +7785 C to T (PD-1.5 or +872), with susceptibility and/or progression of breast carcinoma. Four hundred forty-three women with breast cancer and 328 age-sex match healthy donors were recruited in present study. Genotyping was performed using Nested polymerase chain reaction-restriction fragment length polymorphisms. Arlequin software package was used to check for the Hardy-Weinberg equilibration and to determine the haplotypes. Results revealed no significant differences in the frequencies of genotypes and alleles at PD-1.3 (P=0.252 and 0.279 for genotypes and alleles, respectively) and PD-1.5 positions (P=0.522 and 0.278 for genotypes and alleles, respectively). Four haplotypes were observed among populations with no differences in the frequency between patients and controls. Our results also revealed no association between PD1 genotypes and tumor stage, tumor size, tumor grade, lymph node involvement, vascular invasion, distant metastasis, and Nottingham prognostic index. Present data do not confirm association of PD-1.3 (+7146) G/A and PD-1.5 (+7785 or +872) C/T genetic markers with susceptibility of Iranians to breast cancer.

  5. A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

    PubMed Central

    Wu, Youping; Chung, Chun-Shiang; Chen, Yaping; Monaghan, Sean Farrell; Patel, Sima; Huang, Xin; Heffernan, Daithi Seamus; Ayala, Alfred

    2016-01-01

    Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, the co-inhibitory molecule programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it is not known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability and tissue cytokine levels were assessed. Subsequently, septic or nonseptic colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 in a blinded fashion. Finally, human Caco2 cells were used for in vitro studies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly upregulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability and tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared with WT after sepsis. Comparatively, while Caco2 cell monolayers also responded to inflammatory cytokine stimulation with elevated PD-L1 expression, increased monolayer permeability and altered/decreased monolayer tight junction protein morphology/expression, these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction. PMID:27782294

  6. Programmed cell death 1 correlates with the occurrence and development of MG63 osteosarcoma

    PubMed Central

    Zhao, Fuyou; Wu, Qiong; Dai, Xiusong; Li, Yumei; Gan, Huaiyong; Wang, Ri; Lv, Jie; Chen, Yuqing

    2016-01-01

    The aim of the present study was to investigate the effect of programmed cell death 1 (PD-1) on osteosarcoma (OD) stem cells and T cells, and to determine their correlation. OS stem cells were sorted and identified from OS MG63 cells. Flow cytometry was used to detect the PD-1 expression of the OS tumor stem cell membrane surface. The expression of PD-1 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). MTT was used to detect the effect of PD-1 signals on T-cell proliferation. The results indicated that the cancer cells (cultured in DMEM medium containing 10% fetal bovine serum) exhibited clear proliferation within 1 week of cell culture, which showed their strong proliferation and aggressive ability. The formation of tumor cell spheres was dependent on the support of serum nutrition. The proliferation of MG63 cells in the serum culture medium was significantly higher than the number of OS cell spheres in serum-free suspension culture (P<0.05). Pluripotent stem cells in cancer cell spheres exhibited significantly higher cluster of differentiation 133 expression compared with the MG63 cells. The PD-1 expression levels of the cancer cell spheres was significantly increased compared with the MG63 cells, which is consistent with the results of the RT-PCR. In conclusion, the MG63 cell line possesses the features of OS stem cells. The MG63 cell line can express the certain cancer-associated cell markers. The expression of PD-1 in spheres was also increased significantly compared to the MG63 cells, which can reduce the immune function of patients and may be closely associated with the occurrence and development of tumors. PMID:28105229

  7. Programmed death ligand-1 expression and its prognostic role in esophageal squamous cell carcinoma

    PubMed Central

    Kim, Ryul; Keam, Bhumsuk; Kwon, Dohee; Ock, Chan-Young; Kim, Miso; Kim, Tae Min; Kim, Hak Jae; Jeon, Yoon Kyung; Park, In Kyu; Kang, Chang Hyun; Kim, Dong-Wan; Kim, Young Tae; Heo, Dae Seog

    2016-01-01

    AIM To investigate the expression and prognostic role of programmed death ligand-1 (PD-L1) in locally advanced esophageal squamous cell carcinoma (ESCC). METHODS A total of 200 patients with ESCC who underwent radical esophagectomy with standard lymphadenectomy as the initial definitive treatment in Seoul National University Hospital from December 2000 to April 2013 were eligible for this analysis. Tissue microarrays were constructed by collecting tissue cores from surgical specimens, and immunostained with antibodies directed against PD-L1, p16, and c-Met. Medical records were reviewed retrospectively to assess clinical outcomes. Patients were divided into two groups by PD-L1 status, and significant differences in clinicopathologic characteristics between the two groups were assessed. RESULTS Tumor tissues from 67 ESCC patients (33.5%) were PD-L1-positive. Positive p16 expression was observed in 21 specimens (10.5%). The H-score for c-Met expression was ≥ 50 in 42 specimens (21.0%). Although PD-L1-positivity was not significantly correlated with any clinical characteristics including age, sex, smoking/alcoholic history, stage, or differentiation, H-scores for c-Met expression were significantly associated with PD-L1-positivity (OR = 2.34, 95%CI: 1.16-4.72, P = 0.017). PD-L1 expression was not significantly associated with a change in overall survival (P = 0.656). In contrast, the locoregional relapse rate tended to increase (P = 0.134), and the distant metastasis rate was significantly increased (HR = 1.72, 95%CI: 1.01-2.79, P = 0.028) in patients with PD-L1-positive ESCC compared to those with PD-L1-negative ESCC. CONCLUSION PD-L1 expression is positively correlated with c-Met expression in ESCC. PD-L1 may play a critical role in distant failure and progression of ESCC. PMID:27729745

  8. Blockade of the Programmed Death-1 Pathway Restores Sarcoidosis CD4+ T-Cell Proliferative Capacity

    PubMed Central

    Braun, Nicole A.; Celada, Lindsay J.; Herazo-Maya, Jose D.; Abraham, Susamma; Shaginurova, Guzel; Sevin, Carla M.; Grutters, Jan; Culver, Daniel A.; Dworski, Ryszard; Sheller, James; Massion, Pierre P.; Polosukhin, Vasiliy V.; Johnson, Joyce E.; Kaminski, Naftali; Wilkes, David S.; Oswald-Richter, Kyra A.

    2014-01-01

    Rationale: Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. Objectives: To determine the effects of PD-1 pathway blockade on sarcoidosis CD4+ T-cell proliferative capacity. Methods: Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage–derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. Measurements and Main Results: Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1+ CD4+ T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1+ CD4+ T cells with spontaneous clinical resolution but not with disease progression. Conclusions: Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4+ T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a

  9. Loss of endothelial programmed cell death 10 activates glioblastoma cells and promotes tumor growth

    PubMed Central

    Zhu, Yuan; Zhao, Kai; Prinz, Anja; Keyvani, Kathy; Lambertz, Nicole; Kreitschmann-Andermahr, Ilonka; Lei, Ting; Sure, Ulrich

    2016-01-01

    Background Neo-angiogenesis is a hallmark of glioblastoma (GBM) and is sustained by autocrine and paracrine interactions between neoplastic and nonneoplastic cells. Programmed cell death 10 (PDCD10) is ubiquitously expressed in nearly all tissues and plays crucial roles in regulating angiogenesis and apoptosis. We recently discovered the absence of PDCD10 expression in the tumor vessels of GBM patients. This raised the hypothesis that loss of endothelial PDCD10 affected GBM cell phenotyping and tumor progression. Methods Endothelial PDCD10 was silenced by siRNA and lentiviral shRNA. The tumor cell phenotype was studied in direct and indirect co-culture of endothelial cells (ECs) with U87 or LN229. Angiogenic protein array was performed in the media of PDCD10-silenced ECs. Tumor angiogenesis and tumor growth were investigated in a human GBM xenograft mouse model. Results Endothelial silence of PDCD10 significantly stimulated tumor cell proliferation, migration, adhesion, and invasion and inhibited apoptosis in co-cultures. Stable knockdown of endothelial PDCD10 increased microvessel density and the formation of a functional vascular network, leading to a 4-fold larger tumor mass in mice. Intriguingly, endothelial deletion of PDCD10 increased (≥2-fold) the release of 20 of 55 tested proangiogenic factors including VEGF, which in turn activated Erk1/2 and Akt in GBM cells. Conclusions For the first time, we provide evidence that loss of endothelial PDCD10 activates GBM cells and promotes tumor growth, most likely via a paracrine mechanism. PDCD10 shows a tumor-suppressor-like function in the cross talk between ECs and tumor cells and is potentially implicated in GBM progression. PMID:26254477

  10. Molecular cloning, expression and characterization of programmed cell death 10 from sheep (Ovis aries).

    PubMed

    Yang, Yong-Jie; Liu, Zeng-Shan; Lu, Shi-Ying; Li, Chuang; Hu, Pan; Li, Yan-Song; Liu, Nan-Nan; Tang, Feng; Xu, Yun-Ming; Zhang, Jun-Hui; Li, Zhao-Hui; Feng, Xiao-Li; Zhou, Yu; Ren, Hong-Lin

    2015-03-01

    Programmed cell death 10 (PDCD10) is a highly conserved adaptor protein. Its mutations result in cerebral cavernous malformations (CCMs). In this study, PDCD10 cDNA from the buffy coat of Small Tail Han sheep (Ovis aries) was cloned from a suppression subtractive hybridization cDNA library, named OaPDCD10. The full-length cDNA of OaPDCD10 was 1343bp with a 639bp open reading frame (ORF) encoding 212 amino acid residues. Tissue distribution of OaPDCD10 mRNA determined that it was ubiquitously expressed in all tested tissue samples, and the highest expression was observed in the heart. The differential expression of OaPDCD10 between infected sheep (challenged with Brucella melitensis) and vaccinated sheep (vaccinated with Brucella suis S2) was also investigated. The results revealed that, compared to the control group, the expression of OaPDCD10 from infected and vaccinated sheep was both significantly up-regulated (p<0.05). Moreover, the expression levels of OaPDCD10 from the vaccinated sheep were significantly higher than the infected sheep (p<0.05) after 30days post-inoculation. The recombinant OaPDCD10 (rOaPDCD10) protein was expressed in Escherichia coli BL21 (DE3), and then purified by affinity chromatography. The rOaPDCD10 protein was demonstrated to induce apoptosis and promote cell proliferation. Our studies are intended to discover potential diagnostic biomarkers of brucellosis to discern infected sheep from vaccinated sheep, and OaPDCD10 could be considered as a potential diagnostic biomarker of brucellosis.

  11. Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay.

    PubMed

    Ni, Yan G; Yuan, Xiling; Newitt, John A; Peterson, Jon E; Gleason, Carol R; Haulenbeek, Jonathan; Santockyte, Rasa; Lafont, Virginie; Marsilio, Frank; Neely, Robert J; DeSilva, Binodh; Piccoli, Steven P

    2015-07-01

    Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function-an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals. A clinical assay to quantify sPD-1 would contribute to the understanding of sPD-1-function and facilitate the development of anti-PD-1 drugs. Here, we report the development and validation of a sPD-1 protein assay. The assay validation followed the framework for full validation of a biotherapeutic pharmacokinetic assay. A purified recombinant human PD-1 protein was characterized extensively and was identified as the assay reference material which mimics the endogenous analyte in structure and function. The lower limit of quantitation (LLOQ) was determined to be 100 pg/mL, with a dynamic range spanning three logs to 10,000 pg/mL. The intra- and inter-assay imprecision were ≤15%, and the assay bias (percent deviation) was ≤10%. Potential matrix effects were investigated in sera from both normal healthy volunteers and selected cancer patients. Bulk-prepared frozen standards and pre-coated Streptavidin plates were used in the assay to ensure consistency in assay performance over time. This assay appears to specifically measure total sPD-1 protein since the human anti-PD-1 antibody, nivolumab, and the endogenous ligands of PD-1 protein, PDL-1 and PDL-2, do not interfere with the assay.

  12. Multiple endocrine neoplasia type 1

    PubMed Central

    Marini, Francesca; Falchetti, Alberto; Monte, Francesca Del; Sala, Silvia Carbonell; Gozzini, Alessia; Luzi, Ettore; Brandi, Maria Luisa

    2006-01-01

    Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. It occurs in approximately one in 30,000 individuals. Two different forms, sporadic and familial, have been described. The sporadic form presents with two of the three principal MEN1-related endocrine tumours (parathyroid adenomas, entero-pancreatic tumours and pituitary tumours) within a single patient, while the familial form consists of a MEN1 case with at least one first degree relative showing one of the endocrine characterising tumours. Other endocrine and non-endocrine lesions, such as adrenal cortical tumours, carcinoids of the bronchi, gastrointestinal tract and thymus, lipomas, angiofibromas, collagenomas have been described. The responsible gene, MEN1, maps on chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, with no sequence homology to other known human proteins. MEN1 syndrome is caused by inactivating mutations of the MEN1 tumour suppressor gene. This gene is probably involved in the regulation of several cell functions such as DNA replication and repair and transcriptional machinery. The combination of clinical and genetic investigations, together with the improving of molecular genetics knowledge of the syndrome, helps in the clinical management of patients. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. Currently, DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, to whom routine surveillance (regular biochemical and/or radiological screenings to detect the development of MEN1-associated tumours and lesions) is recommended. PMID:17014705

  13. A major human immunodeficiency virus type 1-initiated killing pathway distinct from apoptosis.

    PubMed Central

    Kolesnitchenko, V; King, L; Riva, A; Tani, Y; Korsmeyer, S J; Cohen, D I

    1997-01-01

    We have investigated the relative contribution of apoptosis or programmed cell death (PCD) to cell killing during acute infection with T-cell-tropic, cytopathic human immunodeficiency virus type 1 (HIV-1), by employing diverse strategies to inhibit PCD or to detect its common end-stage sequelae. When Bcl-2-transfected cell lines were infected with HIV-1, their viability was only slightly higher than that of control infections. Although the adenovirus E1B 19-kDa protein has been reported to be a stronger competitor of apoptosis than Bcl-2, it did not inhibit HIV-mediated cell death better than Bcl-2 protein. Competition for Fas ligand or inactivation of the Fas pathway secondary to intracellular mutation (MOLT-4 T cells) also had modest effects on overall cell death during acute HIV infection. In contrast to these observations with HIV infection or with HIV envelope-initiated cell death, Tat-expressing cell lines were much more susceptible (200% enhancement) to Fas-induced apoptosis than controls and Bcl-2 overexpression strongly (75%) inhibited this apoptotic T-cell death. PCD associated with FasR ligation resulted in the cleavage of common interleukin-1beta-converting enzyme (ICE)-protease targets, poly(ADP-ribose) polymerase (PARP) and pro-ICE, whereas cleaved products were not readily detected during HIV infection of peripheral blood mononuclear cells or T-cell lines even during periods of extensive cell death. These results indicate that one important form of HIV-mediated cell killing proceeds by a pathway that lacks the characteristics of T-cell apoptosis. Our observations support the conclusion that at least two HIV genes (env and tat) can kill T cells by distinct pathways and that an envelope-initiated process of T-cell death can be discriminated from apoptosis by many of the properties most closely associated with apoptotic cell death. PMID:9371641

  14. beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes.

    PubMed

    Eizirik, D L; Darville, M I

    2001-02-01

    Increased evidence suggests that apoptosis is the main mode of beta-cell death in early type 1 diabetes. Cytokines mediate beta-cell apoptosis, and in this article, we discuss some of the cytokine-modified genes that may contribute to beta-cell survival or death. The gene encoding for the inducible form of nitric oxide synthase is induced by interleukin (IL)-1beta or IL-1beta plus gamma-interferon in rodent and human islets, respectively. This leads to nitric oxide (NO) formation, which contributes to a major extent to beta-cell necrosis and to a minor extent to the process of beta-cell apoptosis. The main mode of cell death induced by cytokines in human beta-cells is apoptosis, whereas cytokines lead to both necrosis and apoptosis in rat and mouse beta-cells. It is suggested that the necrotic component in rodent islets is due to NO-induced mitochondrial impairment and consequent decreased ATP production. Human islets, possessing better antioxidant defenses, are able to preserve glucose oxidation and ATP production, and can thus complete the apoptotic program after the death signal delivered by cytokines. We propose that this death signal results from cytokine-induced parallel and/or sequential changes in the expression of multiple proapoptotic and prosurvival genes. The identity of these "gene modules" and of the transcription factors regulating them remains to be established.

  15. Argos induces programmed cell death in the developing Drosophila eye by inhibition of the Ras pathway.

    PubMed

    Sawamoto, K; Taguchi, A; Hirota, Y; Yamada, C; Jin, M H; Okano, H

    1998-04-01

    We studied the role of Ras signaling in the regulation of cell death during Drosophila eye development. Overexpression of Argos, a diffusible inhibitor of the EGF receptor and Ras signaling, caused excessive cell death in developing eyes at pupal stages. The Argos-induced cell death was suppressed by coexpression of the anti-apoptotic genes p35, diap1, or diap2 in the eye as well as by the Df(3L)H99 chromosomal deletion that lacks three apoptosis-inducing genes, reaper, head involution defective (hid) and grim. Transient misexpression of the activated Ras1 protein (Ras1V12) later in pupal development suppressed the Argos-induced cell death. Thus, Argos-induced cell death seemed to have resulted from the suppression of the anti-apoptotic function of Ras. Conversely, cell death induced by overexpression of Hid was suppressed by gain-of-function mutations of the genes coding for MEK and ERK. These results support the idea that Ras signaling functions in two distinct processes during eye development, first triggering the recruitment of cells and later negatively regulating cell death.

  16. Pontocerebellar hypoplasia type 1: new leads for an earlier diagnosis.

    PubMed

    Salman, Michael S; Blaser, Susan; Buncic, J Raymond; Westall, Carol A; Héon, Elise; Becker, Laurence

    2003-03-01

    Pontocerebellar hypoplasia type 1 is a rare disease characterized by pontocerebellar hypoplasia and anterior horn cell degeneration. The oldest reported child died at the age of 26 months. Two siblings were diagnosed with pontocerebellar hypoplasia type 1 after the death of the second sibling at 40 months of age from respiratory failure and the unexpected finding of anterior horn cell degeneration on her autopsy. The older sibling was a boy who was labeled as having cerebral palsy. He died at 14 months of age from pneumonia following a clinical course similar to his sister's, who was born 5 years after his death. Both siblings had significant global developmental delay with axial and peripheral hypotonia initially. Peripheral hypertonia with brisk reflexes developed later but were absent prior to death. Extensive investigations in the second sibling ruled out known metabolic (including congenital disorders of glycosylation) and mitochondrial diseases using skin fibroblast cultures and enzyme analysis. Genetic testing for Friedreich's ataxia; neuropathy, ataxia, and retinitis pigmentosa (NARP); spinal muscular atrophy; and spinocerebellar ataxia type 1, 2, 3, 6, 7, and 8 gene abnormalities was negative. The elecroretinogram showed a previously unreported finding of abnormal and progressive rod/cone response. Our cases provide clinical and previously unreported electroretinographic evidence for neurodegeneration in pontocerebellar hypoplasia type 1 and call for the expansion of the disease phenotype.

  17. Influence of antiretroviral therapy on programmed death-1 (CD279) expression on T cells in lymph nodes of human immunodeficiency virus-infected individuals.

    PubMed

    Ehrhard, Simone; Wernli, Marion; Dürmüller, Ursula; Battegay, Manuel; Gudat, Fred; Erb, Peter

    2009-10-01

    Human immunodeficiency virus infection leads to T-cell exhaustion and involution of lymphoid tissue. Recently, the programmed death-1 pathway was found to be crucial for virus-specific T-cell exhaustion during human immunodeficiency virus infection. Programmed death-1 expression was elevated on human immunodeficiency virus-specific peripheral blood CD8+ and CD4+ T cells and correlated with disease severity. During human immunodeficiency infection, lymphoid tissue acts as a major viral reservoir and is an important site for viral replication, but it is also essential for regulatory processes important for immune recovery. We compared programmed death-1 expression in 2 consecutive inguinal lymph nodes of 14 patients, excised before antiretroviral therapy (antiretroviral therapy as of 1997-1999) and 16 to 20 months under antiretroviral therapy. In analogy to lymph nodes of human immunodeficiency virus-negative individuals, in all treated patients, the germinal center area decreased, whereas the number of germinal centers did not significantly change. Programmed death-1 expression was mostly found in germinal centers. The absolute extent of programmed death 1 expression per section was not significantly altered after antiretroviral therapy resulting in a significant-relative increase of programmed death 1 per shrunken germinal center. In colocalization studies, CD45R0+ cells that include helper/inducer T cells strongly expressed programmed death-1 before and during therapy, whereas CD8+ T cells, fewer in numbers, showed a weak expression for programmed death-1. Thus, although antiretroviral therapy seems to reduce the number of programmed death-1-positive CD8+ T lymphocytes within germinal centers, it does not down-regulate programmed death-1 expression on the helper/inducer T-cell subset that may remain exhausted and therefore unable to trigger immune recovery.

  18. Programmed cell death: similarities and differences in animals and plants. A flower paradigm.

    PubMed

    Mea, M Della; Serafini-Fracassini, D; Duca, S Del

    2007-08-01

    After an overview of the criteria for the definition of cell death in the animal cell and of its different types of death, a comparative analysis of PCD in the plant cell is reported. The cytological characteristics of the plant cell undergoing PCD are described. The role of plant hormones and growth factors in the regulation of this event is discussed with particular emphasis on PCD activation or prevention by polyamine treatment (doses, timing and developmental stage of the organism) in a Developmental cell death plant model: the Nicotiana tabacum (tobacco) flower corolla. Some of the effects of polyamines might be mediated by transglutaminase catalysis. The activity of this enzyme was examined in different parts of the corolla during its life span showing an acropetal trend parallel to the cell death wave. The location of transglutaminase in some sub-cellular compartments suggests that it exerts different functions in the corolla DCD.

  19. Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death

    PubMed Central

    1996-01-01

    Expression of the bcl-2 gene has been shown to effectively confer resistance to programmed cell death under a variety of circumstances. However, despite a wealth of literature describing this phenomenon, very little is known about the mechanism of resistance. In the experiments described here, we show that bcl-2 gene expression can result in an inhibition of cell division cycle progression. These findings are based upon the analysis of cell cycle distribution, cell cycle kinetics, and relative phosphorylation of the retinoblastoma tumor suppressor protein, using primary tissues in vivo, ex vivo, and in vitro, as well as continuous cell lines. The effects of bcl-2 expression on cell cycle progression appear to be focused at the G1 to S phase transition, which is a critical control point in the decision between continued cell cycle progression or the induction programmed cell death. In all systems tested, bcl-2 expression resulted in a substantial 30-60% increase in the length of G1 phase; such an increase is very substantial in the context of other regulators of cell cycle progression. Based upon our findings, and the related findings of others, we propose a mechanism by which bcl-2 expression might exert its well known inhibition of programmed cell death by regulating the kinetics of cell cycle progression at a critical control point. PMID:8642331

  20. Relevance Between Programmed Death Ligand 1 and Radiologic Invasiveness in Pathologic Stage I Lung Adenocarcinoma.

    PubMed

    Toyokawa, Gouji; Takada, Kazuki; Okamoto, Tatsuro; Kawanami, Satoshi; Kozuma, Yuka; Matsubara, Taichi; Haratake, Naoki; Takamori, Shinkichi; Akamine, Takaki; Katsura, Masakazu; Yamada, Yuichi; Shoji, Fumihiro; Baba, Shingo; Kamitani, Takeshi; Oda, Yoshinao; Honda, Hiroshi; Maehara, Yoshihiko

    2017-06-01

    Programmed death ligand 1 (PD-L1) was reported to predict the response of immunotherapy; however, the association between PD-L1 expression and radiologic and pathologic features has yet to be elucidated. In all, 292 patients with resected pathologic stage I adenocarcinoma were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and the radiologic/pathologic invasiveness. Specifically, the radiologic invasiveness and noninvasiveness were determined based on the consolidation/tumor ratio, with a cutoff value of 0.25 by thin-section computed tomography. Among 292 patients, 47 (16.1%) were positive for PD-L1 expression; the remaining 245 patients (83.9%) were negative for PD-L1 expression. Fisher's exact test demonstrated that PD-L1 expression was significantly associated with a higher consolidation/tumor ratio (p = 0.029) and higher maximum standardized uptake value (p = 0.004). The mean values of consolidation/tumor ratio and maximum standardized uptake in patients with and without PD-L1 expression were 0.845 ± 0.052 and 7.241 ± 0.795, and 0.607 ± 0.023 and 3.60 ± 0.364, respectively (p < 0.001 and p < 0.001, respectively). Among 47 adenocarcinomas harboring PD-L1 expression, the frequencies of PD-L1 expression for consolidation/tumor ratios of 0, 0.1 to 0.25, 0.26 to 0.5, and 0.51 or more were 6.4%, 2.1%, 4.3%, and 87.2%, respectively (p = 0.007). Pathologically, PD-L1 was identified exclusively only in more invasive subtypes, not in less invasive ones, such as atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant ones (p < 0.001). Expression of PD-L1 was significantly associated with radiologic/pathologic invasive adenocarcinomas. This study provides the first evidence of the radiologic and pathologic invasiveness in resected pathologic stage I adenocarcinoma with PD-L1 expression. Copyright © 2017 The Society of Thoracic

  1. HIV-1 Vpr potently induces programmed cell death in the CNS in vivo.

    PubMed

    Cheng, Xiaodong; Cheng, Xiandong; Mukhtar, Muhammad; Acheampong, Edward A; Srinivasan, Algarsamy; Rafi, Mohammad; Pomerantz, Roger J; Parveen, Zahida

    2007-02-01

    The human immunodeficiency virus type I (HIV-1) accessory protein Vpr has been associated with the induction of programmed cell death (apoptosis) and cell-cycle arrest. Studies have shown the apoptotic effect of Vpr on primary and established cell lines and on diverse tissues including the central nervous system (CNS) in vitro. However, the relevance of the effect of Vpr observed in vitro to HIV-1 neuropathogenesis in vivo, remains unknown. Due to the narrow host range of HIV-1 infection, no animal model is currently available. This has prompted us to consider a small animal model to evaluate the effects of Vpr on CNS in vivo through surrogate viruses expressing HIV-1Vpr. A single round of replication competent viral vectors, expressing Vpr, were used to investigate the apoptosis-inducing capabilities of HIV-1Vpr in vivo. Viral particles pseudotyped with VSV-G or N2c envelopes were generated from spleen necrosis virus (SNV) and HIV-1-based vectors to transduce CNS cells. The in vitro studies have demonstrated that Vpr generated by SNV vectors had less apoptotic effects on CNS cells compared with Vpr expressed by HIV-1 vectors. The in vivo study has suggested that viral particles, expressing Vpr generated by HIV-1-based vectors, when delivered through the ventricle, caused loss of neurons and dendritic processes in the cortical region. The apoptotic effect was extended beyond the cortical region and affected the hippocampus neurons, the lining of the choroids plexus, and the cerebellum. However, the effect of Vpr, when delivered through the cortex, showed neuronal damage only around the site of injection. Interestingly, the number of apoptotic neurons were significantly higher with HIV-1 vectors expressing Vpr than by the SNV vectors. This may be due to the differences in the proteins expressed by these viral vectors. These results suggest that Vpr induces apoptosis in CNS cells in vitro and in vivo. To our knowledge, this is the first study to investigate the

  2. High programmed death 1 expression on T cells in aplastic anemia.

    PubMed

    Zhao, Wanhong; Zhang, Yilin; Zhang, Pengyu; Yang, Juan; Zhang, Longjin; He, Aili; Zhang, Wanggang; Hideto, Tamura

    2017-03-01

    Programmed death 1 (PD-1) has been reported to be associated with aberrant regulation of T cells activation in aplastic anemia (AA). However, the connection between PD-1 expression status and AA needs to be further explored. The aim of this study is to investigate PD-1 expression status on T cells in AA patients and to explore the effect of PD-1 on apoptosis of T cells and BMHSCs. The concentration of platelet, lymphocyte and hemoglobin in peripheral blood of AA patients and healthy volunteers was detected by automatic blood-counter system. Mononuclear cells (MNCs) of peripheral blood and marrow were isolated from AA patients and healthy volunteers. PD-1 expression level on CD3+, CD4+, CD8+, CD4+CD25+FOXP3+ T cells and bone marrow hematopoietic stem cells (BMHSCs) and B7-H1 expression level on peripheral blood mononuclear cells (PBMCs) and BMHSCs were detected by flow cytometry (FCM). Cell apoptosis on T cells and BMHSCs was also detected by FCM. PD-1, B7-H1, Bax and Bcl-2 mRNA expression levels on T cells of peripheral blood were detected by real-time PCR. MNCs from healthy volunteers were treated with ammonium pyrrolidine dithiocarbamate (PDTC) to block the nuclear factor (NF)-кB pathway. Our results showed that in AA patients, T cells had high levels of PD-1 expression and apoptosis rate. In BMHSCs, apoptosis rate was also higher than healthy volunteers. The expression of PD-1 on T cells was correlated with lymphocyte count and hemoglobin level. PD-1 was highly expressed on CD4+CD25+FOXP3+ T cells of AA patients and PD-1 expression was negatively correlated with the percentage of CD4+CD25+FOXP3+ T cells in AA patients. B7-H1, the ligand of PD-1, was also highly expressed on T cells, B cells, PBMCs and BMHSCs. When the NF-κB pathway was blocked by PDTC, the apoptosis of T cells and BMHSCs was reduced in a dose-dependent manner and PD-1 expression was also decreased in a dose-dependent manner. In conclusion, PD-1 was up-regulated in T cells in AA patients

  3. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations.

    PubMed

    Bergametti, F; Denier, C; Labauge, P; Arnoult, M; Boetto, S; Clanet, M; Coubes, P; Echenne, B; Ibrahim, R; Irthum, B; Jacquet, G; Lonjon, M; Moreau, J J; Neau, J P; Parker, F; Tremoulet, M; Tournier-Lasserve, E

    2005-01-01

    Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and cerebral hemorrhages, which can result in focal neurological deficits. Three CCM loci have been mapped, and loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607 (CCM2) genes. We report herein the identification of PDCD10 (programmed cell death 10) as the CCM3 gene. The CCM3 locus has been previously mapped to 3q26-27 within a 22-cM interval that is bracketed by D3S1763 and D3S1262. We hypothesized that genomic deletions might occur at the CCM3 locus, as reported previously to occur at the CCM2 locus. Through high-density microsatellite genotyping of 20 families, we identified, in one family, null alleles that resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and D3S1614. This de novo deletion encompassed D3S1763, which strongly suggests that the CCM3 gene lies within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional distinct deleterious mutations within PDCD10, one of the five known genes mapped within this interval, were identified in seven families. Three of these mutations were nonsense mutations, and two led to an aberrant splicing of exon 9, with a frameshift and a longer open reading frame within exon 10. The last of the six mutations led to an aberrant splicing of exon 5, without frameshift. Three of these mutations occurred de novo. All of them cosegregated with the disease in the families and were not observed in 200 control chromosomes. PDCD10, also called "TFAR15," had been initially identified through a screening for genes differentially expressed during the induction of apoptosis in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and invertebrates. Its implication in cerebral cavernous malformations strongly suggests that it is a new player in vascular morphogenesis and

  4. Programmed Cell Death in Floral Organs: How and Why do Flowers Die?

    PubMed Central

    ROGERS, HILARY J.

    2006-01-01

    • Background Flowers have a species-specific, limited life span with an irreversible programme of senescence, which is largely independent of environmental factors, unlike leaf senescence, which is much more closely linked with external stimuli. • Timing Life span of the whole flower is regulated for ecological and energetic reasons, but the death of individual tissues and cells within the flower is co-ordinated at many levels to ensure correct timing. Some floral cells die selectively during organ development, whereas others are retained until the whole organ dies. • Triggers Pollination is an important floral cell death trigger in many species, and its effects are mediated by the plant growth regulator (PGR) ethylene. In some species ethylene is a major regulator of floral senescence, but in others it plays a very minor role and the co-ordinating signals involved remain elusive. Other PGRs such as cytokinin and brassinosteroids are also important but their role is understood only in some specific systems. • Mechanisms In two floral cell types (the tapetum and the pollen-tube) there is strong evidence for apoptotic-type cell death, similar to that in animal cells. However, in petals there is stronger evidence for an autophagous type of cell death involving endoplasmic reticulum-derived vesicles and the vacuole. Proteases are important, and homologues to animal caspases, key regulators of animal cell death, exist in plants. However, their role is not yet clear. • Comparison with Other Organs There are similarities to cell death in other plant organs, and many of the same genes are up-regulated in both leaf and petal senescence; however, there are also important differences for example in the role of PGRs. • Conclusions Understanding gene regulation may help to understand cell death in floral organs better, but alone it cannot provide all the answers. PMID:16394024

  5. Programmed cell death in floral organs: how and why do flowers die?

    PubMed

    Rogers, Hilary J

    2006-03-01

    Flowers have a species-specific, limited life span with an irreversible programme of senescence, which is largely independent of environmental factors, unlike leaf senescence, which is much more closely linked with external stimuli. Life span of the whole flower is regulated for ecological and energetic reasons, but the death of individual tissues and cells within the flower is co-ordinated at many levels to ensure correct timing. Some floral cells die selectively during organ development, whereas others are retained until the whole organ dies. Pollination is an important floral cell death trigger in many species, and its effects are mediated by the plant growth regulator (PGR) ethylene. In some species ethylene is a major regulator of floral senescence, but in others it plays a very minor role and the co-ordinating signals involved remain elusive. Other PGRs such as cytokinin and brassinosteroids are also important but their role is understood only in some specific systems. In two floral cell types (the tapetum and the pollen-tube) there is strong evidence for apoptotic-type cell death, similar to that in animal cells. However, in petals there is stronger evidence for an autophagous type of cell death involving endoplasmic reticulum-derived vesicles and the vacuole. Proteases are important, and homologues to animal caspases, key regulators of animal cell death, exist in plants. However, their role is not yet clear. There are similarities to cell death in other plant organs, and many of the same genes are up-regulated in both leaf and petal senescence; however, there are also important differences for example in the role of PGRs. Understanding gene regulation may help to understand cell death in floral organs better, but alone it cannot provide all the answers.

  6. Blood-based signatures in type 1 diabetes

    PubMed Central

    Cabrera, Susanne M.; Chen, Yi-Guang; Hagopian, William A.; Hessner, Martin J.

    2015-01-01

    Type 1 diabetes mellitus is one of the most common chronic diseases in childhood. It develops through autoimmune destruction of the pancreatic beta cells and results in lifelong dependence on exogenous insulin. The pathogenesis of type 1 diabetes involves a complex interplay of genetic and environmental factors and has historically been attributed to aberrant adaptive immunity; however, there is increasing evidence for a role of innate inflammation. Over the past decade new methodologies for the analysis of nucleic acid and protein signals have been applied to type 1 diabetes. These studies are providing a new understanding of type 1 diabetes pathogenesis and have the potential to inform the development of new biomarkers for predicting diabetes onset and monitoring therapeutic interventions. In this review we will focus on blood-based signatures in type 1 diabetes, with special attention to both direct transcriptomic analyses of whole blood and immunocyte subsets, as well as plasma/serum-induced transcriptional signatures. Attention will also be given to proteomics, microRNA assays and markers of beta cell death. We will also discuss the results of blood-based profiling in type 1 diabetes within the context of the genetic and environmental factors implicated in the natural history of autoimmune diabetes. PMID:26699650

  7. Blood-based signatures in type 1 diabetes.

    PubMed

    Cabrera, Susanne M; Chen, Yi-Guang; Hagopian, William A; Hessner, Martin J

    2016-03-01

    Type 1 diabetes mellitus is one of the most common chronic diseases in childhood. It develops through autoimmune destruction of the pancreatic beta cells and results in lifelong dependence on exogenous insulin. The pathogenesis of type 1 diabetes involves a complex interplay of genetic and environmental factors and has historically been attributed to aberrant adaptive immunity; however, there is increasing evidence for a role of innate inflammation. Over the past decade new methodologies for the analysis of nucleic acid and protein signals have been applied to type 1 diabetes. These studies are providing a new understanding of type 1 diabetes pathogenesis and have the potential to inform the development of new biomarkers for predicting diabetes onset and monitoring therapeutic interventions. In this review we will focus on blood-based signatures in type 1 diabetes, with special attention to both direct transcriptomic analyses of whole blood and immunocyte subsets, as well as plasma/serum-induced transcriptional signatures. Attention will also be given to proteomics, microRNA assays and markers of beta cell death. We will also discuss the results of blood-based profiling in type 1 diabetes within the context of the genetic and environmental factors implicated in the natural history of autoimmune diabetes.

  8. Vibrio cholerae Porin OmpU Induces Caspase-independent Programmed Cell Death upon Translocation to the Host Cell Mitochondria.

    PubMed

    Gupta, Shelly; Prasad, G V R Krishna; Mukhopadhaya, Arunika

    2015-12-25

    Porins, a major class of outer membrane proteins in Gram-negative bacteria, primarily act as transport channels. OmpU is one of the major porins of human pathogen, Vibrio cholerae. In the present study, we show that V. cholerae OmpU has the ability to induce target cell death. Although OmpU-mediated cell death shows some characteristics of apoptosis, such as flipping of phosphatidylserine in the membrane as well as cell size shrinkage and increased cell granularity, it does not show the caspase-3 activation and DNA laddering pattern typical of apoptotic cells. Increased release of lactate dehydrogenase in OmpU-treated cells indicates that the OmpU-mediated cell death also has characteristics of necrosis. Further, we show that the mechanism of OmpU-mediated cell death involves major mitochondrial changes in the target cells. We observe that OmpU treatment leads to the disruption of mitochondrial membrane potential, resulting in the release of cytochrome c and apoptosis-inducing factor (AIF). AIF translocates to the host cell nucleus, implying that it has a crucial role in OmpU-mediated cell death. Finally, we observe that OmpU translocates to the target cell mitochondria, where it directly initiates mitochondrial changes leading to mitochondrial membrane permeability transition and AIF release. Partial blocking of AIF release by cyclosporine A in OmpU-treated cells further suggests that OmpU may be inducing the opening of the mitochondrial permeability transition pore. All of these results lead us to the conclusion that OmpU induces cell death in target cells in a programmed manner in which mitochondria play a central role.

  9. Vibrio cholerae Porin OmpU Induces Caspase-independent Programmed Cell Death upon Translocation to the Host Cell Mitochondria*

    PubMed Central

    Gupta, Shelly; Prasad, G. V. R. Krishna; Mukhopadhaya, Arunika

    2015-01-01

    Porins, a major class of outer membrane proteins in Gram-negative bacteria, primarily act as transport channels. OmpU is one of the major porins of human pathogen, Vibrio cholerae. In the present study, we show that V. cholerae OmpU has the ability to induce target cell death. Although OmpU-mediated cell death shows some characteristics of apoptosis, such as flipping of phosphatidylserine in the membrane as well as cell size shrinkage and increased cell granularity, it does not show the caspase-3 activation and DNA laddering pattern typical of apoptotic cells. Increased release of lactate dehydrogenase in OmpU-treated cells indicates that the OmpU-mediated cell death also has characteristics of necrosis. Further, we show that the mechanism of OmpU-mediated cell death involves major mitochondrial changes in the target cells. We observe that OmpU treatment leads to the disruption of mitochondrial membrane potential, resulting in the release of cytochrome c and apoptosis-inducing factor (AIF). AIF translocates to the host cell nucleus, implying that it has a crucial role in OmpU-mediated cell death. Finally, we observe that OmpU translocates to the target cell mitochondria, where it directly initiates mitochondrial changes leading to mitochondrial membrane permeability transition and AIF release. Partial blocking of AIF release by cyclosporine A in OmpU-treated cells further suggests that OmpU may be inducing the opening of the mitochondrial permeability transition pore. All of these results lead us to the conclusion that OmpU induces cell death in target cells in a programmed manner in which mitochondria play a central role. PMID:26559970

  10. Autoimmune diseases associated with neurofibromatosis type 1.

    PubMed

    Nanda, Arti

    2008-01-01

    Associations of autoimmune diseases with neurofibromatosis type 1 have been rarely described. In the present report, we describe two patients of neurofibromatosis type 1 having an association with vitiligo in one, and alopecia areata and autoimmune thyroiditis in another. The associations of neurofibromatosis type 1 with vitiligo, alopecia areata, and autoimmune thyroiditis have not been reported earlier. Whether these associations reflect a causal relationship with neurofibromatosis type 1 or are coincidental needs to be settled.

  11. Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules.

    PubMed

    Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Frey, Blake F; Billeskov, Rolf; Singer, Steven M; Berzofsky, Jay A; Eckmann, Lars; Kagnoff, Martin F

    2016-03-01

    The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild-type but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function.

  12. Position in cell cycle controls the sensitivity of colon cancer cells to nitric oxide-dependent programmed cell death.